1. An isolated polynucleotide encoding a biologically active substance, selected from the group consisting of: (a) a polynucleotide comprising a nucleotide sequence having at least 60% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and subsequences thereof encoding fragments having biological activity; (b) a polynucleotide comprising a nucleotide sequence that hybridizes under at least medium stringency conditions with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and full-length complementary strands thereof; (c) a polynucleotide encoding a biologically active substance comprising an amino acid sequence having at least 60% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity; (d) a polynucleotide encoding an artificial variant comprising a substitution, deletion, and/or insertion of one or more amino acids of an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity; and (e) a polynucleotide comprising or consisting of any of SEQ ID NOs: 2-4876.

2. (canceled)

3. (canceled)

4. (canceled)

5. (canceled)

6. (canceled)

7. The isolated polynucleotide of claim 1, which is contained in the chromosome of Bacillus licheniformis SJ1904 (ATCC PTA-7992).

8. (canceled)

9. (canceled)

10. A recombinant host cell comprising the isolated polynucleotide of claim 1.

11. An isolated biologically active substance, selected from the group consisting of: (a) a biologically active substance comprising an amino acid sequence having at least 60% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity; (b) a biologically active substance encoded by a polynucleotide comprising a nucleotide sequence having at least 60% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and subsequences thereof encoding fragments having biological activity; (c) a biologically active substance encoded by a polynucleotide comprising a nucleotide sequence that hybridizes under at least medium stringency conditions with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and full-length complementary strands thereof; (d) an artificial variant comprising a substitution, deletion, and/or insertion of one or more amino acids of an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity; and (e) a biologically active substance comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity.

12. (canceled)

13. (canceled)

14. (canceled)

15. (canceled)

16. (canceled)

17. The biologically active substance of claim 11, which is encoded by a polynucleotide contained in the chromosome of Bacillus licheniformis SJ1904 (ATCC PTA-7992).

18. (canceled)

19. A method for producing the biologically active substance of claim 11, comprising (a) cultivating a host cell comprising a nucleic acid construct comprising a polynucleotide encoding the biologically active substance under conditions conducive for production of the biologically active substance; and (b) recovering the biologically active substance.

20. A method for producing a mutant of a parent cell, which comprises disrupting or deleting the polynucleotide of claim 1, which results in the mutant producing less of the biologically active substance than the parent cell.

21. A mutant cell produced by the method of claim 20.

22. (canceled)

23. (canceled)

24. (canceled)

25. A transgenic plant, plant part or plant cell, which has been transformed with the isolated polynucleotide of claim 1.

26. A double-stranded inhibitory RNA (dsRNA) molecule comprising a subsequence of the polynucleotide of claim 1, wherein optionally the dsRNA is a siRNA or a miRNA molecule.

27. (canceled)

28. A method of inhibiting the expression of a polypeptide having biological activity in a cell, comprising administering to the cell or expressing in the cell a double-stranded RNA (dsRNA) molecule, wherein the dsRNA comprises a subsequence of the polynucleotide of claim 1.

29. (canceled)

30. A method for isolating a gene encoding an enzyme, comprising: (a) adding a mixture of labeled first nucleic acid probes, isolated from a microbial strain cultured on medium without an inducing substrate, and labeled second nucleic acid probes, isolated from the microbial strain cultured on medium with the inducing substrate, to an array of Bacillus licheniformis polynucleotides of claim 1, under conditions where the labeled nucleic acids hybridize to full-length complementary sequences of the Bacillus licheniformis polynucleotides on the array, wherein the first nucleic acid probes are labeled with a first reporter and the second nucleic acid probes are labeled with a second reporter; (b) examining the array under conditions wherein the relative expression of the genes of the microbial strain is determined by the observed hybridization reporter signal of each spot on the array in which (i) the Bacillus licheniformis polynucleotides on the array that hybridize to the first nucleic acid probes produce a distinct first hybridization reporter signal or to the second nucleic acid probes produce a distinct second hybridization reporter signal indicating induction of a gene by the presence of the inducing substrate in the culture medium of the microorganism, and (ii) the Bacillus licheniformis polynucleotides on the array that hybridize to both the first and second nucleic acid probes produce a distinct combined hybridization reporter signal; and (c) isolating from the microbial strain a gene induced by the presence of the substrate, wherein the gene encodes an enzyme that is involved in the degradation or conversion of the substrate.

31. (canceled)

32. (canceled)

33. (canceled)

34. (canceled)

35. A method for monitoring differential expression of a plurality of genes in a first bacterial cell relative to expression of the same genes in one or more second bacterial cells, comprising: (a) adding a mixture of detection reporter-labeled nucleic acids isolated from the bacterial cells to a substrate containing an array of Bacillus licheniformis polynucleotides of claim 1, under conditions where the detection reporter-labeled nucleic acids hybridize to full-length complementary sequences of the Bacillus licheniformis polynucleotides on the array, wherein the nucleic acids from the first bacterial cell and the one or more second bacterial cells are labeled with a first detection reporter and one or more different second detection reporters, respectively; and (b) examining the array under conditions wherein the relative expression of the genes in the bacterial cells is determined by the observed detection signal of each spot on the array in which (i) the Bacillus licheniformis polynucleotides on the array that hybridize to the nucleic acids obtained from either the first or the one or more second bacterial cells produce a distinct first detection signal or one or more second detection signals, respectively, and (ii) the Bacillus licheniformis polynucleotides on the array that hybridize to the nucleic acids obtained from both the first and one or more second bacterial produce a distinct combined detection signal.

36. (canceled)

37. (canceled)

38. (canceled)

39. A computer readable medium having recorded thereon an array of Bacillus licheniformis polynucleotides of claim 1, for monitoring differential expression of a plurality of genes in a first bacterial cell relative to expression of the same genes in one or more second bacterial cells.

40. (canceled)

41. (canceled)

42. (canceled)

43. (canceled)

44. A computer-based system for monitoring differential expression of a plurality of genes in a first bacterial cell relative to expression of the same genes in one or more second bacterial cells comprising the following elements: (a) a data storage means comprising Bacillus licheniformis polynucleotides of claim 1; (b) a search means for comparing a target sequence to a Bacillus licheniformis polynucleotide sequence of the data storage means of step (a) to identify homologous sequences; and (c) a retrieval means for obtaining the homologous sequence(s) of step (b).

45. A substrate comprising an array of Bacillus licheniformis polynucleotides of claim 1, for monitoring differential expression of a plurality of genes in a first bacterial cell relative to expression of the same genes in one or more second bacterial cells.

46. A method for preparing a synthetic gene, comprising: (a) generating a codon usage table based on codons used in one or more open reading frames or portions thereof of SEQ ID NO: 1; (b) constructing a synthetic gene or portion thereof that contains in place of one or more native codons one or more preferred codons from the codon usage table; and (c) recovering the synthetic gene.

47. (canceled)

48. A synthetic gene obtained by the method of claim 46.

49. (canceled)

50. (canceled)

51. (canceled)

52. A method for producing a polypeptide encoded by the synthetic gene of claim 48 comprising (a) cultivating a host cell comprising the synthetic gene under conditions conducive for production of the polypeptide; and (b) recovering the polypeptide.

53. An isolated polynucleotide of the complete chromosomal DNA molecule of Bacillus licheniformis SJ1904 (ATCC PTA-7992) having the nucleotide sequence of SEQ ID NO: 1.

REFERENCE TO A SEQUENCE LISTING

Incorporated herein by reference are 2 copies of the Sequence Listing on compact disk. Copy 1 is done on a Intel x86 machine format, in Windows XP operating system compatibility, there is one file saved as 01 10930.204-WO SeqList.txt, and is 20,210 KB, and was created on Nov. 28, 2007. Copy 2 is identical to Copy 1. The content of the attached compact disks are the same and includes no new matter.

REFERENCE TO A DEPOSIT OF BIOLOGICAL MATERIAL

This application contains a reference to a deposit of biological material, which deposit is incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to an isolated polynucleotide molecule comprising the complete chromosome of Bacillus licheniformis SJ1904. The present invention also relates to features (polynucleotides) of the complete chromosomal DNA molecule of Bacillus licheniformis SJ1904 that encode biologically active substances and to nucleic acid constructs, vectors, and host cells comprising the features. The present invention also relates to methods for producing biologically active substances encoded by the features and to methods of using the isolated features derived from the complete chromosomal DNA molecule of Bacillus licheniformis SJ1904.

2. Description of the Related Art

Microbes have evolved for some 3.8 billion years and make up most of the earth's biomass. They are found in virtually every environment, surviving and thriving in extremes of heat, cold, radiation, pressure, salt, acidity, and darkness. Often in these environments, no other forms of life are found and the only nutrients come from inorganic matter. The diversity and range of their environmental adaptations indicate that microbes long ago “solved” many problems for which scientists are still actively seeking solutions. The value in determining the complete genome sequence of microbes is that it provides a detailed blueprint for the organism revealing biochemical pathways, substrates, intermediates, and end products as well as regulatory networks, and evolutionary relationships to other microbes. A complete manifest of proteins, both structural and catalytic, is encoded as a list of features in the DNA molecule comprising the genome, as well as their likely cellular location.

Knowledge about the enormous range of microbial capacities has broad and far-reaching implications for environmental, energy, health, and industrial applications, such as cleanup of toxic-waste, production of novel therapeutic and preventive agents (drugs and vaccines), energy generation and development of renewable energy sources, production of chemical catalysts, reagents, and enzymes to improve efficiency of industrial processes, management of environmental carbon, nitrogen and nutrient cycling, detection of disease-causing organisms, monitoring of the safety of food and water supplies, use of genetically altered bacteria as living sensors (biosensors) to detect harmful chemicals in soil, air, or water, and understanding of specialized systems used by microbial cells to live in natural environments. Bacillus licheniformis is a gram positive spore-forming bacterium that is widely distributed as a saprophytic organism in the environment. Unlike most other bacilli that are predominantly aerobic, Bacillus licheniformis is a facultative anaerobe that may allow it to grow in additional ecological niches. This species produces a diverse assortment of extracellular enzymes that are believed to contribute to the process of nutrient cycling in nature (Claus, D. and Berkeley, R. C. W., 1986, In Bergey's Manual of Systematic Bacteriology , Vol. 2., eds. Sneath, P. H. A. et al., Williams and Wilkins Co., Baltimore, Md., pp. 1105-1139). Certain Bacillus licheniformis isolates are capable of denitrification but, the relevance of this characteristic to environmental denitrification may be small since the species generally persists in soil as endospores (Alexander, M., 1977 , Introduction to Soil Microbiology . John Wiley and Sons, Inc., New York).

There are numerous industrial and agricultural uses for Bacillus licheniformis and its extracellular products. The species has been used for decades in the manufacture of industrial enzymes including several proteases, alpha-amylase, penicillinase, pentosanase, cycloglucosyltransferase, beta-mannanase, and several pectinolytic enzymes, owing largely to its ability to secrete sizeable amounts of degradative enzymes. Bacillus licheniformis is also used to produce peptide antibiotics such as bacitracin and proticin, in addition to a number of specialty chemicals such as citric acid, inosine, inosinic acid, and poly-gamma-glutamic acid. The proteases from Bacillus licheniformis are used in the detergent industry as well as for dehairing and batting of leather (Eveleigh, D. E., 1981, Scientific American 245, 155-178). Amylases from Bacillus licheniformis are deployed for the hydrolysis of starch, desizing of textiles, and sizing of paper (Erickson, R. J., 1976, In Microbiology , ed. Schlesinger, D. (Am. Soc. Microbiol., Washington, D.C.), pp. 406-419.). Certain strains of Bacillus licheniformis have shown efficacy to destroy fungal pathogens affecting maize, grasses, and vegetable crops (U.S. Pat. No. 5,589,381; U.S. Pat. No. 5,665,354). As an endospore-forming bacterium, the ability of the organism to survive under unfavorable environmental conditions may enhance its potential as a natural control agent.

Bacillus licheniformis can be differentiated from other bacilli on the basis of metabolic and physiological tests (Logan, N. A. and Berkeley, R. C. W., 1981, In The Aerobic Endospore - Forming Bacteria: Classification and Identification , eds. Berkeley, R. C. W. and Goodfellow, M., Academic Press, Inc., London, pp. 106-140; O'Donnell, A. G., Norris, J. R., Berkeley, R. C. W., Claus, D., Kanero, T., Logan, N. A., and Nozaki, R., 1980, Internat. J. Systematic Bacteriol. 30: 448-459). However, biochemical and phenotypic characteristics may be ambiguous among closely related species. Lapidus et al. (Lapidus, A., Galleron, N., Andersen, J. T., Jørgensen, P. L. Ehrlich, S. D., and Sorokin, A., 2002, FEMS Microbiol. Lett. 209: 23-30) constructed a physical map of the Bacillus licheniformis strain ATCC 14580 chromosome using a PCR approach, and established a number of regions of co-linearity where gene content and organization were conserved with the Bacillus subtilis chromosome. In addition, Rey et al. (Rey, M. W, Ramaiya, P, Nelson, B. A., Brody-Karpin, S. D., Zaretsky, E. J., Tang, M., Lopez de Leon, A., Xiang, H., Gusti, V., Clausen, I. G., Olsen, P. B., Rasmussen, M. D., Andersen, J. T., Jørgensen, P. L., Larsen, T. S., Sorokin, A., Bolotin, A., Lapidus, A., Galleron, N., Ehrlich, S. D., and Berka, R. M. 2004. Complete genome sequence of the industrial bacterium Bacillus licheniformis and comparisons with closely related Bacillus species. Genome Biol. 5: R77) published the complete genome sequence of the Bacillus licheniformis type strain ATCC 14580. They determined that the genome of Bacillus licheniformis ATCC 14580 comprises a circular chromosome of 4,222,336 base-pairs (bp) containing 4,208 predicted protein-coding genes with an average size of 873 bp, seven rRNA operons, and 72 tRNA genes. The Bacillus licheniformis ATCC 14580 chromosome contains large regions that are colinear with the genomes of Bacillus subtilis strain 168 and Bacillus halodurans strain C-125, and approximately 80% of the predicted Bacillus licheniformis ATCC 14580 coding sequences have Bacillus subtilis orthologs. However, despite the unmistakable organizational similarities between these Bacillus licheniformis and Bacillus subtilis genomes, there are notable differences in the numbers and locations of prophages, transposable elements and a number of extracellular enzymes and secondary metabolic pathway operons that distinguish these species. These differences include a region of more than 80 kilobases (kb) that comprises a cluster of polyketide synthase genes and a second operon of 38 kb encoding plipastatin synthase enzymes that are absent in the Bacillus licheniformis ATCC 14580 genome.

Public databases now contain a multitude of complete bacterial genomes, including several genomes from different strains of the same species. Recent analyses have shown, using pairwise whole genome alignments, that different strains of the same species may differ substantially in gene content. For example, genome comparisons of Escherichia coli strains CFT073, EDL933 and MG1655 revealed that only 39.2% of their combined set of proteins (gene products) are common to all three strains highlighting the astonishing diversity among strains of the same species (Welch et al., 2002, Proc. Nat. Acad. Sci. USA 99: 17020-17024; Perna et al., 2001, Nature 409: 529-533; Hayashi et al., 2001, DNA Res. 8: 11-22; Blattner et al., 1997, Science 277: 1453-1474). Furthermore, the genome sequence of E. coli strain CFT073 revealed 1,623 strain-specific genes (21.2%). From comparisons of this type, it is clearly seen that bacterial genomes are segmented into a common conserved backbone and strain-specific sequences. Typically the genome of a given strain within a species shows a mosaic structure in terms of the distribution of conserved “backbone” genes conserved among all strains and non-conserved genes that may have been acquired by horizontal transfer (Welch et al., 2002, Proc. Nat. Acad. Sci. USA 99: 17020-17024; Brzuszkiewicz et al., 2006, Proc. Nat. Acad. Sci. USA 103: 12879-12884).

Therefore, it would be advantageous to the art to have available the complete primary structure of the chromosomal DNA molecule of the Bacillus licheniformis strain SJ1904, an industrial strain that differs from the type strain ATCC 14580. With the complete chromosome data in hand, it should be possible to do comparative genomics and proteomics studies that can lead to improved industrial strains as well as to a better understanding of genome evolution among closely-related bacilli in the subtilis-licheniformis group.

The present invention relates to an isolated polynucleotide of the complete chromosome of Bacillus licheniformis strain SJ1904.

SUMMARY OF THE INVENTION

The present invention relates to an isolated polynucleotide of the complete chromosomal DNA molecule of Bacillus licheniformis SJ1904 (ATCC PTA-7992) having the nucleotide sequence of SEQ ID NO: 1.

The present invention also relates to isolated features (polynucleotides) of the complete chromosomal DNA molecule of Bacillus licheniformis SJ1904 encoding biologically active substances selected from the group consisting of SEQ ID NOs: 2-4876 and subsequences thereof encoding fragments having biological activity.

The present invention also relates to isolated features (polynucleotides) encoding biologically active substances, selected from the group consisting of:

(a) a polynucleotide comprising a nucleotide sequence having preferably at least 60% identity, more preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, more preferably at least 90% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and subsequences thereof encoding fragments having biological activity;

(b) a polynucleotide comprising a nucleotide sequence that hybridizes under preferably at least medium stringency conditions, more preferably at least medium-high stringency conditions, or most preferably at least high stringency conditions with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and full-length complementary strands thereof;

(c) a polynucleotide encoding a biologically active substance comprising an amino acid sequence having preferably at least 60% identity, more preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity; and

(d) a polynucleotide encoding an artificial variant comprising a substitution, deletion, and/or insertion of one or more (several) amino acids of an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity.

The present invention also relates to nucleic acid constructs, vectors, and host cells comprising the isolated polynucleotides.

The present invention also relates to isolated biologically active substances comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity.

The present invention also relates to isolated biologically active substances, selected from the group consisting of:

(a) a biologically active substance comprising an amino acid sequence having preferably at least 60% identity, more preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity;

(b) a biologically active substance encoded by a polynucleotide comprising a nucleotide sequence having preferably at least 60% identity, more preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and subsequences thereof encoding fragments having biological activity;

(c) a biologically active substance encoded by a polynucleotide comprising a nucleotide sequence that hybridizes under preferably at least medium stringency conditions, more preferably at least medium-high stringency conditions, or most preferably at least high stringency conditions with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and full-length complementary strands thereof; and

(d) an artificial variant comprising a substitution, deletion, and/or insertion of one or more (several) amino acids of an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity.

The present invention also relates to methods for producing such substances having biological activity comprising (a) cultivating a recombinant host cell comprising a nucleic acid construct comprising a polynucleotide encoding the biologically active substance under conditions suitable for production of the biologically active substance; and (b) recovering the biologically active substance.

The present invention also relates to methods for monitoring differential expression of a plurality of genes in a first bacterial cell relative to expression of the same genes in one or more (several) second bacterial cells, comprising:

(a) adding a mixture of detection reporter-labeled nucleic acids isolated from the bacterial cells to a substrate containing an array of Bacillus licheniformis polynucleotides selected from the group consisting of SEQ ID NOs: 2-4876, full-length complementary strands of SEQ ID NOs: 2-4876, and fragments of SEQ ID NOs: 2-4876, under conditions where the detection reporter-labeled nucleic acids hybridize to complementary sequences of the Bacillus licheniformis polynucleotides on the array, wherein the nucleic acids from the first bacterial cell and the one or more (several) second bacterial cells are labeled with a first detection reporter and one or more (several) different second detection reporters, respectively; and

(b) examining the array under conditions wherein the relative expression of the genes in the bacterial cells is determined by the observed detection signal of each spot on the array in which (i) the Bacillus licheniformis polynucleotides on the array that hybridize to the nucleic acids obtained from either the first or the one or more (several) second bacterial cells produce a distinct first detection signal or one or more (several) second detection signals, respectively, and (ii) the Bacillus licheniformis polynucleotides on the array that hybridize to the nucleic acids obtained from both the first and one or more (several) second bacterial produce a distinct combined detection signal.

The present invention also relates to methods for isolating a polynucleotide encoding an enzyme, comprising:

(a) adding a mixture of labeled first nucleic acid probes, isolated from a microbial strain cultured on medium without an inducing substrate, and labeled second nucleic acid probes, isolated from the microbial strain cultured on medium with the inducing substrate, to an array of Bacillus licheniformis polynucleotides selected from the group consisting of the polynucleotides of SEQ ID NOs: 2-4876, full-length complementary strands of SEQ ID NOs: 2-4876, and fragments of SEQ ID NOs: 2-4876, under conditions where the labeled nucleic acid probes hybridize to complementary sequences of the Bacillus licheniformis polynucleotides on the array, wherein the first nucleic acid probes are labeled with a first reporter and the second nucleic acid probes are labeled with a second reporter;

(b) examining the array under conditions wherein the relative expression of the genes of the microbial strain is determined by the observed hybridization reporter signal of each spot on the array in which (i) the Bacillus licheniformis polynucleotides on the array that hybridize to the first nucleic acid probes produce a distinct first hybridization reporter signal or the second nucleic acid probes produce a distinct second hybridization reporter signal, and (ii) the Bacillus licheniformis polynucleotides on the array that hybridize to both the first and second nucleic acid probes produce a distinct combined hybridization reporter signal; and

(c) isolating a polynucleotide from the microbial strain that encodes an enzyme that degrades or converts the substrate.

The present invention also relates to genes or polynucleotides isolated by such methods and nucleic acid constructs, vectors, and host cells containing the isolated genes or polynucleotides.

DEFINITIONS

Biologically active substance: The term “substance having biological activity” or “biologically active substance” is defined herein as any substance having biological activity encoded by a single gene or polynucleotide. Such substances include, but are not limited to, polypeptides (e.g., enzymes) and RNA (e.g., mRNA, tRNA, rRNA, and ncRNA). For purposes of the present invention, biological activity is determined according to procedures known in the art such as those described by Carpenter and Sabatini, 2004 , Nature 5: 11-22; Sordie et al., 2003, Proceedings of the National Academy of Sciences USA 100: 11964-11969; Braun and LaBaer, 2003, TRENDS in Biotechnology 21: 383-388; and Kaberdin and McDowall, 2003, Genome Research 13: 1961-1965.

In a preferred aspect, the biologically active substance is a polypeptide. The polypeptide may be any polypeptide having a biological activity of interest. The term “polypeptide” is not meant herein to refer to a specific length of the encoded product and, therefore, encompasses peptides, oligopeptides, and proteins.

In a more preferred aspect, the polypeptide is an antibody, antigen, antimicrobial peptide, enzyme, growth factor, hormone, immunodilator, neurotransmitter, receptor, reporter protein, structural protein, transcription factor, and transporter.

In an even more preferred aspect, the polypeptide is an oxidoreductase, transferase, hydrolase, lyase, isomerase, or ligase.

In a most preferred aspect, the polypeptide is an aminopeptidase, amylase, carbohydrase, carboxypeptidase, catalase, cellulase, chitinase, cutinase, cyclodextrin glycosyltransferase, deoxyribonuclease, esterase, alpha-galactosidase, beta-galactosidase, glucoamylase, glucocerebrosidase, alpha-glucosidase, beta-glucosidase, haloperoxidase, invertase, laccase, lipase, mannosidase, mutanase, oxidase, pectinolytic enzyme, peptidoglutaminase, peroxidase, phospholipase, phytase, polyphenoloxidase, proteolytic enzyme, ribonuclease, transglutaminase, urokinase, or xylanase

In another more preferred aspect, the polypeptide is an albumin, collagen, tropoelastin, elastin, or gelatin.

Isolated biologically active substance: The term “isolated biologically active substance” is defined herein as a substance that is at least 1% pure, preferably at least 5% pure, more preferably at least 10% pure, more preferably at least 20% pure, more preferably at least 40% pure, more preferably at least 60% pure, even more preferably at least 80% pure, and most preferably at least 90% pure, as determined by SDS-PAGE, HPLC, capillary electrophoresis, or any other method used in the art.

Substantially pure biologically active substance or pure biologically active substance: The term “substantially pure biologically active substance” is defined herein as a biologically active substance preparation that contains at most 10%, preferably at most 8%, more preferably at most 6%, more preferably at most 5%, more preferably at most 4%, more preferably at most 3%, even more preferably at most 2%, most preferably at most 1%, and even most preferably at most 0.5% by weight of other material with which it is natively associated. It is, therefore, preferred that the substantially pure biologically active substance is at least 92% pure, preferably at least 94% pure, more preferably at least 95% pure, more preferably at least 96% pure, more preferably at least 96% pure, more preferably at least 97% pure, even more preferably at least 98% pure, most preferably at least 99%, and even most preferably at least 99.5% pure by weight of the total material present in the preparation. The term “pure biologically active substance” is defined as a biologically active substance preparation that contains no other material with which it is natively associated. The biologically active substances of the present invention are preferably in a substantially pure form. In particular, it is preferred that the biologically active substances are in “essentially pure form”, i.e., that the biologically active substance preparation is essentially free of other material with which it is natively or recombinantly associated. This can be accomplished, for example, by preparing the biologically active substance by means of well-known recombinant methods or by classical purification methods.

Identity: The relatedness between two amino acid sequences or between two nucleotide sequences is described by the parameter “identity”.

For purposes of the present invention, the degree of sequence identity between two amino acid sequences is determined by the Smith-Waterman Protein method for the GENEMATCHER2™ as implemented by Paracel Inc. (Pasadena, Calif.), or the BLASTP method as described by Altschul et al., 1990, Journal of Molecular Biology 215: 403-410.

For purposes of the present invention, the degree of sequence identity between two nucleotide sequences is determined by the Smith Waterman nucleotide method for the GENEMATCHER2™ or BLASTN for the BlastMachine as implemented by Paracel Inc.

Polypeptide Fragment The term “polypeptide fragment” is defined herein as a polypeptide, which retains biological activity, having one or more (several) amino acids deleted from the amino and/or carboxyl terminus of a polypeptide encoded by any of the polynucleotides of the present invention, i.e., polypeptides of SEQ ID NOs: 4877-9751. Preferably, a fragment contains at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, and most preferably at least 97% of the amino acid residues of the mature polypeptide product.

Subsequence: The term “subsequence” is defined herein as a polynucleotide comprising a nucleotide sequence of any of SEQ ID NOs: 2-4876 except that one or more (several) nucleotides have been deleted from the 5′ and/or 3′ end. Preferably, a subsequence contains at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, and most preferably at least 97% of the nucleotides of any of the isolated polynucleotides of the present invention.

Substantially pure polynucleotide or pure polynucleotide: The term “substantially pure polynucleotide” as used herein refers to a polynucleotide preparation free of other extraneous or unwanted nucleotides and in a form suitable for use within genetically engineered protein production systems. Thus, a substantially pure polynucleotide contains at most 10%, preferably at most 8%, more preferably at most 6%, more preferably at most 5%, more preferably at most 4%, more preferably at most 3%, even more preferably at most 2%, most preferably at most 1%, and even most preferably at most 0.5% by weight of other polynucleotide material with which it is natively or recombinantly associated. A substantially pure polynucleotide may, however, include naturally occurring 5′ and 3′ untranslated regions, such as promoters and terminators. It is preferred that the substantially pure polynucleotide is at least 90% pure, preferably at least 92% pure, more preferably at least 94% pure, more preferably at least 95% pure, more preferably at least 96% pure, more preferably at least 97% pure, even more preferably at least 98% pure, most preferably at least 99%, and even most preferably at least 99.5% pure by weight. The polynucleotides of the present invention are preferably in a substantially pure form, i.e., that the polynucleotide preparation is essentially free of other polynucleotide material with which it is natively or recombinantly associated. The polynucleotides may be of genomic, cDNA, RNA, semisynthetic, synthetic origin, or any combinations thereof. The term “pure polynucleotide” is defined as a polynucleotide preparation that contains no other material with which it is natively associated.

Nucleic acid construct: The term “nucleic acid construct” as used herein refers to a nucleic acid molecule, either single- or double-stranded, which is isolated from a naturally occurring gene or which is modified to contain segments of nucleic acids in a manner that would not otherwise exist in nature or which is synthetic. The term nucleic acid construct is synonymous with the term “expression cassette” when the nucleic acid construct contains the control sequences required for expression of a coding sequence of the present invention.

Control sequence: The term “control sequences” is defined herein to include all components, which are necessary or advantageous for the expression of a biologically active substance of the present invention. Each control sequence may be native or foreign to the polynucleotide encoding the substance. Such control sequences include, but are not limited to, a leader, propeptide sequence, promoter, signal peptide sequence, and transcription terminator. At a minimum, the control sequences include a promoter, and transcriptional and translational stop signals. The control sequences may be provided with linkers for the purpose of introducing specific restriction sites facilitating ligation of the control sequences with the coding region of the polynucleotide encoding a biologically active substance.

Operably linked: The term “operably linked” as used herein refers to a configuration in which a control sequence is placed at an appropriate position relative to the coding sequence of the DNA sequence, such that the control sequence directs the expression of a biologically active substance.

Coding sequence: When used herein the term “coding sequence” is intended to cover a nucleotide sequence, which directly specifies the amino acid sequence of its protein product. The boundaries of the coding sequence are generally determined by an open reading frame, which usually begins with the ATG start codon or alternative start codons such as GTG and TTG.

Expression: The term “expression” includes any step involved in the production of a biologically active substance including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion.

Expression vector: The term “expression vector” herein covers a DNA molecule, linear or circular, that comprises a segment encoding a biologically active substance of the invention, and is operably linked to additional segments that provide for its transcription.

Host cell: The term “host cell”, as used herein, includes any cell type that is susceptible to transformation, transfection, conjugation, electroporation, etc. with a nucleic acid construct, plasmid, or vector.

Modification: The term “modification” means herein any chemical modification of a biological substance, e.g., polypeptide, as well as genetic manipulation of the DNA encoding that biological substance. The modification can be a substitution, a deletion and/or an insertion of one or more (several) amino acids as well as replacements of one or more (several) amino acid side chains.

Artificial variant: When used herein, the term “artificial variant” means a polypeptide having biological activity produced by an organism expressing a modified nucleotide sequence, or the mature polypeptide coding region thereof. The modified nucleotide sequence is obtained through human intervention by modification of the nucleotide sequence disclosed or a homologous sequence thereof, or the mature polypeptide coding region thereof.

DETAILED DESCRIPTION OF THE INVENTION

Bacillus licheniformis SJ1904 Chromosome and Features (Polynucleotides) Thereof

The present invention relates to an isolated polynucleotide of the complete chromosomal DNA molecule of Bacillus licheniformis SJ1904 (ATCC PTA-7992) having the polynucleotide sequence of SEQ ID NO: 1. Bacillus licheniformis SJ1904 consists of a circular molecule of 4,345,159 base pairs with a mean % G+C content of 46.7%. The chromosome contains 4875 predicted protein-coding genes (SEQ ID NOs: 2-4876) with an average size of 789 bp, 7 rRNA operons, and 72 tRNA genes. The deduced amino acid sequences of the 4876 predicted protein-coding genes are shown in SEQ ID NOs: 4877-9851. SEQ ID NO: 4877 corresponds to SEQ ID NO: 2, SEQ ID NO: 4878 corresponds to SEQ ID NO: 3, SEQ ID NO: 4879 corresponds to SEQ ID NO: 4, etc. The predicted functions of the 4875 gene products are shown in Table 1.

The present invention also relates to isolated features (polynucleotides) of the complete chromosomal DNA molecule of Bacillus licheniformis SJ1904 encoding biologically active substances, selected from the group consisting of SEQ ID NOs: 2-4876 and subsequences thereof encoding fragments having biological activity.

The present invention also relates to isolated features (polynucleotides) encoding biologically active substances, selected from the group consisting of:

(a) a polynucleotide comprising a nucleotide sequence having preferably at least 60% identity, more preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and subsequences thereof encoding fragments having biological activity;

(b) a polynucleotide comprising a nucleotide sequence that hybridizes under preferably at least medium stringency conditions, more preferably at least medium-high stringency conditions, or most preferably at least high stringency conditions with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and full-length complementary strands thereof;

(c) a polynucleotide encoding a biologically active substance comprising an amino acid sequence having preferably at least 60% identity, more preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity; and

(d) a polynucleotide encoding an artificial variant comprising a substitution, deletion, and/or insertion of one or more (several) amino acids of an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity.

In a first aspect, the present invention relates to an isolated polynucleotide having a degree of sequence identity to a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 of at least 60%, preferably at least 65%, more preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, and even most preferably at least 96%, 97%, 98%, or 99%, which encode biologically active substances having a particular biological activity (hereinafter “homologous biologically active substances”).

In a preferred aspect, the present invention relates to an isolated polynucleotide comprising a nucleotide sequence having preferably at least 60% identity, more preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 50, 55, 77, 82, 91, 98, 103, 110, 125, 169, 171, 172, 174, 176, 177, 178, 179, 180, 181, 182, 183, 185, 186, 187, 189, 192, 194, 195, 196, 198, 199, 201, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 225, 226, 227, 228, 229, 230, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 287, 306, 308, 322, 323, 329, 350, 354, 360, 363, 367, 381, 445, 469, 487, 488, 516, 523, 524, 537, 541, 575, 592, 607, 621, 627, 628, 666, 672, 688, 691, 702, 710, 719, 726, 729, 748, 751, 773, 774, 777, 791, 831, 833, 842, 847, 848, 849, 850, 851, 855, 857, 885, 886, 887, 901, 944, 982, 991, 994, 1018, 1032, 1034, 1058, 1078, 1088, 1098, 1108, 1112, 1128, 1148, 1153, 1154, 1158, 1160, 1164, 1175, 1176, 1177, 1180, 1181, 1183, 1184, 1193, 1194, 1199, 1222, 1237, 1244, 1262, 1263, 1265, 1266, 1278, 1302, 1313, 1314, 1315, 1316, 1317, 1318, 1345, 1355, 1373, 1374, 1401, 1424, 1432, 1433, 1440, 1442, 1448, 1455, 1470, 1496, 1497, 1501, 1509, 1527, 1539, 1556, 1565, 1589, 1619, 1629, 1630, 1634, 1635, 1636, 1638, 1639, 1640, 1641, 1642, 1643, 1644, 1645, 1646, 1647, 1649, 1650, 1651, 1652, 1653, 1654, 1655, 1657, 1658, 1659, 1660, 1661, 1662, 1663, 1664, 1665, 1666, 1667, 1668, 1669, 1670, 1671, 1672, 1673, 1675, 1676, 1677, 1679, 1684, 1688, 1692, 1694, 1703, 1704, 1728, 1732, 1734, 1736, 1775, 1783, 1816, 1831, 1838, 1851, 1853, 1866, 1887, 2002, 2007, 2022, 2038, 2044, 2067, 2070, 2072, 2076, 2094, 2106, 2119, 2120, 2121, 2124, 2131, 2139, 2147, 2148, 2166, 2171, 2194, 2196, 2198, 2205, 2211, 2213, 2216, 2221, 2230, 2236, 2240, 2241, 2255, 2258, 2263, 2273, 2277, 2286, 2288, 2289, 2290, 2291, 2292, 2293, 2294, 2295, 2296, 2297, 2298, 2299, 2300, 2301, 2302, 2303, 2304, 2305, 2324, 2327, 2337, 2341, 2347, 2351, 2364, 2381, 2388, 2400, 2403, 2408, 2410, 2411, 2414, 2415, 2424, 2425, 2430, 2435, 2439, 2457, 2467, 2468, 2469, 2483, 2491, 2498, 2504, 2505, 2506, 2507, 2508, 2509, 2510, 2511, 2512, 2514, 2515, 2516, 2517, 2518, 2519, 2520, 2521, 2522, 2524, 2525, 2526, 2527, 2528, 2529, 2530, 2531, 2532, 2533, 2534, 2535, 2536, 2537, 2538, 2539, 2540, 2541, 2542, 2543, 2544, 2545, 2546, 2547, 2548, 2549, 2550, 2551, 2552, 2553, 2554, 2555, 2556, 2557, 2558, 2559, 2560, 2561, 2562, 2564, 2565, 2566, 2567, 2568, 2569, 2570, 2571, 2572, 2573, 2574, 2575, 2576, 2577, 2578, 2579, 2580, 2581, 2582, 2583, 2584, 2585, 2586, 2587, 2588, 2590, 2591, 2592, 2593, 2594, 2595, 2596, 2597, 2598, 2599, 2600, 2601, 2602, 2603, 2604, 2605, 2606, 2607, 2608, 2609, 2610, 2611, 2612, 2613, 2614, 2615, 2616, 2617, 2618, 2619, 2620, 2621, 2622, 2623, 2624, 2625, 2626, 2627, 2628, 2629, 2630, 2631, 2632, 2633, 2634, 2635, 2636, 2637, 2638, 2639, 2640, 2641, 2642, 2643, 2644, 2645, 2646, 2647, 2648, 2649, 2650, 2651, 2652, 2653, 2654, 2655, 2656, 2657, 2658, 2659, 2661, 2664, 2665, 2666, 2667, 2669, 2670, 2671, 2672, 2673, 2674, 2675, 2676, 2677, 2679, 2680, 2681, 2684, 2685, 2686, 2688, 2689, 2690, 2691, 2692, 2693, 2696, 2697, 2698, 2706, 2723, 2730, 2733, 2751, 2762, 2795, 2806, 2813, 2834, 2835, 2841, 2850, 2866, 2867, 2874, 2878, 2898, 2902, 2904, 2917, 2947, 2957, 2960, 2969, 2972, 2973, 2999, 3004, 3019, 3028, 3054, 3064, 3082, 3093, 3123, 3133, 3134, 3135, 3136, 3137, 3138, 3139, 3140, 3141, 3142, 3143, 3144, 3145, 3146, 3147, 3148, 3149, 3150, 3162, 3222, 3224, 3225, 3226, 3227, 3228, 3229, 3231, 3244, 3248, 3259, 3264, 3265, 3287, 3291, 3303, 3310, 3311, 3321, 3324, 3355, 3362, 3371, 3429, 3434, 3442, 3446, 3458, 3471, 3486, 3496, 3499, 3503, 3504, 3508, 3549, 3558, 3577, 3593, 3598, 3601, 3603, 3606, 3611, 3642, 3653, 3655, 3670, 3673, 3682, 3690, 3694, 3707, 3716, 3727, 3736, 3737, 3744, 3753, 3765, 3790, 3798, 3799, 3872, 3881, 3885, 3915, 3916, 3922, 3931, 3938, 3969, 4011, 4017, 4056, 4059, 4068, 4076, 4077, 4081, 4082, 4085, 4090, 4106, 4112, 4117, 4144, 4145, 4158, 4159, 4160, 4161, 4162, 4163, 4164, 4165, 4166, 4167, 4168, 4169, 4170, 4171, 4172, 4173, 4174, 4175, 4176, 4179, 4181, 4182, 4201, 4235, 4285, 4288, 4305, 4323, 4333, 4336, 4353, 4398, 4409, 4417, 4421, 4423, 4429, 4435, 4448, 4450, 4469, 4472, 4476, 4482, 4488, 4513, 4518, 4544, 4559, 4560, 4569, 4571, 4578, 4607, 4622, 4631, 4643, 4647, 4648, 4650, 4658, 4669, 4672, 4682, 4687, 4688, 4704, 4718, 4754, 4767, 4786, 4792, 4797, 4804, 4812, 4814, 4823, 4830, 4833, 4838, 4848, 4849, 4859, 4862, and 4872; preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 909, 911, 1367, 1498, 2663, 2668, 2682, and 2683; preferably at least 80% identity, more preferably at least 85% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 167, 654, 2513, 2589, and 2694; preferably at least 85% identity, more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 163, 184, 910, 1674, 2412, 2660, 2662, 2695, and 3231; preferably at least 90% identity, more preferably at least 95% identity, and most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 27, 166, 168, 170, 193, 202, 231, 543, 776, 888, 889, 890, 898, 908, 916, 1028, 1123, 1133, 1155, 1156, 1157, 1173, 1211, 1212, 1218, 1229, 1230, 1277, 1356, 1357, 1359, 1360, 1368, 1372, 1391, 1500, 1584, 1604, 1627, 1631, 1632, 1637, 1648, 1680, 2101, 2102, 2239, 2358, 2359, 2360, 2404, 2417, 2429, 2494, 2563, 2678, 2724, 3111, 3539, 3850, 4078, 4079, 4080, 4083, 4084, 4180, 4221, 4642, 4689, 4707, and 4727; or preferably at least 95% identity and more preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 83, 84, 85, 86, 87, 88, 89, 90, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 104, 105, 106, 107, 108, 109, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 164, 165, 173, 175, 188, 190, 191, 197, 200, 224, 232, 233, 234, 235, 236, 237, 238, 239, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 307, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 324, 325, 326, 327, 328, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 351, 352, 353, 355, 356, 357, 358, 359, 361, 362, 364, 365, 366, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 517, 518, 519, 520, 521, 522, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 538, 539, 540, 542, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 622, 623, 624, 625, 626, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 667, 668, 669, 670, 671, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 689, 690, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 703, 704, 705, 706, 707, 708, 709, 711, 712, 713, 714, 715, 716, 717, 718, 720, 721, 722, 723, 724, 725, 727, 728, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 749, 750, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 775, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 832, 834, 835, 836, 837, 838, 839, 840, 841, 843, 844, 845, 846, 852, 853, 854, 856, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 891, 892, 893, 894, 895, 896, 897, 899, 900, 902, 903, 904, 905, 906, 907, 912, 913, 914, 915, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 983, 984, 985, 986, 987, 988, 989, 990, 992, 993, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1029, 1030, 1031, 1033, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1079, 1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1109, 1110, 1111, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1124, 1125, 1126, 1127, 1129, 1130, 1131, 1132, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1149, 1150, 1151, 1152, 1159, 1161, 1162, 1163, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1174, 1178, 1179, 1182, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1195, 1196, 1197, 1198, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1213, 1214, 1215, 1216, 1217, 1219, 1220, 1221, 1223, 1224, 1225, 1226, 1227, 1228, 1231, 1232, 1233, 1234, 1235, 1236, 1238, 1239, 1240, 1241, 1242, 1243, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1264, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 1286, 1287, 1288, 1289, 1290, 1291, 1292, 1293, 1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301, 1303, 1304, 1305, 1306, 1307, 1308, 1309, 1310, 1311, 1312, 1319, 1320, 1321, 1322, 1323, 1324, 1325, 1326, 1327, 1328, 1329, 1330, 1331, 1332, 1333, 1334, 1335, 1336, 1337, 1338, 1339, 1340, 1341, 1342, 1343, 1344, 1346, 1347, 1348, 1349, 1350, 1351, 1352, 1353, 1354, 1358, 1361, 1362, 1363, 1364, 1365, 1366, 1369, 1370, 1371, 1375, 1376, 1377, 1378, 1379, 1380, 1381, 1382, 1383, 1384, 1385, 1386, 1387, 1388, 1389, 1390, 1392, 1393, 1394, 1395, 1396, 1397, 1398, 1399, 1400, 1402, 1403, 1404, 1405, 1406, 1407, 1408, 1409, 1410, 1411, 1412, 1413, 1414, 1415, 1416, 1417, 1418, 1419, 1420, 1421, 1422, 1423, 1425, 1426, 1427, 1428, 1429, 1430, 1431, 1434, 1435, 1436, 1437, 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3939, 3940, 3941, 3942, 3943, 3944, 3945, 3946, 3947, 3948, 3949, 3950, 3951, 3952, 3953, 3954, 3955, 3956, 3957, 3958, 3959, 3960, 3961, 3962, 3963, 3964, 3965, 3966, 3967, 3968, 3970, 3971, 3972, 3973, 3974, 3975, 3976, 3977, 3978, 3979, 3980, 3981, 3982, 3983, 3984, 3985, 3986, 3987, 3988, 3989, 3990, 3991, 3992, 3993, 3994, 3995, 3996, 3997, 3998, 3999, 4000, 4001, 4002, 4003, 4004, 4005, 4006, 4007, 4008, 4009, 4010, 4012, 4013, 4014, 4015, 4016, 4018, 4019, 4020, 4021, 4022, 4023, 4024, 4025, 4026, 4027, 4028, 4029, 4030, 4031, 4032, 4033, 4034, 4035, 4036, 4037, 4038, 4039, 4040, 4041, 4042, 4043, 4044, 4045, 4046, 4047, 4048, 4049, 4050, 4051, 4052, 4053, 4054, 4055, 4057, 4058, 4060, 4061, 4062, 4063, 4064, 4065, 4066, 4067, 4069, 4070, 4071, 4072, 4073, 4074, 4075, 4086, 4087, 4088, 4089, 4091, 4092, 4093, 4094, 4095, 4096, 4097, 4098, 4099, 4100, 4101, 4102, 4103, 4104, 4105, 4107, 4108, 4109, 4110, 4111, 4113, 4114, 4115, 4116, 4118, 4119, 4120, 4121, 4122, 4123, 4124, 4125, 4126, 4127, 4128, 4129, 4130, 4131, 4132, 4133, 4134, 4135, 4136, 4137, 4138, 4139, 4140, 4141, 4142, 4143, 4146, 4147, 4148, 4149, 4150, 4151, 4152, 4153, 4154, 4155, 4156, 4157, 4177, 4178, 4183, 4184, 4185, 4186, 4187, 4188, 4189, 4190, 4191, 4192, 4193, 4194, 4195, 4196, 4197, 4198, 4199, 4200, 4202, 4203, 4204, 4205, 4206, 4207, 4208, 4209, 4210, 4211, 4212, 4213, 4214, 4215, 4216, 4217, 4218, 4219, 4220, 4222, 4223, 4224, 4225, 4226, 4227, 4228, 4229, 4230, 4231, 4232, 4233, 4234, 4236, 4237, 4238, 4239, 4240, 4241, 4242, 4243, 4244, 4245, 4246, 4247, 4248, 4249, 4250, 4251, 4252, 4253, 4254, 4255, 4256, 4257, 4258, 4259, 4260, 4261, 4262, 4263, 4264, 4265, 4266, 4267, 4268, 4269, 4270, 4271, 4272, 4273, 4274, 4275, 4276, 4277, 4278, 4279, 4280, 4281, 4282, 4283, 4284, 4286, 4287, 4289, 4290, 4291, 4292, 4293, 4294, 4295, 4296, 4297, 4298, 4299, 4300, 4301, 4302, 4303, 4304, 4306, 4307, 4308, 4309, 4310, 4311, 4312, 4313, 4314, 4315, 4316, 4317, 4318, 4319, 4320, 4321, 4322, 4324, 4325, 4326, 4327, 4328, 4329, 4330, 4331, 4332, 4334, 4335, 4337, 4338, 4339, 4340, 4341, 4342, 4343, 4344, 4345, 4346, 4347, 4348, 4349, 4350, 4351, 4352, 4354, 4355, 4356, 4357, 4358, 4359, 4360, 4361, 4362, 4363, 4364, 4365, 4366, 4367, 4368, 4369, 4370, 4371, 4372, 4373, 4374, 4375, 4376, 4377, 4378, 4379, 4380, 4381, 4382, 4383, 4384, 4385, 4386, 4387, 4388, 4389, 4390, 4391, 4392, 4393, 4394, 4395, 4396, 4397, 4399, 4400, 4401, 4402, 4403, 4404, 4405, 4406, 4407, 4408, 4410, 4411, 4412, 4413, 4414, 4415, 4416, 4418, 4419, 4420, 4422, 4424, 4425, 4426, 4427, 4428, 4430, 4431, 4432, 4433, 4434, 4436, 4437, 4438, 4439, 4440, 4441, 4442, 4443, 4444, 4445, 4446, 4447, 4449, 4451, 4452, 4453, 4454, 4455, 4456, 4457, 4458, 4459, 4460, 4461, 4462, 4463, 4464, 4465, 4466, 4467, 4468, 4470, 4471, 4473, 4474, 4475, 4477, 4478, 4479, 4480, 4481, 4483, 4484, 4485, 4486, 4487, 4489, 4490, 4491, 4492, 4493, 4494, 4495, 4496, 4497, 4498, 4499, 4500, 4501, 4502, 4503, 4504, 4505, 4506, 4507, 4508, 4509, 4510, 4511, 4512, 4514, 4515, 4516, 4517, 4519, 4520, 4521, 4522, 4523, 4524, 4525, 4526, 4527, 4528, 4529, 4530, 4531, 4532, 4533, 4534, 4535, 4536, 4537, 4538, 4539, 4540, 4541, 4542, 4543, 4545, 4546, 4547, 4548, 4549, 4550, 4551, 4552, 4553, 4554, 4555, 4556, 4557, 4558, 4561, 4562, 4563, 4564, 4565, 4566, 4567, 4568, 4570, 4572, 4573, 4574, 4575, 4576, 4577, 4579, 4580, 4581, 4582, 4583, 4584, 4585, 4586, 4587, 4588, 4589, 4590, 4591, 4592, 4593, 4594, 4595, 4596, 4597, 4598, 4599, 4600, 4601, 4602, 4603, 4604, 4605, 4606, 4608, 4609, 4610, 4611, 4612, 4613, 4614, 4615, 4616, 4617, 4618, 4619, 4620, 4621, 4623, 4624, 4625, 4626, 4627, 4628, 4629, 4630, 4632, 4633, 4634, 4635, 4636, 4637, 4638, 4639, 4640, 4641, 4644, 4645, 4646, 4649, 4651, 4652, 4653, 4654, 4655, 4656, 4657, 4659, 4660, 4661, 4662, 4663, 4664, 4665, 4666, 4667, 4668, 4670, 4671, 4673, 4674, 4675, 4676, 4677, 4678, 4679, 4680, 4681, 4683, 4684, 4685, 4686, 4690, 4691, 4692, 4693, 4694, 4695, 4696, 4697, 4698, 4699, 4700, 4701, 4702, 4703, 4705, 4706, 4708, 4709, 4710, 4711, 4712, 4713, 4714, 4715, 4716, 4717, 4719, 4720, 4721, 4722, 4723, 4724, 4725, 4726, 4728, 4729, 4730, 4731, 4732, 4733, 4734, 4735, 4736, 4737, 4738, 4739, 4740, 4741, 4742, 4743, 4744, 4745, 4746, 4747, 4748, 4749, 4750, 4751, 4752, 4753, 4755, 4756, 4757, 4758, 4759, 4760, 4761, 4762, 4763, 4764, 4765, 4766, 4768, 4769, 4770, 4771, 4772, 4773, 4774, 4775, 4776, 4777, 4778, 4779, 4780, 4781, 4782, 4783, 4784, 4785, 4787, 4788, 4789, 4790, 4791, 4793, 4794, 4795, 4796, 4798, 4799, 4800, 4801, 4802, 4803, 4805, 4806, 4807, 4808, 4809, 4810, 4811, 4813, 4815, 4816, 4817, 4818, 4819, 4820, 4821, 4822, 4824, 4825, 4826, 4827, 4828, 4829, 4831, 4832, 4834, 4835, 4836, 4837, 4839, 4840, 4841, 4842, 4843, 4844, 4845, 4846, 4847, 4850, 4851, 4852, 4853, 4854, 4855, 4856, 4857, 4858, 4860, 4861, 4863, 4864, 4865, 4866, 4867, 4868, 4869, 4870, 4871, 4873, 4874, 4875, and 4876.

In a second aspect, the present invention relates to an isolated polynucleotide comprising a nucleotide sequence that hybridizes under very low stringency conditions, preferably low stringency conditions, more preferably medium stringency conditions, more preferably medium-high stringency conditions, even more preferably high stringency conditions, and most preferably very high stringency conditions with any of (i) the polynucleotides of SEQ ID NOs: 2-4876, or subsequences thereof, or (ii) full-length complementary strands thereof (J. Sambrook, E. F. Fritsch, and T. Maniatus, 1989 , Molecular Cloning, A Laboratory Manual, 2d edition, Cold Spring Harbor, N.Y.). Subsequences of SEQ ID NOs: 2-4876 may be preferably at least 90 nucleotides, more preferably at least 150 nucleotide, and most preferably at least 200 nucleotides. Moreover, the subsequences may encode fragments of a gene product that have biological activity.

In a preferred aspect, the present invention relates to an isolated polynucleotide comprising a nucleotide sequence that hybridizes under preferably at least medium stringency conditions, more preferably at least medium-high stringency conditions, or most preferably at least high stringency conditions with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and full-length complementary strands thereof.

The nucleotide sequences of SEQ ID NOs: 2-4876 or subsequences thereof, as well as the amino acid sequences of SEQ ID NOs: 4877-9751 or fragments thereof, may be used to design nucleic acid probes to identify and clone DNA encoding biologically active substances from strains of different genera or species according to methods well known in the art. In particular, such probes can be used for hybridization with the genomic DNA of the genus or species of interest, following standard Southern blotting procedures, in order to identify and isolate the corresponding gene therein. Such probes can be considerably shorter than the entire sequence, but should be at least 14, preferably at least 25, more preferably at least 35 nucleotides in length, such as at least 70 nucleotides in length. It is preferred, however, that the nucleic acid probes are at least 100 nucleotides in length. For example, the nucleic acid probes may be at least 200 nucleotides, at least 300 nucleotides, at least 400 nucleotides, or at least 500 nucleotides in length. Even longer probes may be used, e.g., nucleic acid probes that are at least 600 nucleotides, at least 700 nucleotides, at least 800 nucleotides, or at least 900 nucleotides in length. Both DNA and RNA probes can be used. The probes are typically labeled for detecting the corresponding gene (for example, with ³² P, ³ H, ³⁵ S, biotin, or avidin). Such probes are encompassed by the present invention.

A genomic DNA library prepared from such other organisms may, therefore, be screened for DNA that hybridizes with the probes described above and encodes a biologically active substance. Genomic DNA from such other organisms may be separated by agarose or polyacrylamide gel electrophoresis, or other separation techniques. DNA from the libraries or the separated DNA may be transferred to and immobilized on nitrocellulose or other suitable carrier material. In order to identify a clone or DNA that is homologous with any of SEQ ID NOs: 2-4876 or subsequences thereof, the carrier material is used in a Southern blot.

For purposes of the present invention, hybridization indicates that a polynucleotide hybridizes to a labeled gene having the nucleotide sequence shown in any of SEQ ID NOs: 2-4876, full-length complementary strands thereof, or subsequences thereof, under very low to very high stringency conditions. Molecules to which the nucleic acid probe hybridizes under these conditions can be detected using X-ray film.

In a preferred aspect, the nucleic acid probe is any of the polynucleotides of SEQ ID NOs: 2-4876, or subsequences thereof. In another preferred aspect, the nucleic acid probe is the mature polypeptide coding region of any of the polynucleotides of SEQ ID NOs: 2-4876. In another preferred aspect, the nucleic acid probe is the polynucleotide of any of SEQ ID NOs: 2-4876 contained in chromosome of Bacillus licheniformis SJ1904. In another preferred aspect, the nucleic acid probe is the mature polypeptide coding region of any of the polynucleotides of SEQ ID NOs: 2-4876 contained in Bacillus licheniformis SJ1904.

For long probes of at least 100 nucleotides in length, very low to very high stringency conditions are defined as prehybridization and hybridization at 42° C. in 5×SSPE, 0.3% SDS, 200 μg/ml sheared and denatured salmon sperm DNA, and either 25% formamide for very low and low stringencies, 35% formamide for medium and medium-high stringencies, or 50% formamide for high and very high stringencies, following standard Southern blotting procedures.

For long probes of at least 100 nucleotides in length, the carrier material is finally washed three times each for 15 minutes using 2×SSC, 0.2% SDS preferably at least at 45° C. (very low stringency), more preferably at least at 50° C. (low stringency), more preferably at least at 55° C. (medium stringency), more preferably at least at 60° C. (medium-high stringency), even more preferably at least at 65° C. (high stringency), and most preferably at least at 70° C. (very high stringency).

For short probes of about 14 nucleotides to about 70 nucleotides in length, stringency conditions are defined as prehybridization, hybridization, and washing post-hybridization at about 5° C. to about 10° C. below the calculated T _m using the calculation according to Bolton and McCarthy (1962 , Proceedings of the National Academy of Sciences USA 48:1390) in 0.9 M NaCl, 0.09 M Tris-HCl pH 7.6, 6 mM EDTA, 0.5% NP-40, 1×Denhardt's solution, 1 mM sodium pyrophosphate, 1 mM sodium monobasic phosphate, 0.1 mM ATP, and 0.2 mg of yeast RNA per ml following standard Southern blotting procedures.

For short probes of about 14 nucleotides to about 70 nucleotides in length, the carrier material is washed once in 6×SCC plus 0.1% SDS for 15 minutes and twice each for 15 minutes using 6×SSC at 5° C. to 10° C. below the calculated T _m .

Under salt-containing hybridization conditions, the effective T _m is what controls the degree of sequence identity required between the probe and the filter bound DNA for successful hybridization. The effective T _m may be determined using the formula below to determine the degree of sequence identity required for two DNAs to hybridize under various stringency conditions.

Effective T _m =81.5+0.16.6(log M[Na ⁺ ])+0.41(% G+C )−0.72(% formamide)

The % G+C content of any of the polynucleotides of SEQ ID NOs: 2-4876 can easily be determined. For medium stringency, for example, the concentration of formamide is 35% and the Na ⁺ concentration for 5×SSPE is 0.75 M. Applying this formula to these values, the Effective T _m in ° C. can be calculated. Another relevant relationship is that a 1% mismatch of two DNAs lowers the T _m 1.4° C. To determine the degree of sequence identity required for two DNAs to hybridize under medium stringency conditions at 42° C., the following formula is used:

% Homology=100−[(Effective T _m −Hybridization Temperature)/1.4]

Applying this formula, the degree of sequence identity required for two DNAs to hybridize under medium stringency conditions at 42° C. can be calculated.

Similar calculations can be made under other stringency conditions, as defined herein.

The present invention also relates to isolated polynucleotides obtained by (a) hybridizing a population of DNA under very low, low, medium, medium-high, high, or very high stringency conditions with any of (i) the polynucleotides of SEQ ID NOs: 2-4876, or subsequences thereof, or (ii) full-length complementary strands thereof; and (b) isolating the hybridizing polynucleotide from the population of DNA. In a preferred aspect, the hybridizing polynucleotide encodes a polypeptide of any of SEQ ID NOs: 2-4876, or homologous polypeptides thereof.

In a preferred aspect, the present invention relates to isolated polynucleotides obtained by (a) hybridizing a population of DNA under preferably at least medium stringency conditions, more preferably at least medium-high stringency conditions, or most preferably at least high stringency conditions with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and full-length complementary strands thereof; and (b) isolating the hybridizing polynucleotide from the population of DNA.

In a third aspect, the present invention relates to an isolated polynucleotide encoding a biologically active substance comprising an amino acid sequence having preferably at least 60% identity, more preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, more preferably at least 90% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity.

In a preferred aspect, the biological substance comprises an amino acid sequence an amino acid sequence having a degree of sequence identity of preferably at least 60% identity, more preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, and even most preferably at least 97% with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4944, 4985, 5051, 5058, 5064, 5076, 5079, 5097, 5098, 5099, 5106, 5115, 5117, 5136, 5137, 5197, 5204, 5286, 5459, 5529, 5604, 5723, 5724, 5725, 5726, 5761, 5923, 6056, 6097, 6153, 6192, 6371, 6372, 6376, 6456, 6504, 6531, 6545, 6546, 6547, 6548, 6550, 6945, 6965, 7053, 7116, 7163, 7164, 7165, 7166, 7169, 7170, 7174, 7176, 7177, 7363, 7392, 7397, 7399, 7402, 7420, 7421, 7423, 7425, 7438, 7449, 7453, 7468, 7507, 7562, 7563, 7565, 7573, 7641, 7815, 8003, 8008, 8009, 8010, 8011, 8014, 8015, 8018, 8020, 8021, 8022, 8046, 8099, 8100, 8103, 8140, 8323, 8710, 8711, 8966, 9034, 9035, 9036, 9049, 9051, 9054, 9056, 9057, 9224, 9516, 9525, 9547, 9562, 9564, 4900, 4925, 4930, 4952, 4957, 4966, 4973, 4978, 5000, 5010, 5044, 5046, 5047, 5049, 5052, 5053, 5054, 5055, 5056, 5057, 5060, 5061, 5062, 5067, 5069, 5070, 5071, 5073, 5074, 5078, 5080, 5081, 5082, 5083, 5084, 5085, 5086, 5087, 5088, 5089, 5090, 5091, 5092, 5093, 5094, 5095, 5096, 5100, 5101, 5102, 5103, 5104, 5105, 5112, 5116, 5118, 5119, 5120, 5121, 5122, 5123, 5124, 5125, 5126, 5127, 5128, 5129, 5130, 5131, 5132, 5133, 5134, 5135, 5138, 5139, 5140, 5141, 5151, 5162, 5173, 5180, 5181, 5183, 5192, 5198, 5225, 5229, 5235, 5236, 5238, 5242, 5249, 5256, 5290, 5297, 5307, 5320, 5344, 5347, 5353, 5354, 5362, 5363, 5366, 5373, 5391, 5396, 5398, 5399, 5412, 5416, 5428, 5445, 5450, 5456, 5467, 5482, 5493, 5496, 5502, 5503, 5506, 5541, 5547, 5563, 5566, 5574, 5577, 5585, 5594, 5601, 5609, 5623, 5626, 5639, 5648, 5649, 5652, 5664, 5666, 5702, 5704, 5706, 5708, 5717, 5722, 5730, 5732, 5760, 5762, 5776, 5784, 5819, 5832, 5852, 5857, 5866, 5869, 5890, 5893, 5897, 5907, 5909, 5912, 5933, 5953, 5955, 5963, 5966, 5973, 5983, 5986, 5987, 5993, 6003, 6005, 6023, 6026, 6028, 6029, 6033, 6035, 6039, 6045, 6050, 6051, 6052, 6055, 6058, 6059, 6068, 6069, 6074, 6083, 6090, 6095, 6112, 6119, 6137, 6138, 6140, 6141, 6167, 6177, 6188, 6189, 6190, 6191, 6193, 6195, 6209, 6220, 6230, 6245, 6248, 6249, 6276, 6286, 6294, 6296, 6299, 6307, 6308, 6315, 6317, 6323, 6330, 6341, 6345, 6384, 6402, 6414, 6431, 6440, 6445, 6464, 6494, 6506, 6509, 6510, 6511, 6513, 6514, 6515, 6516, 6517, 6518, 6519, 6520, 6521, 6522, 6524, 6525, 6526, 6527, 6528, 6529, 6530, 6532, 6533, 6534, 6535, 6536, 6537, 6538, 6539, 6540, 6541, 6542, 6543, 6544, 6552, 6557, 6559, 6563, 6567, 6569, 6572, 6578, 6579, 6603, 6607, 6609, 6611, 6626, 6650, 6654, 6658, 6661, 6667, 6670, 6673, 6691, 6706, 6711, 6713, 6726, 6728, 6741, 6758, 6762, 6819, 6821, 6877, 6882, 6897, 6913, 6919, 6923, 6940, 6942, 6947, 6951, 6958, 6969, 6981, 6984, 6994, 6995, 6996, 6999, 7006, 7014, 7022, 7023, 7041, 7046, 7069, 7071, 7073, 7079, 7080, 7086, 7088, 7091, 7096, 7100, 7105, 7111, 7115, 7129, 7130, 7133, 7138, 7148, 7152, 7157, 7161, 7167, 7171, 7172, 7173, 7175, 7178, 7179, 7180, 7199, 7200, 7202, 7211, 7212, 7216, 7222, 7226, 7229, 7237, 7239, 7256, 7263, 7275, 7278, 7279, 7283, 7285, 7286, 7287, 7289, 7290, 7299, 7300, 7305, 7310, 7314, 7321, 7324, 7332, 7339, 7342, 7343, 7344, 7351, 7358, 7366, 7373, 7375, 7379, 7380, 7381, 7382, 7383, 7384, 7385, 7386, 7387, 7388, 7389, 7390, 7391, 7393, 7394, 7395, 7396, 7400, 7401, 7403, 7404, 7405, 7406, 7407, 7408, 7409, 7410, 7411, 7412, 7413, 7414, 7415, 7416, 7417, 7418, 7419, 7422, 7424, 7426, 7427, 7428, 7429, 7430, 7431, 7432, 7433, 7434, 7435, 7436, 7437, 7439, 7440, 7442, 7443, 7444, 7445, 7446, 7447, 7448, 7450, 7451, 7452, 7454, 7455, 7456, 7457, 7458, 7459, 7460, 7461, 7462, 7463, 7464, 7465, 7466, 7467, 7469, 7470, 7471, 7472, 7473, 7474, 7475, 7476, 7477, 7478, 7479, 7480, 7481, 7482, 7483, 7484, 7485, 7486, 7487, 7488, 7489, 7490, 7491, 7492, 7493, 7494, 7495, 7496, 7497, 7498, 7499, 7500, 7501, 7502, 7503, 7504, 7505, 7506, 7508, 7509, 7510, 7511, 7513, 7514, 7515, 7516, 7517, 7518, 7519, 7520, 7521, 7522, 7523, 7524, 7525, 7526, 7527, 7528, 7529, 7530, 7531, 7532, 7533, 7534, 7536, 7539, 7540, 7542, 7544, 7545, 7546, 7547, 7548, 7549, 7550, 7551, 7552, 7553, 7554, 7555, 7556, 7559, 7560, 7561, 7564, 7566, 7567, 7568, 7571, 7572, 7581, 7583, 7592, 7595, 7598, 7605, 7608, 7626, 7637, 7646, 7670, 7681, 7688, 7709, 7710, 7716, 7725, 7741, 7742, 7749, 7753, 7758, 7766, 7773, 7777, 7779, 7792, 7822, 7832, 7835, 7844, 7847, 7848, 7874, 7879, 7893, 7894, 7903, 7921, 7929, 7939, 7944, 7957, 7962, 7968, 7987, 7998, 8012, 8016, 8017, 8019, 8023, 8024, 8025, 8037, 8090, 8097, 8101, 8102, 8104, 8106, 8119, 8123, 8134, 8136, 8139, 8162, 8166, 8174, 8178, 8185, 8186, 8196, 8198, 8199, 8208, 8230, 8237, 8246, 8299, 8304, 8306, 8309, 8317, 8321, 8332, 8333, 8346, 8361, 8368, 8371, 8374, 8378, 8379, 8383, 8384, 8394, 8424, 8433, 8452, 8462, 8468, 8473, 8476, 8478, 8481, 8486, 8517, 8528, 8530, 8545, 8548, 8557, 8565, 8569, 8582, 8584, 8591, 8602, 8610, 8611, 8612, 8619, 8628, 8640, 8645, 8655, 8665, 8667, 8673, 8674, 8693, 8700, 8714, 8747, 8754, 8756, 8760, 8779, 8786, 8790, 8791, 8797, 8801, 8806, 8813, 8844, 8886, 8892, 8893, 8908, 8912, 8923, 8930, 8931, 8934, 8943, 8951, 8952, 8953, 8956, 8957, 8960, 8961, 8965, 8981, 8987, 8992, 9019, 9020, 9033, 9037, 9038, 9039, 9040, 9041, 9042, 9043, 9044, 9045, 9046, 9047, 9048, 9050, 9076, 9096, 9110, 9114, 9118, 9160, 9163, 9180, 9198, 9208, 9211, 9228, 9245, 9273, 9284, 9292, 9296, 9298, 9304, 9310, 9321, 9323, 9325, 9337, 9344, 9347, 9349, 9351, 9357, 9362, 9363, 9374, 9384, 9385, 9388, 9393, 9419, 9433, 9434, 9435, 9436, 9444, 9446, 9453, 9475, 9480, 9482, 9497, 9506, 9508, 9518, 9520, 9522, 9523, 9524, 9533, 9544, 9557, 9568, 9579, 9583, 9593, 9597, 9629, 9642, 9661, 9667, 9672, 9679, 9687, 9689, 9698, 9705, 9708, 9713, 9723, 9724, 9729, 9734, 9737, and 9747; preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, and even most preferably at least 97% with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4991, 5068, 5308, 5463, 5919, 6549, 6648, 6680, 6948, 7298, 7541, 7896, 7911, 8497, 8702, 8729, 8737, 9052, 9690, and 9709; preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, and even most preferably at least 97% with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4986, 5041, 5043, 5418, 5427, 5500, 5515, 5696, 5713, 5785, 5939, 6106, 6109, 6171, 6260, 6503, 6677, 6724, 7054, 7260, 7295, 7316, 7341, 7512, 7538, 7591, 7628, 7735, 7912, 8050, 8076, 8206, 8207, 8240, 8327, 8406, 8428, 8860, 8955, 9061, 9099, 9115, 9262, 9591, 9641, and 9720; preferably at least 75% identity, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, and even most preferably at least 97% with an amino acid sequence selected from the group consisting of SEQ ID NOs: 5038, 5059, 5240, 5403, 5444, 5508, 5559, 5562, 5642, 5651, 5846, 5885, 5921, 5942, 6015, 6067, 6071, 6164, 6215, 6293, 6373, 6390, 6446, 6624, 6704, 6717, 6749, 6759, 6808, 6847, 6848, 6852, 6854, 7292, 7297, 7308, 7317, 7537, 7543, 7557, 7603, 7651, 7858, 7949, 7954, 7996, 8074, 8200, 8221, 8263, 8288, 8614, 8684, 8720, 8728, 8740, 8749, 8787, 8864, 8958, 9055, 9176, 9196, 9283, 9308, 9352, 9491, 9512, 9602, 9653, 9684, 9719, and 9731; preferably at least 80% identity, more preferably at least 85% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4891, 4956, 5042, 5072, 5169, 5190, 5195, 5217, 5241, 5266, 5305, 5369, 5374, 5377, 5409, 5435, 5512, 5524, 5538, 5595, 5613, 5647, 5657, 5665, 5667, 5735, 5743, 5830, 5878, 5900, 5903, 5977, 5988, 6000, 6060, 6066, 6070, 6073, 6075, 6105, 6120, 6139, 6152, 6174, 6291, 6335, 6375, 6437, 6466, 6492, 6505, 6507, 6523, 6553, 6592, 6651, 6694, 6730, 6732, 6774, 6843, 6929, 6943, 6964, 7093, 7132, 7144, 7224, 7349, 7374, 7398, 7570, 7578, 7632, 7635, 7643, 7680, 7682, 7685, 7700, 7713, 7727, 7800, 7843, 7864, 7918, 7947, 7982, 7989, 7991, 7999, 8055, 8057, 8085, 8095, 8170, 8182, 8191, 8210, 8255, 8261, 8328, 8365, 8399, 8410, 8479, 8551, 8561, 8577, 8589, 8649, 8679, 8742, 8744, 8784, 8789, 8796, 8818, 8832, 8835, 8845, 8854, 8858, 8868, 8878, 8900, 8950, 9007, 9102, 9108, 9151, 9169, 9207, 9241, 9246, 9248, 9250, 9299, 9341, 9343, 9412, 9443, 9470, 9476, 9511, 9528, 9559, 9565, 9577, 9584, 9594, 9595, 9682, and 9714; preferably at least 85% identity, more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4913, 4948, 4968, 5025, 5034, 5066, 5109, 5110, 5146, 5160, 5199, 5200, 5203, 5211, 5221, 5223, 5226, 5252, 5269, 5273, 5293, 5309, 5318, 5342, 5352, 5393, 5394, 5421, 5430, 5431, 5434, 5447, 5458, 5492, 5507, 5511, 5514, 5525, 5526, 5530, 5544, 5570, 5616, 5617, 5621, 5640, 5661, 5663, 5691, 5716, 5738, 5751, 5753, 5757, 5759, 5786, 5802, 5820, 5826, 5855, 5858, 5871, 5872, 5902, 5905, 5908, 5915, 5936, 5937, 5938, 5947, 6006, 6011, 6012, 6025, 6030, 6032, 6034, 6057, 6080, 6084, 6093, 6096, 6110, 6131, 6178, 6183, 6199, 6232, 6236, 6243, 6257, 6258, 6313, 6331, 6354, 6360, 6362, 6386, 6417, 6421, 6435, 6455, 6468, 6472, 6475, 6476, 6478, 6495, 6555, 6566, 6568, 6604, 6608, 6641, 6662, 6663, 6665, 6692, 6699, 6736, 6752, 6763, 6807, 6809, 6810, 6840, 6842, 6844, 6853, 6855, 6857, 6866, 6906, 6908, 6915, 6922, 6953, 6962, 6977, 6989, 7004, 7025, 7032, 7042, 7045, 7058, 7072, 7085, 7134, 7139, 7145, 7182, 7188, 7194, 7208, 7227, 7249, 7261, 7272, 7293, 7309, 7320, 7331, 7333, 7334, 7354, 7367, 7371, 7558, 7597, 7602, 7623, 7664, 7677, 7679, 7687, 7732, 7734, 7739, 7744, 7752, 7765, 7769, 7790, 7801, 7818, 7823, 7833, 7837, 7860, 7867, 7877, 7882, 7915, 7931, 7932, 7946, 7948, 7959, 7967, 7973, 7975, 7977, 7978, 7986, 8071, 8072, 8096, 8107, 8129, 8146, 8148, 8153, 8164, 8165, 8169, 8203, 8211, 8216, 8218, 8234, 8245, 8253, 8275, 8297, 8315, 8334, 8340, 8357, 8362, 8372, 8386, 8398, 8425, 8438, 8455, 8460, 8470, 8480, 8490, 8506, 8531, 8533, 8572, 8593, 8600, 8615, 8623, 8627, 8630, 8634, 8664, 8687, 8703, 8704, 8705, 8726, 8739, 8750, 8752, 8753, 8769, 8780, 8781, 8805, 8816, 8825, 8846, 8869, 8870, 8883, 8913, 8938, 8944, 8945, 8948, 8959, 8962, 8973, 8976, 8980, 8991, 9000, 9006, 9017, 9068, 9093, 9097, 9103, 9109, 9146, 9155, 9159, 9255, 9258, 9260, 9266, 9269, 9271, 9278, 9293, 9350, 9373, 9394, 9415, 9420, 9449, 9466, 9472, 9477, 9486, 9500, 9504, 9514, 9517, 9535, 9573, 9590, 9599, 9601, 9623, 9645, 9648, 9652, 9654, 9659, 9726, 9728, 9736, and 9748; preferably at least 90% identity, more preferably at least 95% identity, and most preferably at least 97% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4890, 4895, 4921, 4923, 4927, 4933, 4934, 4937, 4939, 4943, 4946, 4950, 4951, 4955, 4958, 4967, 4970, 4981, 4982, 4987, 4989, 4999, 5017, 5022, 5029, 5048, 5111, 5113, 5145, 5152, 5157, 5165, 5171, 5178, 5179, 5182, 5186, 5202, 5213, 5214, 5215, 5218, 5227, 5230, 5233, 5245, 5268, 5272, 5274, 5279, 5281, 5283, 5298, 5303, 5315, 5324, 5326, 5328, 5329, 5330, 5336, 5337, 5338, 5339, 5346, 5357, 5360, 5376, 5380, 5387, 5400, 5401, 5414, 5417, 5419, 5422, 5424, 5436, 5442, 5446, 5448, 5455, 5457, 5466, 5475, 5499, 5501, 5510, 5537, 5539, 5542, 5550, 5552, 5557, 5565, 5571, 5573, 5586, 5589, 5612, 5615, 5620, 5622, 5628, 5632, 5634, 5638, 5645, 5646, 5660, 5670, 5677, 5678, 5681, 5688, 5705, 5707, 5710, 5739, 5748, 5754, 5756, 5763, 5764, 5765, 5766, 5768, 5779, 5782, 5783, 5787, 5791, 5792, 5793, 5799, 5808, 5813, 5821, 5827, 5828, 5834, 5835, 5837, 5842, 5850, 5856, 5859, 5864, 5870, 5884, 5906, 5914, 5917, 5945, 5946, 5958, 5964, 5965, 5985, 5989, 5994, 5998, 6007, 6009, 6016, 6017, 6019, 6022, 6031, 6048, 6062, 6064, 6079, 6081, 6086, 6089, 6098, 6103, 6107, 6113, 6121, 6122, 6125, 6156, 6163, 6165, 6181, 6205, 6212, 6223, 6235, 6238, 6239, 6242, 6244, 6250, 6251, 6255, 6261, 6262, 6265, 6267, 6269, 6281, 6283, 6284, 6290, 6292, 6300, 6301, 6318, 6324, 6327, 6332, 6333, 6338, 6339, 6344, 6349, 6353, 6361, 6363, 6374, 6377, 6383, 6387, 6396, 6397, 6399, 6400, 6413, 6423, 6449, 6450, 6462, 6465, 6467, 6471, 6484, 6493, 6501, 6512, 6565, 6573, 6574, 6575, 6576, 6580, 6583, 6585, 6589, 6594, 6598, 6600, 6605, 6619, 6629, 6635, 6636, 6637, 6638, 6642, 6647, 6664, 6669, 6686, 6688, 6695, 6696, 6697, 6698, 6700, 6710, 6712, 6729, 6735, 6740, 6742, 6743, 6744, 6745, 6768, 6779, 6780, 6781, 6782, 6786, 6792, 6793, 6795, 6800, 6801, 6802, 6804, 6823, 6827, 6829, 6833, 6834, 6836, 6838, 6861, 6862, 6863, 6867, 6868, 6871, 6872, 6887, 6903, 6918, 6920, 6927, 6933, 6939, 6944, 6949, 6960, 6966, 6973, 6976, 6979, 7000, 7002, 7015, 7017, 7019, 7036, 7040, 7051, 7055, 7056, 7063, 7075, 7077, 7087, 7090, 7092, 7097, 7102, 7103, 7104, 7109, 7112, 7117, 7118, 7122, 7123, 7125, 7126, 7127, 7158, 7162, 7181, 7186, 7196, 7201, 7203, 7206, 7209, 7210, 7219, 7221, 7230, 7231, 7232, 7233, 7235, 7236, 7244, 7248, 7251, 7252, 7257, 7268, 7271, 7274, 7281, 7304, 7326, 7335, 7352, 7356, 7357, 7360, 7364, 7577, 7579, 7601, 7607, 7615, 7624, 7625, 7639, 7650, 7658, 7672, 7696, 7712, 7718, 7728, 7729, 7730, 7745, 7747, 7748, 7751, 7754, 7756, 7774, 7780, 7786, 7808, 7810, 7826, 7831, 7840, 7849, 7854, 7871, 7872, 7886, 7892, 7914, 7925, 7928, 7933, 7934, 7937, 7941, 7945, 7969, 7970, 7980, 8032, 8039, 8040, 8060, 8063, 8065, 8066, 8075, 8077, 8078, 8086, 8122, 8133, 8138, 8149, 8157, 8158, 8159, 8177, 8180, 8184, 8188, 8195, 8205, 8209, 8220, 8223, 8235, 8241, 8243, 8247, 8250, 8252, 8257, 8271, 8280, 8282, 8283, 8295, 8298, 8305, 8310, 8325, 8342, 8344, 8347, 8358, 8363, 8366, 8373, 8377, 8382, 8387, 8392, 8400, 8404, 8405, 8407, 8413, 8417, 8419, 8421, 8426, 8429, 8434, 8436, 8442, 8450, 8457, 8458, 8461, 8463, 8469, 8491, 8494, 8501, 8504, 8507, 8508, 8516, 8523, 8532, 8536, 8544, 8550, 8552, 8554, 8564, 8566, 8587, 8603, 8622, 8629, 8632, 8635, 8636, 8646, 8647, 8652, 8653, 8654, 8657, 8682, 8690, 8698, 8701, 8709, 8712, 8724, 8725, 8736, 8755, 8767, 8772, 8776, 8798, 8803, 8804, 8817, 8836, 8843, 8852, 8857, 8859, 8861, 8866, 8880, 8881, 8882, 8884, 8885, 8891, 8894, 8901, 8904, 8905, 8910, 8911, 8927, 8933, 8954, 8963, 8971, 8975, 8977, 8984, 8995, 8997, 9004, 9008, 9023, 9026, 9031, 9063, 9078, 9080, 9083, 9091, 9092, 9112, 9120, 9127, 9134, 9140, 9149, 9156, 9164, 9168, 9185, 9189, 9190, 9193, 9197, 9202, 9204, 9214, 9217, 9220, 9232, 9233, 9236, 9243, 9259, 9274, 9275, 9280, 9286, 9291, 9300, 9305, 9306, 9317, 9329, 9356, 9364, 9366, 9367, 9378, 9382, 9389, 9390, 9392, 9396, 9399, 9405, 9417, 9422, 9425, 9428, 9438, 9441, 9451, 9454, 9462, 9463, 9468, 9473, 9496, 9499, 9501, 9502, 9510, 9539, 9540, 9550, 9556, 9561, 9570, 9574, 9585, 9587, 9604, 9605, 9606, 9613, 9616, 9618, 9630, 9632, 9633, 9635, 9650, 9651, 9655, 9656, 9670, 9680, 9683, 9686, 9699, 9704, 9716, 9727, and 9749; or preferably at least 95% identity and more preferably at least 97% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877, 4878, 4879, 4880, 4881, 4882, 4883, 4884, 4885, 4886, 4887, 4888, 4889, 4892, 4893, 4894, 4896, 4897, 4898, 4899, 4901, 4902, 4903, 4904, 4905, 4906, 4907, 4908, 4909, 4910, 4911, 4912, 4914, 4915, 4916, 4917, 4918, 4919, 4920, 4922, 4924, 4926, 4928, 4929, 4931, 4932, 4935, 4936, 4938, 4940, 4941, 4942, 4945, 4947, 4949, 4953, 4954, 4959, 4960, 4961, 4962, 4963, 4964, 4965, 4969, 4971, 4972, 4974, 4975, 4976, 4977, 4979, 4980, 4983, 4984, 4988, 4990, 4992, 4993, 4994, 4995, 4996, 4997, 4998, 5001, 5002, 5003, 5004, 5005, 5006, 5007, 5008, 5009, 5011, 5012, 5013, 5014, 5015, 5016, 5018, 5019, 5020, 5021, 5023, 5024, 5026, 5027, 5028, 5030, 5031, 5032, 5033, 5035, 5036, 5037, 5039, 5045, 5050, 5063, 5065, 5075, 5077, 5107, 5108, 5114, 5142, 5143, 5144, 5147, 5148, 5149, 5150, 5153, 5154, 5155, 5156, 5158, 5159, 5161, 5163, 5164, 5166, 5167, 5168, 5170, 5172, 5174, 5175, 5176, 5177, 5184, 5185, 5187, 5188, 5189, 5191, 5193, 5194, 5196, 5201, 5205, 5206, 5207, 5208, 5209, 5210, 5212, 5216, 5219, 5220, 5222, 5224, 5228, 5231, 5232, 5234, 5237, 5239, 5243, 5244, 5246, 5247, 5248, 5250, 5251, 5254, 5255, 5257, 5258, 5259, 5260, 5261, 5262, 5263, 5264, 5265, 5267, 5270, 5271, 5275, 5276, 5277, 5278, 5280, 5282, 5284, 5285, 5287, 5288, 5289, 5291, 5292, 5294, 5295, 5296, 5299, 5300, 5301, 5302, 5304, 5306, 5310, 5311, 5312, 5313, 5314, 5316, 5317, 5319, 5321, 5322, 5323, 5325, 5327, 5331, 5332, 5333, 5334, 5335, 5340, 5341, 5343, 5345, 5348, 5349, 5350, 5351, 5355, 5356, 5358, 5359, 5361, 5364, 5365, 5367, 5368, 5370, 5371, 5372, 5375, 5379, 5381, 5382, 5383, 5384, 5385, 5386, 5388, 5389, 5390, 5392, 5395, 5397, 5402, 5404, 5405, 5406, 5407, 5408, 5410, 5411, 5413, 5415, 5420, 5423, 5425, 5426, 5429, 5432, 5433, 5437, 5438, 5439, 5440, 5441, 5443, 5449, 5451, 5452, 5453, 5454, 5460, 5461, 5462, 5464, 5465, 5468, 5469, 5470, 5471, 5472, 5473, 5474, 5476, 5477, 5478, 5479, 5480, 5481, 5483, 5484, 5485, 5486, 5487, 5488, 5489, 5490, 5491, 5494, 5495, 5497, 5498, 5504, 5505, 5509, 5513, 5516, 5517, 5518, 5519, 5520, 5521, 5522, 5523, 5527, 5528, 5531, 5532, 5533, 5534, 5535, 5536, 5540, 5543, 5545, 5546, 5548, 5549, 5551, 5553, 5554, 5555, 5556, 5558, 5560, 5561, 5564, 5568, 5569, 5572, 5575, 5576, 5578, 5579, 5580, 5581, 5582, 5583, 5584, 5587, 5588, 5590, 5591, 5592, 5593, 5596, 5597, 5598, 5599, 5600, 5602, 5603, 5605, 5606, 5607, 5608, 5610, 5611, 5614, 5618, 5619, 5624, 5625, 5627, 5629, 5630, 5631, 5633, 5635, 5636, 5637, 5641, 5643, 5644, 5650, 5653, 5654, 5655, 5656, 5658, 5659, 5662, 5668, 5669, 5671, 5672, 5673, 5674, 5675, 5676, 5679, 5680, 5682, 5683, 5684, 5685, 5686, 5687, 5689, 5690, 5692, 5693, 5694, 5695, 5697, 5698, 5699, 5700, 5701, 5703, 5709, 5711, 5712, 5714, 5715, 5718, 5719, 5720, 5721, 5728, 5729, 5731, 5733, 5734, 5736, 5737, 5740, 5741, 5742, 5744, 5745, 5746, 5747, 5749, 5750, 5752, 5755, 5758, 5767, 5769, 5770, 5771, 5772, 5773, 5774, 5775, 5777, 5778, 5780, 5781, 5788, 5789, 5790, 5794, 5795, 5796, 5797, 5798, 5800, 5801, 5803, 5804, 5805, 5806, 5807, 5809, 5810, 5811, 5812, 5814, 5815, 5816, 5817, 5818, 5822, 5823, 5824, 5825, 5829, 5831, 5833, 5836, 5838, 5839, 5840, 5841, 5843, 5844, 5845, 5847, 5848, 5849, 5851, 5853, 5854, 5860, 5861, 5862, 5863, 5865, 5867, 5868, 5873, 5874, 5875, 5876, 5877, 5879, 5880, 5881, 5882, 5883, 5886, 5887, 5888, 5889, 5891, 5892, 5894, 5895, 5896, 5899, 5901, 5904, 5910, 5911, 5913, 5916, 5918, 5920, 5922, 5924, 5925, 5926, 5927, 5928, 5929, 5930, 5931, 5932, 5934, 5935, 5940, 5941, 5943, 5944, 5948, 5949, 5950, 5951, 5952, 5954, 5956, 5957, 5959, 5960, 5961, 5962, 5967, 5968, 5969, 5970, 5971, 5972, 5974, 5975, 5976, 5978, 5979, 5980, 5981, 5982, 5984, 5990, 5991, 5992, 5995, 5996, 5997, 5999, 6001, 6002, 6004, 6008, 6010, 6013, 6014, 6018, 6020, 6021, 6024, 6027, 6036, 6037, 6038, 6040, 6041, 6042, 6043, 6044, 6046, 6047, 6049, 6053, 6054, 6061, 6063, 6065, 6072, 6076, 6077, 6078, 6082, 6085, 6087, 6088, 6091, 6092, 6094, 6099, 6100, 6101, 6102, 6104, 6108, 6111, 6114, 6115, 6116, 6117, 6118, 6123, 6124, 6126, 6127, 6128, 6129, 6130, 6132, 6133, 6134, 6135, 6136, 6142, 6143, 6144, 6145, 6146, 6147, 6148, 6149, 6150, 6151, 6154, 6155, 6157, 6158, 6159, 6160, 6161, 6162, 6166, 6168, 6169, 6170, 6172, 6173, 6175, 6176, 6179, 6180, 6182, 6184, 6185, 6186, 6187, 6194, 6196, 6197, 6198, 6200, 6201, 6202, 6203, 6204, 6206, 6207, 6208, 6210, 6211, 6213, 6214, 6216, 6217, 6218, 6219, 6221, 6222, 6224, 6225, 6226, 6227, 6228, 6229, 6231, 6233, 6234, 6237, 6240, 6246, 6247, 6252, 6253, 6254, 6256, 6259, 6263, 6264, 6266, 6268, 6270, 6271, 6272, 6273, 6274, 6275, 6277, 6278, 6279, 6280, 6282, 6285, 6287, 6288, 6289, 6295, 6297, 6298, 6302, 6303, 6304, 6305, 6306, 6309, 6310, 6311, 6312, 6314, 6316, 6319, 6320, 6321, 6322, 6325, 6326, 6328, 6329, 6336, 6337, 6340, 6342, 6343, 6346, 6347, 6348, 6350, 6351, 6352, 6355, 6356, 6357, 6358, 6359, 6364, 6365, 6366, 6367, 6368, 6369, 6378, 6379, 6380, 6381, 6382, 6385, 6388, 6389, 6391, 6392, 6393, 6394, 6395, 6398, 6401, 6403, 6404, 6405, 6406, 6407, 6408, 6409, 6410, 6411, 6412, 6415, 6416, 6418, 6419, 6420, 6422, 6424, 6425, 6426, 6427, 6428, 6429, 6430, 6432, 6433, 6434, 6436, 6438, 6439, 6441, 6442, 6443, 6444, 6447, 6448, 6451, 6452, 6453, 6454, 6457, 6458, 6459, 6460, 6461, 6463, 6469, 6470, 6473, 6474, 6477, 6479, 6480, 6481, 6482, 6483, 6485, 6486, 6487, 6488, 6489, 6490, 6491, 6496, 6497, 6498, 6499, 6500, 6502, 6508, 6556, 6558, 6560, 6561, 6562, 6564, 6570, 6571, 6577, 6581, 6582, 6584, 6586, 6587, 6588, 6590, 6591, 6593, 6595, 6596, 6597, 6599, 6601, 6602, 6606, 6610, 6612, 6613, 6614, 6615, 6616, 6617, 6618, 6620, 6621, 6622, 6623, 6625, 6627, 6628, 6630, 6631, 6632, 6633, 6634, 6639, 6640, 6643, 6644, 6645, 6646, 6649, 6652, 6653, 6655, 6656, 6657, 6659, 6660, 6666, 6668, 6671, 6672, 6674, 6675, 6676, 6678, 6679, 6681, 6682, 6683, 6684, 6685, 6687, 6689, 6690, 6693, 6701, 6702, 6703, 6705, 6707, 6708, 6709, 6714, 6715, 6716, 6718, 6719, 6720, 6721, 6722, 6723, 6725, 6727, 6731, 6733, 6734, 6737, 6738, 6739, 6746, 6747, 6748, 6750, 6751, 6753, 6754, 6755, 6756, 6757, 6760, 6761, 6764, 6765, 6766, 6767, 6769, 6770, 6771, 6772, 6773, 6775, 6776, 6777, 6778, 6783, 6784, 6785, 6787, 6788, 6789, 6790, 6791, 6794, 6796, 6797, 6798, 6799, 6803, 6805, 6806, 6811, 6812, 6813, 6814, 6815, 6816, 6817, 6818, 6820, 6822, 6824, 6825, 6826, 6828, 6830, 6831, 6832, 6835, 6837, 6839, 6841, 6845, 6846, 6849, 6850, 6851, 6856, 6858, 6859, 6860, 6864, 6865, 6869, 6870, 6873, 6874, 6875, 6876, 6878, 6879, 6880, 6881, 6883, 6884, 6885, 6886, 6888, 6889, 6890, 6891, 6892, 6893, 6894, 6895, 6896, 6898, 6899, 6900, 6901, 6902, 6904, 6905, 6907, 6909, 6910, 6911, 6912, 6914, 6916, 6917, 6921, 6924, 6925, 6926, 6928, 6930, 6931, 6932, 6934, 6935, 6936, 6937, 6938, 6941, 6950, 6952, 6954, 6955, 6956, 6957, 6959, 6961, 6967, 6968, 6970, 6971, 6972, 6974, 6975, 6978, 6980, 6982, 6983, 6985, 6986, 6987, 6988, 6990, 6991, 6992, 6993, 6997, 6998, 7001, 7003, 7005, 7007, 7008, 7009, 7010, 7011, 7012, 7013, 7016, 7018, 7020, 7021, 7024, 7026, 7027, 7028, 7029, 7030, 7031, 7033, 7034, 7035, 7037, 7038, 7039, 7043, 7044, 7047, 7048, 7049, 7050, 7052, 7057, 7059, 7060, 7061, 7062, 7064, 7065, 7066, 7067, 7068, 7070, 7074, 7076, 7078, 7081, 7082, 7083, 7084, 7089, 7094, 7095, 7098, 7099, 7101, 7106, 7107, 7108, 7110, 7113, 7114, 7119, 7120, 7121, 7124, 7128, 7131, 7135, 7136, 7137, 7140, 7141, 7142, 7143, 7146, 7147, 7149, 7150, 7151, 7153, 7154, 7155, 7156, 7159, 7160, 7183, 7184, 7185, 7187, 7189, 7190, 7191, 7192, 7193, 7197, 7198, 7204, 7205, 7207, 7213, 7214, 7215, 7217, 7218, 7220, 7223, 7225, 7228, 7234, 7238, 7240, 7241, 7242, 7243, 7245, 7246, 7247, 7250, 7253, 7254, 7255, 7258, 7259, 7262, 7264, 7265, 7266, 7267, 7269, 7270, 7273, 7276, 7277, 7280, 7282, 7284, 7288, 7291, 7294, 7296, 7301, 7302, 7303, 7306, 7307, 7311, 7312, 7313, 7315, 7318, 7319, 7322, 7323, 7325, 7327, 7328, 7329, 7330, 7336, 7337, 7338, 7340, 7345, 7346, 7347, 7348, 7350, 7355, 7359, 7361, 7362, 7365, 7368, 7369, 7370, 7372, 7376, 7377, 7378, 7574, 7575, 7576, 7580, 7582, 7584, 7585, 7586, 7587, 7588, 7589, 7590, 7593, 7594, 7596, 7599, 7600, 7604, 7606, 7609, 7610, 7611, 7612, 7613, 7614, 7616, 7617, 7618, 7619, 7620, 7621, 7622, 7627, 7629, 7630, 7631, 7633, 7634, 7636, 7638, 7640, 7642, 7644, 7645, 7647, 7648, 7649, 7652, 7653, 7654, 7655, 7656, 7657, 7659, 7660, 7661, 7662, 7663, 7665, 7666, 7667, 7668, 7669, 7671, 7673, 7674, 7675, 7676, 7678, 7683, 7684, 7686, 7689, 7690, 7691, 7692, 7693, 7694, 7695, 7697, 7698, 7699, 7701, 7702, 7703, 7704, 7705, 7706, 7707, 7708, 7711, 7714, 7715, 7717, 7719, 7720, 7721, 7722, 7723, 7724, 7726, 7731, 7733, 7736, 7737, 7738, 7740, 7743, 7746, 7750, 7755, 7757, 7759, 7760, 7761, 7762, 7763, 7764, 7767, 7768, 7770, 7771, 7772, 7775, 7776, 7778, 7781, 7782, 7783, 7784, 7785, 7787, 7788, 7789, 7791, 7793, 7794, 7795, 7796, 7797, 7798, 7799, 7802, 7803, 7804, 7805, 7806, 7807, 7809, 7811, 7812, 7813, 7814, 7816, 7817, 7819, 7820, 7821, 7824, 7825, 7827, 7828, 7829, 7830, 7834, 7836, 7838, 7839, 7841, 7842, 7845, 7846, 7850, 7851, 7852, 7853, 7855, 7856, 7857, 7859, 7861, 7862, 7863, 7865, 7866, 7868, 7869, 7870, 7873, 7875, 7876, 7878, 7880, 7881, 7883, 7884, 7885, 7887, 7888, 7889, 7891, 7895, 7897, 7898, 7899, 7900, 7901, 7902, 7904, 7905, 7906, 7907, 7908, 7909, 7910, 7913, 7916, 7917, 7919, 7920, 7922, 7923, 7924, 7926, 7927, 7930, 7935, 7936, 7938, 7940, 7942, 7943, 7950, 7951, 7952, 7953, 7955, 7956, 7958, 7960, 7961, 7963, 7964, 7965, 7966, 7971, 7972, 7974, 7976, 7979, 7981, 7983, 7984, 7985, 7988, 7990, 7992, 7993, 7994, 7995, 7997, 8000, 8001, 8002, 8004, 8005, 8006, 8007, 8026, 8027, 8028, 8029, 8030, 8031, 8033, 8034, 8035, 8036, 8038, 8041, 8042, 8043, 8044, 8045, 8047, 8048, 8049, 8051, 8052, 8053, 8054, 8056, 8058, 8059, 8061, 8062, 8064, 8067, 8068, 8069, 8070, 8073, 8079, 8080, 8081, 8082, 8083, 8084, 8087, 8088, 8089, 8091, 8092, 8093, 8094, 8098, 8105, 8108, 8109, 8110, 8111, 8112, 8113, 8114, 8115, 8116, 8117, 8118, 8120, 8121, 8124, 8125, 8126, 8127, 8128, 8130, 8131, 8132, 8135, 8137, 8141, 8142, 8143, 8144, 8145, 8147, 8150, 8151, 8152, 8154, 8155, 8156, 8160, 8161, 8163, 8167, 8168, 8171, 8172, 8173, 8175, 8176, 8179, 8181, 8183, 8187, 8189, 8190, 8192, 8193, 8194, 8197, 8201, 8202, 8204, 8212, 8213, 8214, 8215, 8217, 8219, 8222, 8224, 8225, 8226, 8227, 8228, 8229, 8231, 8232, 8233, 8236, 8238, 8239, 8242, 8244, 8248, 8249, 8251, 8254, 8256, 8258, 8259, 8260, 8262, 8264, 8265, 8266, 8267, 8268, 8269, 8270, 8272, 8273, 8274, 8276, 8277, 8278, 8279, 8281, 8284, 8285, 8286, 8287, 8289, 8290, 8291, 8292, 8293, 8294, 8296, 8300, 8301, 8302, 8303, 8307, 8308, 8311, 8312, 8313, 8314, 8316, 8318, 8319, 8320, 8322, 8324, 8326, 8329, 8330, 8331, 8335, 8336, 8337, 8338, 8339, 8341, 8343, 8345, 8348, 8349, 8350, 8351, 8352, 8353, 8354, 8355, 8356, 8359, 8360, 8364, 8367, 8369, 8370, 8375, 8376, 8380, 8381, 8385, 8388, 8389, 8390, 8391, 8393, 8395, 8396, 8397, 8401, 8402, 8403, 8408, 8409, 8411, 8412, 8414, 8415, 8416, 8418, 8420, 8422, 8423, 8427, 8430, 8431, 8432, 8435, 8437, 8439, 8440, 8441, 8443, 8444, 8445, 8446, 8447, 8448, 8449, 8451, 8453, 8454, 8456, 8459, 8464, 8465, 8466, 8467, 8471, 8472, 8474, 8475, 8477, 8482, 8483, 8484, 8485, 8487, 8488, 8489, 8492, 8493, 8495, 8496, 8498, 8499, 8500, 8502, 8503, 8505, 8509, 8510, 8511, 8512, 8513, 8514, 8515, 8518, 8519, 8520, 8521, 8522, 8524, 8525, 8526, 8527, 8529, 8534, 8535, 8537, 8538, 8539, 8540, 8541, 8542, 8543, 8546, 8547, 8549, 8553, 8555, 8556, 8558, 8559, 8560, 8562, 8563, 8567, 8568, 8570, 8571, 8573, 8574, 8575, 8576, 8578, 8579, 8580, 8581, 8583, 8585, 8586, 8588, 8590, 8592, 8594, 8595, 8596, 8597, 8598, 8599, 8601, 8604, 8605, 8606, 8607, 8608, 8609, 8613, 8616, 8617, 8618, 8620, 8621, 8624, 8625, 8626, 8631, 8633, 8637, 8638, 8639, 8641, 8642, 8643, 8644, 8648, 8650, 8651, 8656, 8658, 8659, 8660, 8661, 8662, 8663, 8666, 8668, 8669, 8670, 8671, 8672, 8675, 8676, 8677, 8678, 8680, 8681, 8683, 8685, 8686, 8688, 8689, 8691, 8692, 8694, 8695, 8696, 8697, 8699, 8706, 8707, 8708, 8713, 8715, 8716, 8717, 8718, 8719, 8721, 8722, 8723, 8727, 8730, 8731, 8732, 8733, 8734, 8735, 8738, 8741, 8743, 8745, 8746, 8748, 8751, 8757, 8758, 8759, 8761, 8762, 8763, 8764, 8765, 8766, 8768, 8770, 8771, 8773, 8774, 8775, 8777, 8778, 8782, 8783, 8785, 8788, 8792, 8793, 8794, 8795, 8799, 8800, 8802, 8807, 8808, 8809, 8810, 8811, 8812, 8814, 8815, 8819, 8820, 8821, 8822, 8823, 8824, 8826, 8827, 8828, 8829, 8830, 8831, 8833, 8834, 8837, 8838, 8839, 8840, 8841, 8842, 8847, 8848, 8849, 8850, 8851, 8853, 8855, 8856, 8862, 8863, 8865, 8867, 8871, 8872, 8873, 8874, 8875, 8876, 8877, 8879, 8887, 8888, 8889, 8890, 8895, 8896, 8897, 8898, 8899, 8902, 8903, 8906, 8907, 8909, 8914, 8915, 8916, 8917, 8918, 8919, 8920, 8921, 8922, 8924, 8925, 8926, 8928, 8929, 8932, 8935, 8936, 8937, 8939, 8940, 8941, 8942, 8946, 8947, 8949, 8964, 8967, 8968, 8969, 8970, 8972, 8974, 8979, 8982, 8983, 8985, 8986, 8988, 8989, 8990, 8993, 8994, 8996, 8998, 8999, 9001, 9002, 9003, 9005, 9009, 9010, 9011, 9012, 9013, 9014, 9015, 9016, 9018, 9021, 9022, 9024, 9025, 9027, 9028, 9029, 9030, 9032, 9053, 9058, 9059, 9060, 9062, 9064, 9065, 9066, 9067, 9069, 9070, 9071, 9072, 9073, 9074, 9075, 9077, 9079, 9081, 9082, 9084, 9085, 9086, 9087, 9088, 9089, 9090, 9094, 9095, 9098, 9100, 9101, 9104, 9105, 9106, 9107, 9111, 9113, 9116, 9117, 9119, 9121, 9122, 9123, 9124, 9125, 9126, 9128, 9129, 9130, 9131, 9132, 9133, 9135, 9136, 9137, 9138, 9139, 9141, 9142, 9143, 9144, 9145, 9147, 9148, 9150, 9152, 9153, 9154, 9157, 9158, 9161, 9162, 9165, 9166, 9167, 9170, 9171, 9172, 9173, 9174, 9175, 9177, 9178, 9179, 9181, 9182, 9183, 9184, 9186, 9187, 9188, 9191, 9192, 9194, 9195, 9199, 9200, 9201, 9203, 9205, 9206, 9209, 9210, 9212, 9213, 9215, 9216, 9218, 9219, 9221, 9222, 9223, 9225, 9226, 9227, 9229, 9230, 9231, 9234, 9235, 9237, 9238, 9239, 9240, 9242, 9244, 9247, 9249, 9251, 9252, 9253, 9254, 9256, 9257, 9261, 9263, 9264, 9265, 9267, 9268, 9270, 9272, 9276, 9277, 9279, 9281, 9282, 9285, 9287, 9288, 9289, 9290, 9294, 9295, 9297, 9301, 9302, 9303, 9307, 9309, 9311, 9312, 9313, 9314, 9315, 9316, 9318, 9319, 9320, 9322, 9324, 9326, 9327, 9328, 9330, 9331, 9332, 9333, 9334, 9335, 9336, 9338, 9339, 9340, 9342, 9345, 9346, 9348, 9353, 9354, 9355, 9358, 9359, 9360, 9361, 9365, 9368, 9369, 9370, 9371, 9372, 9375, 9376, 9377, 9379, 9380, 9381, 9383, 9386, 9387, 9391, 9395, 9397, 9398, 9400, 9401, 9402, 9403, 9404, 9406, 9407, 9408, 9409, 9410, 9411, 9413, 9414, 9416, 9418, 9421, 9423, 9424, 9426, 9427, 9429, 9430, 9431, 9432, 9437, 9439, 9440, 9442, 9445, 9448, 9450, 9452, 9455, 9456, 9457, 9458, 9459, 9460, 9461, 9464, 9465, 9467, 9469, 9471, 9474, 9478, 9479, 9481, 9483, 9484, 9485, 9487, 9488, 9489, 9490, 9492, 9493, 9494, 9495, 9498, 9503, 9505, 9507, 9509, 9513, 9515, 9519, 9521, 9526, 9527, 9529, 9530, 9531, 9532, 9534, 9536, 9537, 9538, 9541, 9542, 9543, 9545, 9546, 9548, 9549, 9551, 9552, 9553, 9554, 9555, 9558, 9560, 9566, 9567, 9569, 9571, 9572, 9575, 9576, 9578, 9580, 9581, 9582, 9586, 9588, 9589, 9592, 9596, 9598, 9600, 9603, 9607, 9608, 9609, 9610, 9611, 9612, 9614, 9615, 9617, 9619, 9620, 9621, 9622, 9624, 9625, 9626, 9627, 9628, 9631, 9634, 9636, 9637, 9638, 9639, 9640, 9643, 9644, 9646, 9647, 9649, 9657, 9658, 9660, 9662, 9663, 9664, 9665, 9666, 9668, 9669, 9671, 9673, 9674, 9675, 9676, 9677, 9678, 9681, 9685, 9688, 9691, 9692, 9693, 9694, 9695, 9696, 9697, 9700, 9701, 9702, 9703, 9706, 9707, 9710, 9711, 9712, 9715, 9717, 9718, 9721, 9722, 9725, 9730, 9732, 9733, 9735, 9738, 9739, 9740, 9741, 9742, 9743, 9744, 9745, 9746, 9750, and 9751

In a fourth aspect, the present invention relates to a polynucleotide encoding an artificial variant comprising a substitution, deletion, and/or insertion of one or more (several) amino acids of any of SEQ ID NOs: 4877-9751 or a homologous sequence thereof; or the mature polypeptide thereof. Preferably, amino acid changes are of a minor nature, that is conservative amino acid substitutions or insertions that do not significantly affect the folding and/or activity of the protein; small deletions, typically of one to about 30 amino acids; small amino- or carboxyl-terminal extensions, such as an amino-terminal methionine residue; a small linker peptide of up to about 20-25 residues; or a small extension that facilitates purification by changing net charge or another function, such as a poly-histidine tract, an antigenic epitope or a binding domain.

Examples of conservative substitutions are within the group of basic amino acids (arginine, lysine and histidine), acidic amino acids (glutamic acid and aspartic acid), polar amino acids (glutamine and asparagine), hydrophobic amino acids (leucine, isoleucine and valine), aromatic amino acids (phenylalanine, tryptophan and tyrosine), and small amino acids (glycine, alanine, serine, threonine and methionine). Amino acid substitutions that do not generally alter specific activity are known in the art and are described, for example, by H. Neurath and R. L. Hill, 1979, In, The Proteins , Academic Press, New York. The most commonly occurring exchanges are Ala/Ser, Val/Ile, Asp/Glu, Thr/Ser, Ala/Gly, Ala/Thr, Ser/Asn, Ala/Val, Ser/Gly, Tyr/Phe, Ala/Pro, Lys/Arg, Asp/Asn, Leu/Ile, Leu/Val, Ala/Glu, and Asp/Gly.

In addition to the 20 standard amino acids, non-standard amino acids (such as 4-hydroxyproline, 6-N-methyl lysine, 2-aminoisobutyric acid, isovaline, and alpha-methyl serine) may be substituted for amino acid residues of a wild-type polypeptide. A limited number of non-conservative amino acids, amino acids that are not encoded by the genetic code, and unnatural amino acids may be substituted for amino acid residues. “Unnatural amino acids” have been modified after protein synthesis, and/or have a chemical structure in their side chain(s) different from that of the standard amino acids. Unnatural amino acids can be chemically synthesized, and preferably, are commercially available, and include pipecolic acid, thiazolidine carboxylic acid, dehydroproline, 3- and 4-methylproline, and 3,3-dimethylproline.

Alternatively, the amino acid changes are of such a nature that the physico-chemical properties of the polypeptides are altered. For example, amino acid changes may improve the thermal stability of the polypeptide, alter the substrate specificity, change the pH optimum, and the like.

Essential amino acids in the parent polypeptide can be identified according to procedures known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (Cunningham and Wells, 1989, Science 244: 1081-1085). In the latter technique, single alanine mutations are introduced at every residue in the molecule, and the resultant mutant molecules are tested for biological activity to identify amino acid residues that are critical to the activity of the molecule. See also, Hilton et al., 1996, J. Biol. Chem. 271: 4699-4708. The active site of the enzyme or other biological interaction can also be determined by physical analysis of structure, as determined by such techniques as nuclear magnetic resonance, crystallography, electron diffraction, or photoaffinity labeling, in conjunction with mutation of putative contact site amino acids. See, for example, de Vos et al., 1992, Science 255: 306-312; Smith et al., 1992, J. Mol. Biol. 224: 899-904; Wlodaver et al., 1992 , FEBS Lett. 309: 59-64. The identities of essential amino acids can also be inferred from analysis of identities with polypeptides that are related to a polypeptide according to the invention.

Single or multiple amino acid substitutions, deletions, and/or insertions can be made and tested using known methods of mutagenesis, recombination, and/or shuffling, followed by a relevant screening procedure, such as those disclosed by Reidhaar-Olson and Sauer, 1988, Science 241: 53-57; Bowie and Sauer, 1989, Proc. Natl. Acad. Sci. USA 86: 2152-2156; WO 95/17413; or WO 95/22625. Other methods that can be used include error-prone PCR, phage display (e.g., Lowman et al., 1991, Biochem. 30: 10832-10837; U.S. Pat. No. 5,223,409; WO 92/06204), and region-directed mutagenesis (Derbyshire et al., 1986, Gene 46: 145; Ner et al., 1988, DNA 7: 127).

Mutagenesis/shuffling methods can be combined with high-throughput, automated screening methods to detect activity of cloned, mutagenized polypeptides expressed by host cells (Ness et al., 1999, Nature Biotechnology 17: 893-896). Mutagenized DNA molecules that encode active polypeptides can be recovered from the host cells and rapidly sequenced using standard methods in the art. These methods allow the rapid determination of the importance of individual amino acid residues in a polypeptide of interest, and can be applied to polypeptides of unknown structure.

The total number of amino acid substitutions, deletions and/or insertions of any of SEQ ID NOs: 4877-9751 is 10, preferably 9, more preferably 8, more preferably 7, more preferably at most 6, more preferably 5, more preferably 4, even more preferably 3, most preferably 2, and even most preferably 1.

Biologically Active Substances

The present invention also relates to isolated biologically active substances, selected from the group consisting of:

(a) a biologically active substance comprising an amino acid sequence having preferably at least 60% identity, more preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, more preferably at least 90% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity;

(b) a biologically active substance encoded by a polynucleotide comprising a nucleotide sequence having preferably at least 60% identity, more preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, more preferably at least 90% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and subsequences thereof encoding fragments having biological activity;

(c) a biologically active substance encoded by a polynucleotide comprising a nucleotide sequence that hybridizes under preferably at least medium stringency conditions, more preferably at least medium-high stringency conditions, or most preferably at least high stringency conditions with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and full-length complementary strands thereof; and

(d) an artificial variant comprising a substitution, deletion, and/or insertion of one or more (several) amino acids of an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity.

In a first aspect, the present invention also relates to an isolated biologically active substance comprising an amino acid sequence having a degree of sequence identity to any of SEQ ID NOs: 4877-9751 of at least 60%, preferably at least 65%, more preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, and even most preferably at least 97%, which have biological activity (hereinafter “homologous polypeptides”). In a preferred aspect, the homologous polypeptides have an amino acid sequence that differs by ten amino acids, preferably by five amino acids, more preferably by four amino acids, even more preferably by three amino acids, most preferably by two amino acids, and even most preferably by one amino acid from the amino acid sequences of SEQ ID NOs: 4877-9751.

In a preferred aspect, the present invention relates to an isolated biological substance comprising an amino acid sequence having a degree of sequence identity of preferably at least 60% identity, more preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, and even most preferably at least 97% with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4944, 4985, 5051, 5058, 5064, 5076, 5079, 5097, 5098, 5099, 5106, 5115, 5117, 5136, 5137, 5197, 5204, 5286, 5459, 5529, 5604, 5723, 5724, 5725, 5726, 5761, 5923, 6056, 6097, 6153, 6192, 6371, 6372, 6376, 6456, 6504, 6531, 6545, 6546, 6547, 6548, 6550, 6945, 6965, 7053, 7116, 7163, 7164, 7165, 7166, 7169, 7170, 7174, 7176, 7177, 7363, 7392, 7397, 7399, 7402, 7420, 7421, 7423, 7425, 7438, 7449, 7453, 7468, 7507, 7562, 7563, 7565, 7573, 7641, 7815, 8003, 8008, 8009, 8010, 8011, 8014, 8015, 8018, 8020, 8021, 8022, 8046, 8099, 8100, 8103, 8140, 8323, 8710, 8711, 8966, 9034, 9035, 9036, 9049, 9051, 9054, 9056, 9057, 9224, 9516, 9525, 9547, 9562, 9564, 4900, 4925, 4930, 4952, 4957, 4966, 4973, 4978, 5000, 5010, 5044, 5046, 5047, 5049, 5052, 5053, 5054, 5055, 5056, 5057, 5060, 5061, 5062, 5067, 5069, 5070, 5071, 5073, 5074, 5078, 5080, 5081, 5082, 5083, 5084, 5085, 5086, 5087, 5088, 5089, 5090, 5091, 5092, 5093, 5094, 5095, 5096, 5100, 5101, 5102, 5103, 5104, 5105, 5112, 5116, 5118, 5119, 5120, 5121, 5122, 5123, 5124, 5125, 5126, 5127, 5128, 5129, 5130, 5131, 5132, 5133, 5134, 5135, 5138, 5139, 5140, 5141, 5151, 5162, 5173, 5180, 5181, 5183, 5192, 5198, 5225, 5229, 5235, 5236, 5238, 5242, 5249, 5256, 5290, 5297, 5307, 5320, 5344, 5347, 5353, 5354, 5362, 5363, 5366, 5373, 5391, 5396, 5398, 5399, 5412, 5416, 5428, 5445, 5450, 5456, 5467, 5482, 5493, 5496, 5502, 5503, 5506, 5541, 5547, 5563, 5566, 5574, 5577, 5585, 5594, 5601, 5609, 5623, 5626, 5639, 5648, 5649, 5652, 5664, 5666, 5702, 5704, 5706, 5708, 5717, 5722, 5730, 5732, 5760, 5762, 5776, 5784, 5819, 5832, 5852, 5857, 5866, 5869, 5890, 5893, 5897, 5907, 5909, 5912, 5933, 5953, 5955, 5963, 5966, 5973, 5983, 5986, 5987, 5993, 6003, 6005, 6023, 6026, 6028, 6029, 6033, 6035, 6039, 6045, 6050, 6051, 6052, 6055, 6058, 6059, 6068, 6069, 6074, 6083, 6090, 6095, 6112, 6119, 6137, 6138, 6140, 6141, 6167, 6177, 6188, 6189, 6190, 6191, 6193, 6195, 6209, 6220, 6230, 6245, 6248, 6249, 6276, 6286, 6294, 6296, 6299, 6307, 6308, 6315, 6317, 6323, 6330, 6341, 6345, 6384, 6402, 6414, 6431, 6440, 6445, 6464, 6494, 6506, 6509, 6510, 6511, 6513, 6514, 6515, 6516, 6517, 6518, 6519, 6520, 6521, 6522, 6524, 6525, 6526, 6527, 6528, 6529, 6530, 6532, 6533, 6534, 6535, 6536, 6537, 6538, 6539, 6540, 6541, 6542, 6543, 6544, 6552, 6557, 6559, 6563, 6567, 6569, 6572, 6578, 6579, 6603, 6607, 6609, 6611, 6626, 6650, 6654, 6658, 6661, 6667, 6670, 6673, 6691, 6706, 6711, 6713, 6726, 6728, 6741, 6758, 6762, 6819, 6821, 6877, 6882, 6897, 6913, 6919, 6923, 6940, 6942, 6947, 6951, 6958, 6969, 6981, 6984, 6994, 6995, 6996, 6999, 7006, 7014, 7022, 7023, 7041, 7046, 7069, 7071, 7073, 7079, 7080, 7086, 7088, 7091, 7096, 7100, 7105, 7111, 7115, 7129, 7130, 7133, 7138, 7148, 7152, 7157, 7161, 7167, 7171, 7172, 7173, 7175, 7178, 7179, 7180, 7199, 7200, 7202, 7211, 7212, 7216, 7222, 7226, 7229, 7237, 7239, 7256, 7263, 7275, 7278, 7279, 7283, 7285, 7286, 7287, 7289, 7290, 7299, 7300, 7305, 7310, 7314, 7321, 7324, 7332, 7339, 7342, 7343, 7344, 7351, 7358, 7366, 7373, 7375, 7379, 7380, 7381, 7382, 7383, 7384, 7385, 7386, 7387, 7388, 7389, 7390, 7391, 7393, 7394, 7395, 7396, 7400, 7401, 7403, 7404, 7405, 7406, 7407, 7408, 7409, 7410, 7411, 7412, 7413, 7414, 7415, 7416, 7417, 7418, 7419, 7422, 7424, 7426, 7427, 7428, 7429, 7430, 7431, 7432, 7433, 7434, 7435, 7436, 7437, 7439, 7440, 7442, 7443, 7444, 7445, 7446, 7447, 7448, 7450, 7451, 7452, 7454, 7455, 7456, 7457, 7458, 7459, 7460, 7461, 7462, 7463, 7464, 7465, 7466, 7467, 7469, 7470, 7471, 7472, 7473, 7474, 7475, 7476, 7477, 7478, 7479, 7480, 7481, 7482, 7483, 7484, 7485, 7486, 7487, 7488, 7489, 7490, 7491, 7492, 7493, 7494, 7495, 7496, 7497, 7498, 7499, 7500, 7501, 7502, 7503, 7504, 7505, 7506, 7508, 7509, 7510, 7511, 7513, 7514, 7515, 7516, 7517, 7518, 7519, 7520, 7521, 7522, 7523, 7524, 7525, 7526, 7527, 7528, 7529, 7530, 7531, 7532, 7533, 7534, 7536, 7539, 7540, 7542, 7544, 7545, 7546, 7547, 7548, 7549, 7550, 7551, 7552, 7553, 7554, 7555, 7556, 7559, 7560, 7561, 7564, 7566, 7567, 7568, 7571, 7572, 7581, 7583, 7592, 7595, 7598, 7605, 7608, 7626, 7637, 7646, 7670, 7681, 7688, 7709, 7710, 7716, 7725, 7741, 7742, 7749, 7753, 7758, 7766, 7773, 7777, 7779, 7792, 7822, 7832, 7835, 7844, 7847, 7848, 7874, 7879, 7893, 7894, 7903, 7921, 7929, 7939, 7944, 7957, 7962, 7968, 7987, 7998, 8012, 8016, 8017, 8019, 8023, 8024, 8025, 8037, 8090, 8097, 8101, 8102, 8104, 8106, 8119, 8123, 8134, 8136, 8139, 8162, 8166, 8174, 8178, 8185, 8186, 8196, 8198, 8199, 8208, 8230, 8237, 8246, 8299, 8304, 8306, 8309, 8317, 8321, 8332, 8333, 8346, 8361, 8368, 8371, 8374, 8378, 8379, 8383, 8384, 8394, 8424, 8433, 8452, 8462, 8468, 8473, 8476, 8478, 8481, 8486, 8517, 8528, 8530, 8545, 8548, 8557, 8565, 8569, 8582, 8584, 8591, 8602, 8610, 8611, 8612, 8619, 8628, 8640, 8645, 8655, 8665, 8667, 8673, 8674, 8693, 8700, 8714, 8747, 8754, 8756, 8760, 8779, 8786, 8790, 8791, 8797, 8801, 8806, 8813, 8844, 8886, 8892, 8893, 8908, 8912, 8923, 8930, 8931, 8934, 8943, 8951, 8952, 8953, 8956, 8957, 8960, 8961, 8965, 8981, 8987, 8992, 9019, 9020, 9033, 9037, 9038, 9039, 9040, 9041, 9042, 9043, 9044, 9045, 9046, 9047, 9048, 9050, 9076, 9096, 9110, 9114, 9118, 9160, 9163, 9180, 9198, 9208, 9211, 9228, 9245, 9273, 9284, 9292, 9296, 9298, 9304, 9310, 9321, 9323, 9325, 9337, 9344, 9347, 9349, 9351, 9357, 9362, 9363, 9374, 9384, 9385, 9388, 9393, 9419, 9433, 9434, 9435, 9436, 9444, 9446, 9453, 9475, 9480, 9482, 9497, 9506, 9508, 9518, 9520, 9522, 9523, 9524, 9533, 9544, 9557, 9568, 9579, 9583, 9593, 9597, 9629, 9642, 9661, 9667, 9672, 9679, 9687, 9689, 9698, 9705, 9708, 9713, 9723, 9724, 9729, 9734, 9737, and 9747; preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, and even most preferably at least 97% with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4991, 5068, 5308, 5463, 5919, 6549, 6648, 6680, 6948, 7298, 7541, 7896, 7911, 8497, 8702, 8729, 8737, 9052, 9690, and 9709; preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, and even most preferably at least 97% with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4986, 5041, 5043, 5418, 5427, 5500, 5515, 5696, 5713, 5785, 5939, 6106, 6109, 6171, 6260, 6503, 6677, 6724, 7054, 7260, 7295, 7316, 7341, 7512, 7538, 7591, 7628, 7735, 7912, 8050, 8076, 8206, 8207, 8240, 8327, 8406, 8428, 8860, 8955, 9061, 9099, 9115, 9262, 9591, 9641, and 9720; preferably at least 75% identity, more preferably at least 80%, more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%, and even most preferably at least 97% with an amino acid sequence selected from the group consisting of SEQ ID NOs: 5038, 5059, 5240, 5403, 5444, 5508, 5559, 5562, 5642, 5651, 5846, 5885, 5921, 5942, 6015, 6067, 6071, 6164, 6215, 6293, 6373, 6390, 6446, 6624, 6704, 6717, 6749, 6759, 6808, 6847, 6848, 6852, 6854, 7292, 7297, 7308, 7317, 7537, 7543, 7557, 7603, 7651, 7858, 7949, 7954, 7996, 8074, 8200, 8221, 8263, 8288, 8614, 8684, 8720, 8728, 8740, 8749, 8787, 8864, 8958, 9055, 9176, 9196, 9283, 9308, 9352, 9491, 9512, 9602, 9653, 9684, 9719, and 9731; preferably at least 80% identity, more preferably at least 85% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4891, 4956, 5042, 5072, 5169, 5190, 5195, 5217, 5241, 5266, 5305, 5369, 5374, 5377, 5409, 5435, 5512, 5524, 5538, 5595, 5613, 5647, 5657, 5665, 5667, 5735, 5743, 5830, 5878, 5900, 5903, 5977, 5988, 6000, 6060, 6066, 6070, 6073, 6075, 6105, 6120, 6139, 6152, 6174, 6291, 6335, 6375, 6437, 6466, 6492, 6505, 6507, 6523, 6553, 6592, 6651, 6694, 6730, 6732, 6774, 6843, 6929, 6943, 6964, 7093, 7132, 7144, 7224, 7349, 7374, 7398, 7570, 7578, 7632, 7635, 7643, 7680, 7682, 7685, 7700, 7713, 7727, 7800, 7843, 7864, 7918, 7947, 7982, 7989, 7991, 7999, 8055, 8057, 8085, 8095, 8170, 8182, 8191, 8210, 8255, 8261, 8328, 8365, 8399, 8410, 8479, 8551, 8561, 8577, 8589, 8649, 8679, 8742, 8744, 8784, 8789, 8796, 8818, 8832, 8835, 8845, 8854, 8858, 8868, 8878, 8900, 8950, 9007, 9102, 9108, 9151, 9169, 9207, 9241, 9246, 9248, 9250, 9299, 9341, 9343, 9412, 9443, 9470, 9476, 9511, 9528, 9559, 9565, 9577, 9584, 9594, 9595, 9682, and 9714; preferably at least 85% identity, more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4913, 4948, 4968, 5025, 5034, 5066, 5109, 5110, 5146, 5160, 5199, 5200, 5203, 5211, 5221, 5223, 5226, 5252, 5269, 5273, 5293, 5309, 5318, 5342, 5352, 5393, 5394, 5421, 5430, 5431, 5434, 5447, 5458, 5492, 5507, 5511, 5514, 5525, 5526, 5530, 5544, 5570, 5616, 5617, 5621, 5640, 5661, 5663, 5691, 5716, 5738, 5751, 5753, 5757, 5759, 5786, 5802, 5820, 5826, 5855, 5858, 5871, 5872, 5902, 5905, 5908, 5915, 5936, 5937, 5938, 5947, 6006, 6011, 6012, 6025, 6030, 6032, 6034, 6057, 6080, 6084, 6093, 6096, 6110, 6131, 6178, 6183, 6199, 6232, 6236, 6243, 6257, 6258, 6313, 6331, 6354, 6360, 6362, 6386, 6417, 6421, 6435, 6455, 6468, 6472, 6475, 6476, 6478, 6495, 6555, 6566, 6568, 6604, 6608, 6641, 6662, 6663, 6665, 6692, 6699, 6736, 6752, 6763, 6807, 6809, 6810, 6840, 6842, 6844, 6853, 6855, 6857, 6866, 6906, 6908, 6915, 6922, 6953, 6962, 6977, 6989, 7004, 7025, 7032, 7042, 7045, 7058, 7072, 7085, 7134, 7139, 7145, 7182, 7188, 7194, 7208, 7227, 7249, 7261, 7272, 7293, 7309, 7320, 7331, 7333, 7334, 7354, 7367, 7371, 7558, 7597, 7602, 7623, 7664, 7677, 7679, 7687, 7732, 7734, 7739, 7744, 7752, 7765, 7769, 7790, 7801, 7818, 7823, 7833, 7837, 7860, 7867, 7877, 7882, 7915, 7931, 7932, 7946, 7948, 7959, 7967, 7973, 7975, 7977, 7978, 7986, 8071, 8072, 8096, 8107, 8129, 8146, 8148, 8153, 8164, 8165, 8169, 8203, 8211, 8216, 8218, 8234, 8245, 8253, 8275, 8297, 8315, 8334, 8340, 8357, 8362, 8372, 8386, 8398, 8425, 8438, 8455, 8460, 8470, 8480, 8490, 8506, 8531, 8533, 8572, 8593, 8600, 8615, 8623, 8627, 8630, 8634, 8664, 8687, 8703, 8704, 8705, 8726, 8739, 8750, 8752, 8753, 8769, 8780, 8781, 8805, 8816, 8825, 8846, 8869, 8870, 8883, 8913, 8938, 8944, 8945, 8948, 8959, 8962, 8973, 8976, 8980, 8991, 9000, 9006, 9017, 9068, 9093, 9097, 9103, 9109, 9146, 9155, 9159, 9255, 9258, 9260, 9266, 9269, 9271, 9278, 9293, 9350, 9373, 9394, 9415, 9420, 9449, 9466, 9472, 9477, 9486, 9500, 9504, 9514, 9517, 9535, 9573, 9590, 9599, 9601, 9623, 9645, 9648, 9652, 9654, 9659, 9726, 9728, 9736, and 9748; preferably at least 90% identity, more preferably at least 95% identity, and most preferably at least 97% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4890, 4895, 4921, 4923, 4927, 4933, 4934, 4937, 4939, 4943, 4946, 4950, 4951, 4955, 4958, 4967, 4970, 4981, 4982, 4987, 4989, 4999, 5017, 5022, 5029, 5048, 5111, 5113, 5145, 5152, 5157, 5165, 5171, 5178, 5179, 5182, 5186, 5202, 5213, 5214, 5215, 5218, 5227, 5230, 5233, 5245, 5268, 5272, 5274, 5279, 5281, 5283, 5298, 5303, 5315, 5324, 5326, 5328, 5329, 5330, 5336, 5337, 5338, 5339, 5346, 5357, 5360, 5376, 5380, 5387, 5400, 5401, 5414, 5417, 5419, 5422, 5424, 5436, 5442, 5446, 5448, 5455, 5457, 5466, 5475, 5499, 5501, 5510, 5537, 5539, 5542, 5550, 5552, 5557, 5565, 5571, 5573, 5586, 5589, 5612, 5615, 5620, 5622, 5628, 5632, 5634, 5638, 5645, 5646, 5660, 5670, 5677, 5678, 5681, 5688, 5705, 5707, 5710, 5739, 5748, 5754, 5756, 5763, 5764, 5765, 5766, 5768, 5779, 5782, 5783, 5787, 5791, 5792, 5793, 5799, 5808, 5813, 5821, 5827, 5828, 5834, 5835, 5837, 5842, 5850, 5856, 5859, 5864, 5870, 5884, 5906, 5914, 5917, 5945, 5946, 5958, 5964, 5965, 5985, 5989, 5994, 5998, 6007, 6009, 6016, 6017, 6019, 6022, 6031, 6048, 6062, 6064, 6079, 6081, 6086, 6089, 6098, 6103, 6107, 6113, 6121, 6122, 6125, 6156, 6163, 6165, 6181, 6205, 6212, 6223, 6235, 6238, 6239, 6242, 6244, 6250, 6251, 6255, 6261, 6262, 6265, 6267, 6269, 6281, 6283, 6284, 6290, 6292, 6300, 6301, 6318, 6324, 6327, 6332, 6333, 6338, 6339, 6344, 6349, 6353, 6361, 6363, 6374, 6377, 6383, 6387, 6396, 6397, 6399, 6400, 6413, 6423, 6449, 6450, 6462, 6465, 6467, 6471, 6484, 6493, 6501, 6512, 6565, 6573, 6574, 6575, 6576, 6580, 6583, 6585, 6589, 6594, 6598, 6600, 6605, 6619, 6629, 6635, 6636, 6637, 6638, 6642, 6647, 6664, 6669, 6686, 6688, 6695, 6696, 6697, 6698, 6700, 6710, 6712, 6729, 6735, 6740, 6742, 6743, 6744, 6745, 6768, 6779, 6780, 6781, 6782, 6786, 6792, 6793, 6795, 6800, 6801, 6802, 6804, 6823, 6827, 6829, 6833, 6834, 6836, 6838, 6861, 6862, 6863, 6867, 6868, 6871, 6872, 6887, 6903, 6918, 6920, 6927, 6933, 6939, 6944, 6949, 6960, 6966, 6973, 6976, 6979, 7000, 7002, 7015, 7017, 7019, 7036, 7040, 7051, 7055, 7056, 7063, 7075, 7077, 7087, 7090, 7092, 7097, 7102, 7103, 7104, 7109, 7112, 7117, 7118, 7122, 7123, 7125, 7126, 7127, 7158, 7162, 7181, 7186, 7196, 7201, 7203, 7206, 7209, 7210, 7219, 7221, 7230, 7231, 7232, 7233, 7235, 7236, 7244, 7248, 7251, 7252, 7257, 7268, 7271, 7274, 7281, 7304, 7326, 7335, 7352, 7356, 7357, 7360, 7364, 7577, 7579, 7601, 7607, 7615, 7624, 7625, 7639, 7650, 7658, 7672, 7696, 7712, 7718, 7728, 7729, 7730, 7745, 7747, 7748, 7751, 7754, 7756, 7774, 7780, 7786, 7808, 7810, 7826, 7831, 7840, 7849, 7854, 7871, 7872, 7886, 7892, 7914, 7925, 7928, 7933, 7934, 7937, 7941, 7945, 7969, 7970, 7980, 8032, 8039, 8040, 8060, 8063, 8065, 8066, 8075, 8077, 8078, 8086, 8122, 8133, 8138, 8149, 8157, 8158, 8159, 8177, 8180, 8184, 8188, 8195, 8205, 8209, 8220, 8223, 8235, 8241, 8243, 8247, 8250, 8252, 8257, 8271, 8280, 8282, 8283, 8295, 8298, 8305, 8310, 8325, 8342, 8344, 8347, 8358, 8363, 8366, 8373, 8377, 8382, 8387, 8392, 8400, 8404, 8405, 8407, 8413, 8417, 8419, 8421, 8426, 8429, 8434, 8436, 8442, 8450, 8457, 8458, 8461, 8463, 8469, 8491, 8494, 8501, 8504, 8507, 8508, 8516, 8523, 8532, 8536, 8544, 8550, 8552, 8554, 8564, 8566, 8587, 8603, 8622, 8629, 8632, 8635, 8636, 8646, 8647, 8652, 8653, 8654, 8657, 8682, 8690, 8698, 8701, 8709, 8712, 8724, 8725, 8736, 8755, 8767, 8772, 8776, 8798, 8803, 8804, 8817, 8836, 8843, 8852, 8857, 8859, 8861, 8866, 8880, 8881, 8882, 8884, 8885, 8891, 8894, 8901, 8904, 8905, 8910, 8911, 8927, 8933, 8954, 8963, 8971, 8975, 8977, 8984, 8995, 8997, 9004, 9008, 9023, 9026, 9031, 9063, 9078, 9080, 9083, 9091, 9092, 9112, 9120, 9127, 9134, 9140, 9149, 9156, 9164, 9168, 9185, 9189, 9190, 9193, 9197, 9202, 9204, 9214, 9217, 9220, 9232, 9233, 9236, 9243, 9259, 9274, 9275, 9280, 9286, 9291, 9300, 9305, 9306, 9317, 9329, 9356, 9364, 9366, 9367, 9378, 9382, 9389, 9390, 9392, 9396, 9399, 9405, 9417, 9422, 9425, 9428, 9438, 9441, 9451, 9454, 9462, 9463, 9468, 9473, 9496, 9499, 9501, 9502, 9510, 9539, 9540, 9550, 9556, 9561, 9570, 9574, 9585, 9587, 9604, 9605, 9606, 9613, 9616, 9618, 9630, 9632, 9633, 9635, 9650, 9651, 9655, 9656, 9670, 9680, 9683, 9686, 9699, 9704, 9716, 9727, and 9749; or preferably at least 95% identity and more preferably at least 97% identity with an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877, 4878, 4879, 4880, 4881, 4882, 4883, 4884, 4885, 4886, 4887, 4888, 4889, 4892, 4893, 4894, 4896, 4897, 4898, 4899, 4901, 4902, 4903, 4904, 4905, 4906, 4907, 4908, 4909, 4910, 4911, 4912, 4914, 4915, 4916, 4917, 4918, 4919, 4920, 4922, 4924, 4926, 4928, 4929, 4931, 4932, 4935, 4936, 4938, 4940, 4941, 4942, 4945, 4947, 4949, 4953, 4954, 4959, 4960, 4961, 4962, 4963, 4964, 4965, 4969, 4971, 4972, 4974, 4975, 4976, 4977, 4979, 4980, 4983, 4984, 4988, 4990, 4992, 4993, 4994, 4995, 4996, 4997, 4998, 5001, 5002, 5003, 5004, 5005, 5006, 5007, 5008, 5009, 5011, 5012, 5013, 5014, 5015, 5016, 5018, 5019, 5020, 5021, 5023, 5024, 5026, 5027, 5028, 5030, 5031, 5032, 5033, 5035, 5036, 5037, 5039, 5045, 5050, 5063, 5065, 5075, 5077, 5107, 5108, 5114, 5142, 5143, 5144, 5147, 5148, 5149, 5150, 5153, 5154, 5155, 5156, 5158, 5159, 5161, 5163, 5164, 5166, 5167, 5168, 5170, 5172, 5174, 5175, 5176, 5177, 5184, 5185, 5187, 5188, 5189, 5191, 5193, 5194, 5196, 5201, 5205, 5206, 5207, 5208, 5209, 5210, 5212, 5216, 5219, 5220, 5222, 5224, 5228, 5231, 5232, 5234, 5237, 5239, 5243, 5244, 5246, 5247, 5248, 5250, 5251, 5254, 5255, 5257, 5258, 5259, 5260, 5261, 5262, 5263, 5264, 5265, 5267, 5270, 5271, 5275, 5276, 5277, 5278, 5280, 5282, 5284, 5285, 5287, 5288, 5289, 5291, 5292, 5294, 5295, 5296, 5299, 5300, 5301, 5302, 5304, 5306, 5310, 5311, 5312, 5313, 5314, 5316, 5317, 5319, 5321, 5322, 5323, 5325, 5327, 5331, 5332, 5333, 5334, 5335, 5340, 5341, 5343, 5345, 5348, 5349, 5350, 5351, 5355, 5356, 5358, 5359, 5361, 5364, 5365, 5367, 5368, 5370, 5371, 5372, 5375, 5379, 5381, 5382, 5383, 5384, 5385, 5386, 5388, 5389, 5390, 5392, 5395, 5397, 5402, 5404, 5405, 5406, 5407, 5408, 5410, 5411, 5413, 5415, 5420, 5423, 5425, 5426, 5429, 5432, 5433, 5437, 5438, 5439, 5440, 5441, 5443, 5449, 5451, 5452, 5453, 5454, 5460, 5461, 5462, 5464, 5465, 5468, 5469, 5470, 5471, 5472, 5473, 5474, 5476, 5477, 5478, 5479, 5480, 5481, 5483, 5484, 5485, 5486, 5487, 5488, 5489, 5490, 5491, 5494, 5495, 5497, 5498, 5504, 5505, 5509, 5513, 5516, 5517, 5518, 5519, 5520, 5521, 5522, 5523, 5527, 5528, 5531, 5532, 5533, 5534, 5535, 5536, 5540, 5543, 5545, 5546, 5548, 5549, 5551, 5553, 5554, 5555, 5556, 5558, 5560, 5561, 5564, 5567, 5568, 5569, 5572, 5575, 5576, 5578, 5579, 5580, 5581, 5582, 5583, 5584, 5587, 5588, 5590, 5591, 5592, 5593, 5596, 5597, 5598, 5599, 5600, 5602, 5603, 5605, 5606, 5607, 5608, 5610, 5611, 5614, 5618, 5619, 5624, 5625, 5627, 5629, 5630, 5631, 5633, 5635, 5636, 5637, 5641, 5643, 5644, 5650, 5653, 5654, 5655, 5656, 5658, 5659, 5662, 5668, 5669, 5671, 5672, 5673, 5674, 5675, 5676, 5679, 5680, 5682, 5683, 5684, 5685, 5686, 5687, 5689, 5690, 5692, 5693, 5694, 5695, 5697, 5698, 5699, 5700, 5701, 5703, 5709, 5711, 5712, 5714, 5715, 5718, 5719, 5720, 5721, 5728, 5729, 5731, 5733, 5734, 5736, 5737, 5740, 5741, 5742, 5744, 5745, 5746, 5747, 5749, 5750, 5752, 5755, 5758, 5767, 5769, 5770, 5771, 5772, 5773, 5774, 5775, 5777, 5778, 5780, 5781, 5788, 5789, 5790, 5794, 5795, 5796, 5797, 5798, 5800, 5801, 5803, 5804, 5805, 5806, 5807, 5809, 5810, 5811, 5812, 5814, 5815, 5816, 5817, 5818, 5822, 5823, 5824, 5825, 5829, 5831, 5833, 5836, 5838, 5839, 5840, 5841, 5843, 5844, 5845, 5847, 5848, 5849, 5851, 5853, 5854, 5860, 5861, 5862, 5863, 5865, 5867, 5868, 5873, 5874, 5875, 5876, 5877, 5879, 5880, 5881, 5882, 5883, 5886, 5887, 5888, 5889, 5891, 5892, 5894, 5895, 5896, 5899, 5901, 5904, 5910, 5911, 5913, 5916, 5918, 5920, 5922, 5924, 5925, 5926, 5927, 5928, 5929, 5930, 5931, 5932, 5934, 5935, 5940, 5941, 5943, 5944, 5948, 5949, 5950, 5951, 5952, 5954, 5956, 5957, 5959, 5960, 5961, 5962, 5967, 5968, 5969, 5970, 5971, 5972, 5974, 5975, 5976, 5978, 5979, 5980, 5981, 5982, 5984, 5990, 5991, 5992, 5995, 5996, 5997, 5999, 6001, 6002, 6004, 6008, 6010, 6013, 6014, 6018, 6020, 6021, 6024, 6027, 6036, 6037, 6038, 6040, 6041, 6042, 6043, 6044, 6046, 6047, 6049, 6053, 6054, 6061, 6063, 6065, 6072, 6076, 6077, 6078, 6082, 6085, 6087, 6088, 6091, 6092, 6094, 6099, 6100, 6101, 6102, 6104, 6108, 6111, 6114, 6115, 6116, 6117, 6118, 6123, 6124, 6126, 6127, 6128, 6129, 6130, 6132, 6133, 6134, 6135, 6136, 6142, 6143, 6144, 6145, 6146, 6147, 6148, 6149, 6150, 6151, 6154, 6155, 6157, 6158, 6159, 6160, 6161, 6162, 6166, 6168, 6169, 6170, 6172, 6173, 6175, 6176, 6179, 6180, 6182, 6184, 6185, 6186, 6187, 6194, 6196, 6197, 6198, 6200, 6201, 6202, 6203, 6204, 6206, 6207, 6208, 6210, 6211, 6213, 6214, 6216, 6217, 6218, 6219, 6221, 6222, 6224, 6225, 6226, 6227, 6228, 6229, 6231, 6233, 6234, 6237, 6240, 6246, 6247, 6252, 6253, 6254, 6256, 6259, 6263, 6264, 6266, 6268, 6270, 6271, 6272, 6273, 6274, 6275, 6277, 6278, 6279, 6280, 6282, 6285, 6287, 6288, 6289, 6295, 6297, 6298, 6302, 6303, 6304, 6305, 6306, 6309, 6310, 6311, 6312, 6314, 6316, 6319, 6320, 6321, 6322, 6325, 6326, 6328, 6329, 6336, 6337, 6340, 6342, 6343, 6346, 6347, 6348, 6350, 6351, 6352, 6355, 6356, 6357, 6358, 6359, 6364, 6365, 6366, 6367, 6368, 6369, 6378, 6379, 6380, 6381, 6382, 6385, 6388, 6389, 6391, 6392, 6393, 6394, 6395, 6398, 6401, 6403, 6404, 6405, 6406, 6407, 6408, 6409, 6410, 6411, 6412, 6415, 6416, 6418, 6419, 6420, 6422, 6424, 6425, 6426, 6427, 6428, 6429, 6430, 6432, 6433, 6434, 6436, 6438, 6439, 6441, 6442, 6443, 6444, 6447, 6448, 6451, 6452, 6453, 6454, 6457, 6458, 6459, 6460, 6461, 6463, 6469, 6470, 6473, 6474, 6477, 6479, 6480, 6481, 6482, 6483, 6485, 6486, 6487, 6488, 6489, 6490, 6491, 6496, 6497, 6498, 6499, 6500, 6502, 6508, 6556, 6558, 6560, 6561, 6562, 6564, 6570, 6571, 6577, 6581, 6582, 6584, 6586, 6587, 6588, 6590, 6591, 6593, 6595, 6596, 6597, 6599, 6601, 6602, 6606, 6610, 6612, 6613, 6614, 6615, 6616, 6617, 6618, 6620, 6621, 6622, 6623, 6625, 6627, 6628, 6630, 6631, 6632, 6633, 6634, 6639, 6640, 6643, 6644, 6645, 6646, 6649, 6652, 6653, 6655, 6656, 6657, 6659, 6660, 6666, 6668, 6671, 6672, 6674, 6675, 6676, 6678, 6679, 6681, 6682, 6683, 6684, 6685, 6687, 6689, 6690, 6693, 6701, 6702, 6703, 6705, 6707, 6708, 6709, 6714, 6715, 6716, 6718, 6719, 6720, 6721, 6722, 6723, 6725, 6727, 6731, 6733, 6734, 6737, 6738, 6739, 6746, 6747, 6748, 6750, 6751, 6753, 6754, 6755, 6756, 6757, 6760, 6761, 6764, 6765, 6766, 6767, 6769, 6770, 6771, 6772, 6773, 6775, 6776, 6777, 6778, 6783, 6784, 6785, 6787, 6788, 6789, 6790, 6791, 6794, 6796, 6797, 6798, 6799, 6803, 6805, 6806, 6811, 6812, 6813, 6814, 6815, 6816, 6817, 6818, 6820, 6822, 6824, 6825, 6826, 6828, 6830, 6831, 6832, 6835, 6837, 6839, 6841, 6845, 6846, 6849, 6850, 6851, 6856, 6858, 6859, 6860, 6864, 6865, 6869, 6870, 6873, 6874, 6875, 6876, 6878, 6879, 6880, 6881, 6883, 6884, 6885, 6886, 6888, 6889, 6890, 6891, 6892, 6893, 6894, 6895, 6896, 6898, 6899, 6900, 6901, 6902, 6904, 6905, 6907, 6909, 6910, 6911, 6912, 6914, 6916, 6917, 6921, 6924, 6925, 6926, 6928, 6930, 6931, 6932, 6934, 6935, 6936, 6937, 6938, 6941, 6950, 6952, 6954, 6955, 6956, 6957, 6959, 6961, 6967, 6968, 6970, 6971, 6972, 6974, 6975, 6978, 6980, 6982, 6983, 6985, 6986, 6987, 6988, 6990, 6991, 6992, 6993, 6997, 6998, 7001, 7003, 7005, 7007, 7008, 7009, 7010, 7011, 7012, 7013, 7016, 7018, 7020, 7021, 7024, 7026, 7027, 7028, 7029, 7030, 7031, 7033, 7034, 7035, 7037, 7038, 7039, 7043, 7044, 7047, 7048, 7049, 7050, 7052, 7057, 7059, 7060, 7061, 7062, 7064, 7065, 7066, 7067, 7068, 7070, 7074, 7076, 7078, 7081, 7082, 7083, 7084, 7089, 7094, 7095, 7098, 7099, 7101, 7106, 7107, 7108, 7110, 7113, 7114, 7119, 7120, 7121, 7124, 7128, 7131, 7135, 7136, 7137, 7140, 7141, 7142, 7143, 7146, 7147, 7149, 7150, 7151, 7153, 7154, 7155, 7156, 7159, 7160, 7183, 7184, 7185, 7187, 7189, 7190, 7191, 7192, 7193, 7197, 7198, 7204, 7205, 7207, 7213, 7214, 7215, 7217, 7218, 7220, 7223, 7225, 7228, 7234, 7238, 7240, 7241, 7242, 7243, 7245, 7246, 7247, 7250, 7253, 7254, 7255, 7258, 7259, 7262, 7264, 7265, 7266, 7267, 7269, 7270, 7273, 7276, 7277, 7280, 7282, 7284, 7288, 7291, 7294, 7296, 7301, 7302, 7303, 7306, 7307, 7311, 7312, 7313, 7315, 7318, 7319, 7322, 7323, 7325, 7327, 7328, 7329, 7330, 7336, 7337, 7338, 7340, 7345, 7346, 7347, 7348, 7350, 7355, 7359, 7361, 7362, 7365, 7368, 7369, 7370, 7372, 7376, 7377, 7378, 7574, 7575, 7576, 7580, 7582, 7584, 7585, 7586, 7587, 7588, 7589, 7590, 7593, 7594, 7596, 7599, 7600, 7604, 7606, 7609, 7610, 7611, 7612, 7613, 7614, 7616, 7617, 7618, 7619, 7620, 7621, 7622, 7627, 7629, 7630, 7631, 7633, 7634, 7636, 7638, 7640, 7642, 7644, 7645, 7647, 7648, 7649, 7652, 7653, 7654, 7655, 7656, 7657, 7659, 7660, 7661, 7662, 7663, 7665, 7666, 7667, 7668, 7669, 7671, 7673, 7674, 7675, 7676, 7678, 7683, 7684, 7686, 7689, 7690, 7691, 7692, 7693, 7694, 7695, 7697, 7698, 7699, 7701, 7702, 7703, 7704, 7705, 7706, 7707, 7708, 7711, 7714, 7715, 7717, 7719, 7720, 7721, 7722, 7723, 7724, 7726, 7731, 7733, 7736, 7737, 7738, 7740, 7743, 7746, 7750, 7755, 7757, 7759, 7760, 7761, 7762, 7763, 7764, 7767, 7768, 7770, 7771, 7772, 7775, 7776, 7778, 7781, 7782, 7783, 7784, 7785, 7787, 7788, 7789, 7791, 7793, 7794, 7795, 7796, 7797, 7798, 7799, 7802, 7803, 7804, 7805, 7806, 7807, 7809, 7811, 7812, 7813, 7814, 7816, 7817, 7819, 7820, 7821, 7824, 7825, 7827, 7828, 7829, 7830, 7834, 7836, 7838, 7839, 7841, 7842, 7845, 7846, 7850, 7851, 7852, 7853, 7855, 7856, 7857, 7859, 7861, 7862, 7863, 7865, 7866, 7868, 7869, 7870, 7873, 7875, 7876, 7878, 7880, 7881, 7883, 7884, 7885, 7887, 7888, 7889, 7891, 7895, 7897, 7898, 7899, 7900, 7901, 7902, 7904, 7905, 7906, 7907, 7908, 7909, 7910, 7913, 7916, 7917, 7919, 7920, 7922, 7923, 7924, 7926, 7927, 7930, 7935, 7936, 7938, 7940, 7942, 7943, 7950, 7951, 7952, 7953, 7955, 7956, 7958, 7960, 7961, 7963, 7964, 7965, 7966, 7971, 7972, 7974, 7976, 7979, 7981, 7983, 7984, 7985, 7988, 7990, 7992, 7993, 7994, 7995, 7997, 8000, 8001, 8002, 8004, 8005, 8006, 8007, 8026, 8027, 8028, 8029, 8030, 8031, 8033, 8034, 8035, 8036, 8038, 8041, 8042, 8043, 8044, 8045, 8047, 8048, 8049, 8051, 8052, 8053, 8054, 8056, 8058, 8059, 8061, 8062, 8064, 8067, 8068, 8069, 8070, 8073, 8079, 8080, 8081, 8082, 8083, 8084, 8087, 8088, 8089, 8091, 8092, 8093, 8094, 8098, 8105, 8108, 8109, 8110, 8111, 8112, 8113, 8114, 8115, 8116, 8117, 8118, 8120, 8121, 8124, 8125, 8126, 8127, 8128, 8130, 8131, 8132, 8135, 8137, 8141, 8142, 8143, 8144, 8145, 8147, 8150, 8151, 8152, 8154, 8155, 8156, 8160, 8161, 8163, 8167, 8168, 8171, 8172, 8173, 8175, 8176, 8179, 8181, 8183, 8187, 8189, 8190, 8192, 8193, 8194, 8197, 8201, 8202, 8204, 8212, 8213, 8214, 8215, 8217, 8219, 8222, 8224, 8225, 8226, 8227, 8228, 8229, 8231, 8232, 8233, 8236, 8238, 8239, 8242, 8244, 8248, 8249, 8251, 8254, 8256, 8258, 8259, 8260, 8262, 8264, 8265, 8266, 8267, 8268, 8269, 8270, 8272, 8273, 8274, 8276, 8277, 8278, 8279, 8281, 8284, 8285, 8286, 8287, 8289, 8290, 8291, 8292, 8293, 8294, 8296, 8300, 8301, 8302, 8303, 8307, 8308, 8311, 8312, 8313, 8314, 8316, 8318, 8319, 8320, 8322, 8324, 8326, 8329, 8330, 8331, 8335, 8336, 8337, 8338, 8339, 8341, 8343, 8345, 8348, 8349, 8350, 8351, 8352, 8353, 8354, 8355, 8356, 8359, 8360, 8364, 8367, 8369, 8370, 8375, 8376, 8380, 8381, 8385, 8388, 8389, 8390, 8391, 8393, 8395, 8396, 8397, 8401, 8402, 8403, 8408, 8409, 8411, 8412, 8414, 8415, 8416, 8418, 8420, 8422, 8423, 8427, 8430, 8431, 8432, 8435, 8437, 8439, 8440, 8441, 8443, 8444, 8445, 8446, 8447, 8448, 8449, 8451, 8453, 8454, 8456, 8459, 8464, 8465, 8466, 8467, 8471, 8472, 8474, 8475, 8477, 8482, 8483, 8484, 8485, 8487, 8488, 8489, 8492, 8493, 8495, 8496, 8498, 8499, 8500, 8502, 8503, 8505, 8509, 8510, 8511, 8512, 8513, 8514, 8515, 8518, 8519, 8520, 8521, 8522, 8524, 8525, 8526, 8527, 8529, 8534, 8535, 8537, 8538, 8539, 8540, 8541, 8542, 8543, 8546, 8547, 8549, 8553, 8555, 8556, 8558, 8559, 8560, 8562, 8563, 8567, 8568, 8570, 8571, 8573, 8574, 8575, 8576, 8578, 8579, 8580, 8581, 8583, 8585, 8586, 8588, 8590, 8592, 8594, 8595, 8596, 8597, 8598, 8599, 8601, 8604, 8605, 8606, 8607, 8608, 8609, 8613, 8616, 8617, 8618, 8620, 8621, 8624, 8625, 8626, 8631, 8633, 8637, 8638, 8639, 8641, 8642, 8643, 8644, 8648, 8650, 8651, 8656, 8658, 8659, 8660, 8661, 8662, 8663, 8666, 8668, 8669, 8670, 8671, 8672, 8675, 8676, 8677, 8678, 8680, 8681, 8683, 8685, 8686, 8688, 8689, 8691, 8692, 8694, 8695, 8696, 8697, 8699, 8706, 8707, 8708, 8713, 8715, 8716, 8717, 8718, 8719, 8721, 8722, 8723, 8727, 8730, 8731, 8732, 8733, 8734, 8735, 8738, 8741, 8743, 8745, 8746, 8748, 8751, 8757, 8758, 8759, 8761, 8762, 8763, 8764, 8765, 8766, 8768, 8770, 8771, 8773, 8774, 8775, 8777, 8778, 8782, 8783, 8785, 8788, 8792, 8793, 8794, 8795, 8799, 8800, 8802, 8807, 8808, 8809, 8810, 8811, 8812, 8814, 8815, 8819, 8820, 8821, 8822, 8823, 8824, 8826, 8827, 8828, 8829, 8830, 8831, 8833, 8834, 8837, 8838, 8839, 8840, 8841, 8842, 8847, 8848, 8849, 8850, 8851, 8853, 8855, 8856, 8862, 8863, 8865, 8867, 8871, 8872, 8873, 8874, 8875, 8876, 8877, 8879, 8887, 8888, 8889, 8890, 8895, 8896, 8897, 8898, 8899, 8902, 8903, 8906, 8907, 8909, 8914, 8915, 8916, 8917, 8918, 8919, 8920, 8921, 8922, 8924, 8925, 8926, 8928, 8929, 8932, 8935, 8936, 8937, 8939, 8940, 8941, 8942, 8946, 8947, 8949, 8964, 8967, 8968, 8969, 8970, 8972, 8974, 8979, 8982, 8983, 8985, 8986, 8988, 8989, 8990, 8993, 8994, 8996, 8998, 8999, 9001, 9002, 9003, 9005, 9009, 9010, 9011, 9012, 9013, 9014, 9015, 9016, 9018, 9021, 9022, 9024, 9025, 9027, 9028, 9029, 9030, 9032, 9053, 9058, 9059, 9060, 9062, 9064, 9065, 9066, 9067, 9069, 9070, 9071, 9072, 9073, 9074, 9075, 9077, 9079, 9081, 9082, 9084, 9085, 9086, 9087, 9088, 9089, 9090, 9094, 9095, 9098, 9100, 9101, 9104, 9105, 9106, 9107, 9111, 9113, 9116, 9117, 9119, 9121, 9122, 9123, 9124, 9125, 9126, 9128, 9129, 9130, 9131, 9132, 9133, 9135, 9136, 9137, 9138, 9139, 9141, 9142, 9143, 9144, 9145, 9147, 9148, 9150, 9152, 9153, 9154, 9157, 9158, 9161, 9162, 9165, 9166, 9167, 9170, 9171, 9172, 9173, 9174, 9175, 9177, 9178, 9179, 9181, 9182, 9183, 9184, 9186, 9187, 9188, 9191, 9192, 9194, 9195, 9199, 9200, 9201, 9203, 9205, 9206, 9209, 9210, 9212, 9213, 9215, 9216, 9218, 9219, 9221, 9222, 9223, 9225, 9226, 9227, 9229, 9230, 9231, 9234, 9235, 9237, 9238, 9239, 9240, 9242, 9244, 9247, 9249, 9251, 9252, 9253, 9254, 9256, 9257, 9261, 9263, 9264, 9265, 9267, 9268, 9270, 9272, 9276, 9277, 9279, 9281, 9282, 9285, 9287, 9288, 9289, 9290, 9294, 9295, 9297, 9301, 9302, 9303, 9307, 9309, 9311, 9312, 9313, 9314, 9315, 9316, 9318, 9319, 9320, 9322, 9324, 9326, 9327, 9328, 9330, 9331, 9332, 9333, 9334, 9335, 9336, 9338, 9339, 9340, 9342, 9345, 9346, 9348, 9353, 9354, 9355, 9358, 9359, 9360, 9361, 9365, 9368, 9369, 9370, 9371, 9372, 9375, 9376, 9377, 9379, 9380, 9381, 9383, 9386, 9387, 9391, 9395, 9397, 9398, 9400, 9401, 9402, 9403, 9404, 9406, 9407, 9408, 9409, 9410, 9411, 9413, 9414, 9416, 9418, 9421, 9423, 9424, 9426, 9427, 9429, 9430, 9431, 9432, 9437, 9439, 9440, 9442, 9445, 9448, 9450, 9452, 9455, 9456, 9457, 9458, 9459, 9460, 9461, 9464, 9465, 9467, 9469, 9471, 9474, 9478, 9479, 9481, 9483, 9484, 9485, 9487, 9488, 9489, 9490, 9492, 9493, 9494, 9495, 9498, 9503, 9505, 9507, 9509, 9513, 9515, 9519, 9521, 9526, 9527, 9529, 9530, 9531, 9532, 9534, 9536, 9537, 9538, 9541, 9542, 9543, 9545, 9546, 9548, 9549, 9551, 9552, 9553, 9554, 9555, 9558, 9560, 9566, 9567, 9569, 9571, 9572, 9575, 9576, 9578, 9580, 9581, 9582, 9586, 9588, 9589, 9592, 9596, 9598, 9600, 9603, 9607, 9608, 9609, 9610, 9611, 9612, 9614, 9615, 9617, 9619, 9620, 9621, 9622, 9624, 9625, 9626, 9627, 9628, 9631, 9634, 9636, 9637, 9638, 9639, 9640, 9643, 9644, 9646, 9647, 9649, 9657, 9658, 9660, 9662, 9663, 9664, 9665, 9666, 9668, 9669, 9671, 9673, 9674, 9675, 9676, 9677, 9678, 9681, 9685, 9688, 9691, 9692, 9693, 9694, 9695, 9696, 9697, 9700, 9701, 9702, 9703, 9706, 9707, 9710, 9711, 9712, 9715, 9717, 9718, 9721, 9722, 9725, 9730, 9732, 9733, 9735, 9738, 9739, 9740, 9741, 9742, 9743, 9744, 9745, 9746, 9750, and 9751.

A biologically active substance preferably comprises the amino acid sequence of any of SEQ ID NOs: 4877-9751; or fragments thereof that have biological activity. In a more preferred aspect, a biologically active substance comprises the amino acid sequence of any of SEQ ID NOs: 4877-9751. In another preferred aspect, a biologically active substance comprises the mature polypeptide region of any of SEQ ID NOs: 4877-9751, or fragments thereof that have biological activity. In another preferred aspect, a biologically active substance comprises the mature polypeptide region of any of SEQ ID NOs: 4877-9751. In another preferred aspect, a biologically active substance consists of the amino acid sequence of any of SEQ ID NOs: 4877-9751; or fragments thereof that have biological activity. In another preferred aspect, a biologically active substance consists of the amino acid sequence of any of SEQ ID NOs: 4877-9751. In another preferred aspect, a biologically active substance consists of the mature polypeptide region of any of SEQ ID NOs: 4877-9751; or fragments thereof that have biological activity. In another preferred aspect, a biologically active substance consists of the mature polypeptide region of any of SEQ ID NOs: 4877-9751.

In a second aspect, the present invention relates to a biologically active substance encoded by a polynucleotide comprising a nucleotide sequence having preferably at least 60% identity, more preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, more preferably at least 90% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 2-4876 and subsequences thereof encoding fragments having biological activity.

In preferred aspect, the biologically active substance is encoded by a polynucleotide comprising a nucleotide sequence having preferably at least 60% identity, more preferably at least 65% identity, more preferably at least 70% identity, more preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 50, 55, 77, 82, 91, 98, 103, 110, 125, 169, 171, 172, 174, 176, 177, 178, 179, 180, 181, 182, 183, 185, 186, 187, 189, 192, 194, 195, 196, 198, 199, 201, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 225, 226, 227, 228, 229, 230, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 287, 306, 308, 322, 323, 329, 350, 354, 360, 363, 367, 381, 445, 469, 487, 488, 516, 523, 524, 537, 541, 575, 592, 607, 621, 627, 628, 666, 672, 688, 691, 702, 710, 719, 726, 729, 748, 751, 773, 774, 777, 791, 831, 833, 842, 847, 848, 849, 850, 851, 855, 857, 885, 886, 887, 901, 944, 982, 991, 994, 1018, 1032, 1034, 1058, 1078, 1088, 1098, 1108, 1112, 1128, 1148, 1153, 1154, 1158, 1160, 1164, 1175, 1176, 1177, 1180, 1181, 1183, 1184, 1193, 1194, 1199, 1222, 1237, 1244, 1262, 1263, 1265, 1266, 1278, 1302, 1313, 1314, 1315, 1316, 1317, 1318, 1345, 1355, 1373, 1374, 1401, 1424, 1432, 1433, 1440, 1442, 1448, 1455, 1470, 1496, 1497, 1501, 1509, 1527, 1539, 1556, 1565, 1589, 1619, 1629, 1630, 1634, 1635, 1636, 1638, 1639, 1640, 1641, 1642, 1643, 1644, 1645, 1646, 1647, 1649, 1650, 1651, 1652, 1653, 1654, 1655, 1657, 1658, 1659, 1660, 1661, 1662, 1663, 1664, 1665, 1666, 1667, 1668, 1669, 1670, 1671, 1672, 1673, 1675, 1676, 1677, 1679, 1684, 1688, 1692, 1694, 1703, 1704, 1728, 1732, 1734, 1736, 1775, 1783, 1816, 1831, 1838, 1851, 1853, 1866, 1887, 2002, 2007, 2022, 2038, 2044, 2067, 2070, 2072, 2076, 2094, 2106, 2119, 2120, 2121, 2124, 2131, 2139, 2147, 2148, 2166, 2171, 2194, 2196, 2198, 2205, 2211, 2213, 2216, 2221, 2230, 2236, 2240, 2241, 2255, 2258, 2263, 2273, 2277, 2286, 2288, 2289, 2290, 2291, 2292, 2293, 2294, 2295, 2296, 2297, 2298, 2299, 2300, 2301, 2302, 2303, 2304, 2305, 2324, 2327, 2337, 2341, 2347, 2351, 2364, 2381, 2388, 2400, 2403, 2408, 2410, 2411, 2414, 2415, 2424, 2425, 2430, 2435, 2439, 2457, 2467, 2468, 2469, 2483, 2491, 2498, 2504, 2505, 2506, 2507, 2508, 2509, 2510, 2511, 2512, 2514, 2515, 2516, 2517, 2518, 2519, 2520, 2521, 2522, 2524, 2525, 2526, 2527, 2528, 2529, 2530, 2531, 2532, 2533, 2534, 2535, 2536, 2537, 2538, 2539, 2540, 2541, 2542, 2543, 2544, 2545, 2546, 2547, 2548, 2549, 2550, 2551, 2552, 2553, 2554, 2555, 2556, 2557, 2558, 2559, 2560, 2561, 2562, 2564, 2565, 2566, 2567, 2568, 2569, 2570, 2571, 2572, 2573, 2574, 2575, 2576, 2577, 2578, 2579, 2580, 2581, 2582, 2583, 2584, 2585, 2586, 2587, 2588, 2590, 2591, 2592, 2593, 2594, 2595, 2596, 2597, 2598, 2599, 2600, 2601, 2602, 2603, 2604, 2605, 2606, 2607, 2608, 2609, 2610, 2611, 2612, 2613, 2614, 2615, 2616, 2617, 2618, 2619, 2620, 2621, 2622, 2623, 2624, 2625, 2626, 2627, 2628, 2629, 2630, 2631, 2632, 2633, 2634, 2635, 2636, 2637, 2638, 2639, 2640, 2641, 2642, 2643, 2644, 2645, 2646, 2647, 2648, 2649, 2650, 2651, 2652, 2653, 2654, 2655, 2656, 2657, 2658, 2659, 2661, 2664, 2665, 2666, 2667, 2669, 2670, 2671, 2672, 2673, 2674, 2675, 2676, 2677, 2679, 2680, 2681, 2684, 2685, 2686, 2688, 2689, 2690, 2691, 2692, 2693, 2696, 2697, 2698, 2706, 2723, 2730, 2733, 2751, 2762, 2795, 2806, 2813, 2834, 2835, 2841, 2850, 2866, 2867, 2874, 2878, 2898, 2902, 2904, 2917, 2947, 2957, 2960, 2969, 2972, 2973, 2999, 3004, 3019, 3028, 3054, 3064, 3082, 3093, 3123, 3133, 3134, 3135, 3136, 3137, 3138, 3139, 3140, 3141, 3142, 3143, 3144, 3145, 3146, 3147, 3148, 3149, 3150, 3162, 3222, 3224, 3225, 3226, 3227, 3228, 3229, 3231, 3244, 3248, 3259, 3264, 3265, 3287, 3291, 3303, 3310, 3311, 3321, 3324, 3355, 3362, 3371, 3429, 3434, 3442, 3446, 3458, 3471, 3486, 3496, 3499, 3503, 3504, 3508, 3549, 3558, 3577, 3593, 3598, 3601, 3603, 3606, 3611, 3642, 3653, 3655, 3670, 3673, 3682, 3690, 3694, 3707, 3716, 3727, 3736, 3737, 3744, 3753, 3765, 3790, 3798, 3799, 3872, 3881, 3885, 3915, 3916, 3922, 3931, 3938, 3969, 4011, 4017, 4056, 4059, 4068, 4076, 4077, 4081, 4082, 4085, 4090, 4106, 4112, 4117, 4144, 4145, 4158, 4159, 4160, 4161, 4162, 4163, 4164, 4165, 4166, 4167, 4168, 4169, 4170, 4171, 4172, 4173, 4174, 4175, 4176, 4179, 4181, 4182, 4201, 4235, 4285, 4288, 4305, 4323, 4333, 4336, 4353, 4398, 4409, 4417, 4421, 4423, 4429, 4435, 4448, 4450, 4469, 4472, 4476, 4482, 4488, 4513, 4518, 4544, 4559, 4560, 4569, 4571, 4578, 4607, 4622, 4631, 4643, 4647, 4648, 4650, 4658, 4669, 4672, 4682, 4687, 4688, 4704, 4718, 4754, 4767, 4786, 4792, 4797, 4804, 4812, 4814, 4823, 4830, 4833, 4838, 4848, 4849, 4859, 4862, and 4872; preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 909, 911, 1367, 1498, 2663, 2668, 2682, and 2683; preferably at least 80% identity, more preferably at least 85% identity, even more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 167, 654, 2513, 2589, and 2694; preferably at least 85% identity, more preferably at least 90% identity, most preferably at least 95% identity, and even most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 163, 184, 910, 1674, 2412, 2660, 2662, 2695, and 3231; preferably at least 90% identity, more preferably at least 95% identity, and most preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 27, 166, 168, 170, 193, 202, 231, 543, 776, 888, 889, 890, 898, 908, 916, 1028, 1123, 1133, 1155, 1156, 1157, 1173, 1211, 1212, 1218, 1229, 1230, 1277, 1356, 1357, 1359, 1360, 1368, 1372, 1391, 1500, 1584, 1604, 1627, 1631, 1632, 1637, 1648, 1680, 2101, 2102, 2239, 2358, 2359, 2360, 2404, 2417, 2429, 2494, 2563, 2678, 2724, 3111, 3539, 3850, 4078, 4079, 4080, 4083, 4084, 4180, 4221, 4642, 4689, 4707, and 4727; or preferably at least 95% identity and more preferably at least 97% identity with a polynucleotide selected from the group consisting of SEQ ID NOs: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 83, 84, 85, 86, 87, 88, 89, 90, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 104, 105, 106, 107, 108, 109, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 164, 165, 173, 175, 188, 190, 191, 197, 200, 224, 232, 233, 234, 235, 236, 237, 238, 239, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 307, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 324, 325, 326, 327, 328, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 351, 352, 353, 355, 356, 357, 358, 359, 361, 362, 364, 365, 366, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 517, 518, 519, 520, 521, 522, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 538, 539, 540, 542, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 622, 623, 624, 625, 626, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 667, 668, 669, 670, 671, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 689, 690, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 703, 704, 705, 706, 707, 708, 709, 711, 712, 713, 714, 715, 716, 717, 718, 720, 721, 722, 723, 724, 725, 727, 728, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 749, 750, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 775, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 832, 834, 835, 836, 837, 838, 839, 840, 841, 843, 844, 845, 846, 852, 853, 854, 856, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 891, 892, 893, 894, 895, 896, 897, 899, 900, 902, 903, 904, 905, 906, 907, 912, 913, 914, 915, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 983, 984, 985, 986, 987, 988, 989, 990, 992, 993, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1029, 1030, 1031, 1033, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1079, 1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1109, 1110, 1111, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1124, 1125, 1126, 1127, 1129, 1130, 1131, 1132, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1149, 1150, 1151, 1152, 1159, 1161, 1162, 1163, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1174, 1178, 1179, 1182, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1195, 1196, 1197, 1198, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1213, 1214, 1215, 1216, 1217, 1219, 1220, 1221, 1223, 1224, 1225, 1226, 1227, 1228, 1231, 1232, 1233, 1234, 1235, 1236, 1238, 1239, 1240, 1241, 1242, 1243, 1245, 1246, 1247, 1248, 1249, 1250, 1251, 1252, 1253, 1254, 1255, 1256, 1257, 1258, 1259, 1260, 1261, 1264, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1279, 1280, 1281, 1282, 1283, 1284, 1285, 1286, 1287, 1288, 1289, 1290, 1291, 1292, 1293, 1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301, 1303, 1304, 1305, 1306, 1307, 1308, 1309, 1310, 1311, 1312, 1319, 1320, 1321, 1322, 1323, 1324, 1325, 1326, 1327, 1328, 1329, 1330, 1331, 1332, 1333, 1334, 1335, 1336, 1337, 1338, 1339, 1340, 1341, 1342, 1343, 1344, 1346, 1347, 1348, 1349, 1350, 1351, 1352, 1353, 1354, 1358, 1361, 1362, 1363, 1364, 1365, 1366, 1369, 1370, 1371, 1375, 1376, 1377, 1378, 1379, 1380, 1381, 1382, 1383, 1384, 1385; 1386, 1387, 1388, 1389, 1390, 1392, 1393, 1394, 1395, 1396, 1397, 1398, 1399, 1400, 1402, 1403, 1404, 1405, 1406, 1407, 1408, 1409, 1410, 1411, 1412, 1413, 1414, 1415, 1416, 1417, 1418, 1419, 1420, 1421, 1422, 1423, 1425, 1426, 1427, 1428, 1429, 1430, 1431, 1434, 1435, 1436, 1437, 1438, 1439, 1441, 1443, 1444, 1445, 1446, 1447, 1449, 1450, 1451, 1452, 1453, 1454, 1456, 1457, 1458, 1459, 1460, 1461, 1462, 1463, 1464, 1465, 1466, 1467, 1468, 1469, 1471, 1472, 1473, 1474, 1475, 1476, 1477, 1478, 1479, 1480, 1481, 1482, 1483, 1484, 1485, 1486, 1487, 1488, 1489, 1490, 1491, 1492, 1493, 1494, 1495, 1499, 1502, 1503, 1504, 1505, 1506, 1507, 1508, 1510, 1511, 1512, 1513, 1514, 1515, 1516, 1517, 1518, 1519, 1520, 1521, 1522, 1523, 1524, 1525, 1526, 1528, 1529, 1530, 1531, 1532, 1533, 1534, 1535, 1536, 1537, 1538, 1540, 1541, 1542, 1543, 1544, 1545, 1546, 1547, 1548, 1549, 1550, 1551, 1552, 1553, 1554, 1555, 1557, 1558, 1559, 1560, 1561, 1562, 1563, 1564, 1566, 1567, 1568, 1569, 1570, 1571, 1572, 1573, 1574, 1575, 1576, 1577, 1578, 1579, 1580, 1581, 1582, 1583, 1585, 1586, 1587, 1588, 1590, 1591, 1592, 1593, 1594, 1595, 1596, 1597, 1598, 1599, 1600, 1601, 1602, 1603, 1605, 1606, 1607, 1608, 1609, 1610, 1611, 1612, 1613, 1614, 1615, 1616, 1617, 1618, 1620, 1621, 1622, 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4125, 4126, 4127, 4128, 4129, 4130, 4131, 4132, 4133, 4134, 4135, 4136, 4137, 4138, 4139, 4140, 4141, 4142, 4143, 4146, 4147, 4148, 4149, 4150, 4151, 4152, 4153, 4154, 4155, 4156, 4157, 4177, 4178, 4183, 4184, 4185, 4186, 4187, 4188, 4189, 4190, 4191, 4192, 4193, 4194, 4195, 4196, 4197, 4198, 4199, 4200, 4202, 4203, 4204, 4205, 4206, 4207, 4208, 4209, 4210, 4211, 4212, 4213, 4214, 4215, 4216, 4217, 4218, 4219, 4220, 4222, 4223, 4224, 4225, 4226, 4227, 4228, 4229, 4230, 4231, 4232, 4233, 4234, 4236, 4237, 4238, 4239, 4240, 4241, 4242, 4243, 4244, 4245, 4246, 4247, 4248, 4249, 4250, 4251, 4252, 4253, 4254, 4255, 4256, 4257, 4258, 4259, 4260, 4261, 4262, 4263, 4264, 4265, 4266, 4267, 4268, 4269, 4270, 4271, 4272, 4273, 4274, 4275, 4276, 4277, 4278, 4279, 4280, 4281, 4282, 4283, 4284, 4286, 4287, 4289, 4290, 4291, 4292, 4293, 4294, 4295, 4296, 4297, 4298, 4299, 4300, 4301, 4302, 4303, 4304, 4306, 4307, 4308, 4309, 4310, 4311, 4312, 4313, 4314, 4315, 4316, 4317, 4318, 4319, 4320, 4321, 4322, 4324, 4325, 4326, 4327, 4328, 4329, 4330, 4331, 4332, 4334, 4335, 4337, 4338, 4339, 4340, 4341, 4342, 4343, 4344, 4345, 4346, 4347, 4348, 4349, 4350, 4351, 4352, 4354, 4355, 4356, 4357, 4358, 4359, 4360, 4361, 4362, 4363, 4364, 4365, 4366, 4367, 4368, 4369, 4370, 4371, 4372, 4373, 4374, 4375, 4376, 4377, 4378, 4379, 4380, 4381, 4382, 4383, 4384, 4385, 4386, 4387, 4388, 4389, 4390, 4391, 4392, 4393, 4394, 4395, 4396, 4397, 4399, 4400, 4401, 4402, 4403, 4404, 4405, 4406, 4407, 4408, 4410, 4411, 4412, 4413, 4414, 4415, 4416, 4418, 4419, 4420, 4422, 4424, 4425, 4426, 4427, 4428, 4430, 4431, 4432, 4433, 4434, 4436, 4437, 4438, 4439, 4440, 4441, 4442, 4443, 4444, 4445, 4446, 4447, 4449, 4451, 4452, 4453, 4454, 4455, 4456, 4457, 4458, 4459, 4460, 4461, 4462, 4463, 4464, 4465, 4466, 4467, 4468, 4470, 4471, 4473, 4474, 4475, 4477, 4478, 4479, 4480, 4481, 4483, 4484, 4485, 4486, 4487, 4489, 4490, 4491, 4492, 4493, 4494, 4495, 4496, 4497, 4498, 4499, 4500, 4501, 4502, 4503, 4504, 4505, 4506, 4507, 4508, 4509, 4510, 4511, 4512, 4514, 4515, 4516, 4517, 4519, 4520, 4521, 4522, 4523, 4524, 4525, 4526, 4527, 4528, 4529, 4530, 4531, 4532, 4533, 4534, 4535, 4536, 4537, 4538, 4539, 4540, 4541, 4542, 4543, 4545, 4546, 4547, 4548, 4549, 4550, 4551, 4552, 4553, 4554, 4555, 4556, 4557, 4558, 4561, 4562, 4563, 4564, 4565, 4566, 4567, 4568, 4570, 4572, 4573, 4574, 4575, 4576, 4577, 4579, 4580, 4581, 4582, 4583, 4584, 4585, 4586, 4587, 4588, 4589, 4590, 4591, 4592, 4593, 4594, 4595, 4596, 4597, 4598, 4599, 4600, 4601, 4602, 4603, 4604, 4605, 4606, 4608, 4609, 4610, 4611, 4612, 4613, 4614, 4615, 4616, 4617, 4618, 4619, 4620, 4621, 4623, 4624, 4625, 4626, 4627, 4628, 4629, 4630, 4632, 4633, 4634, 4635, 4636, 4637, 4638, 4639, 4640, 4641, 4644, 4645, 4646, 4649, 4651, 4652, 4653, 4654, 4655, 4656, 4657, 4659, 4660, 4661, 4662, 4663, 4664, 4665, 4666, 4667, 4668, 4670, 4671, 4673, 4674, 4675, 4676, 4677, 4678, 4679, 4680, 4681, 4683, 4684, 4685, 4686, 4690, 4691, 4692, 4693, 4694, 4695, 4696, 4697, 4698, 4699, 4700, 4701, 4702, 4703, 4705, 4706, 4708, 4709, 4710, 4711, 4712, 4713, 4714, 4715, 4716, 4717, 4719, 4720, 4721, 4722, 4723, 4724, 4725, 4726, 4728, 4729, 4730, 4731, 4732, 4733, 4734, 4735, 4736, 4737, 4738, 4739, 4740, 4741, 4742, 4743, 4744, 4745, 4746, 4747, 4748, 4749, 4750, 4751, 4752, 4753, 4755, 4756, 4757, 4758, 4759, 4760, 4761, 4762, 4763, 4764, 4765, 4766, 4768, 4769, 4770, 4771, 4772, 4773, 4774, 4775, 4776, 4777, 4778, 4779, 4780, 4781, 4782, 4783, 4784, 4785, 4787, 4788, 4789, 4790, 4791, 4793, 4794, 4795, 4796, 4798, 4799, 4800, 4801, 4802, 4803, 4805, 4806, 4807, 4808, 4809, 4810, 4811, 4813, 4815, 4816, 4817, 4818, 4819, 4820, 4821, 4822, 4824, 4825, 4826, 4827, 4828, 4829, 4831, 4832, 4834, 4835, 4836, 4837, 4839, 4840, 4841, 4842, 4843, 4844, 4845, 4846, 4847, 4850, 4851, 4852, 4853, 4854, 4855, 4856, 4857, 4858, 4860, 4861, 4863, 4864, 4865, 4866, 4867, 4868, 4869, 4870, 4871, 4873, 4874, 4875, and 4876.

In a third aspect, the present invention relates to an isolated biologically active substance encoded by a polynucleotide that hybridizes, as described above, under very low stringency conditions, preferably low stringency conditions, more preferably medium stringency conditions, more preferably medium-high stringency conditions, even more preferably high stringency conditions, and most preferably very high stringency conditions with a polynucleotide selected from the group consisting of (i) the polynucleotides of SEQ ID NOs: 2-4876, and subsequences thereof, and (ii) full-length complementary strands thereof. A subsequence of any of SEQ ID NOs: 2-4876 may be at least 100 nucleotides or preferably at least 200 nucleotides. Moreover, the subsequence may encode a fragment, e.g., a fragment that has biological activity.

In a fourth aspect, the present invention relates to an artificial variant comprising a substitution, deletion, and/or insertion of one or more (several) amino acids of an amino acid sequence selected from the group consisting of SEQ ID NOs: 4877-9751 and fragments thereof retaining biological activity, as described above.

Nucleic Acid Constructs

The present invention also relates to nucleic acid constructs comprising an isolated polynucleotide or isolated polynucleotides (e.g., operon) of the present invention operably linked to one or more (several) control sequences that direct the expression of the coding sequence in a suitable host cell under conditions compatible with the control sequences.

An isolated polynucleotide(s) of the present invention may be manipulated in a variety of ways to provide for production of a biologically active substance encoded directly or indirectly by the polynucleotide(s). Manipulation of the nucleotide sequence prior to its insertion into a vector may be desirable or necessary depending on the expression vector. The techniques for modifying nucleotide sequences utilizing recombinant DNA methods are well known in the art.

The control sequence may be an appropriate promoter sequence, a nucleotide sequence that is recognized by a host cell for expression of the polynucleotide(s) encoding the biologically active substance. The promoter sequence contains transcriptional control sequences that mediate the expression of the biologically active substance. The promoter may be any nucleotide sequence that shows transcriptional activity in the host cell of choice including mutant, truncated, and hybrid promoters, and may be obtained from genes encoding extracellular or intracellular polypeptides or biologically active substances either homologous or heterologous to the host cell.

Examples of suitable promoters for directing the transcription of the nucleic acid constructs of the present invention, especially in a bacterial host cell, are the promoters obtained from the E. coli lac operon, Streptomyces coelicolor agarase gene (dagA), Bacillus subtilis levansucrase gene (sacB), Bacillus licheniformis alpha-amylase gene (amyL), Bacillus stearothermophilus maltogenic amylase gene (amyM), Bacillus amyloliquefaciens alpha-amylase gene (amyQ), Bacillus licheniformis penicillinase gene (penP), Bacillus subtilis xylA and xylB genes, and prokaryotic beta-lactamase gene (VIIIa-Kamaroff et al., 1978 , Proceedings of the National Academy of Sciences USA 75: 3727-3731), as well as the tac promoter (DeBoer et al., 1983 , Proceedings of the National Academy of Sciences USA 80: 21-25). Further promoters are described in “Useful proteins from recombinant bacteria” in Scientific American, 1980, 242: 74-94; and in Sambrook et al., 1989, supra.

The control sequence may also be a suitable transcription terminator sequence, a sequence recognized by a host cell to terminate transcription. The terminator sequence is operably linked to the 3′ terminus of the gene encoding the biologically active substance. Any terminator that is functional in the host cell of choice may be used in the present invention.

The control sequence may also be a signal peptide coding region that codes for an amino acid sequence linked to the amino terminus of a polypeptide and directs the encoded polypeptide into the cell's secretory pathway. The 5′ end of the coding sequence of the nucleotide sequence may inherently contain a signal peptide coding region naturally linked in translation reading frame with the segment of the coding region that encodes the secreted polypeptide. Alternatively, the 5′ end of the coding sequence may contain a signal peptide coding region that is foreign to the coding sequence. The foreign signal peptide coding region may be required where the coding sequence does not naturally contain a signal peptide coding region. Alternatively, the foreign signal peptide coding region may simply replace the natural signal peptide coding region in order to enhance secretion of the polypeptide. However, any signal peptide coding region that directs the expressed polypeptide into the secretory pathway of a host cell of choice may be used in the present invention.

Effective signal peptide coding regions for bacterial host cells are the signal peptide coding regions obtained from the genes for Bacillus NCIB 11837 maltogenic amylase, Bacillus stearothermophilus alpha-amylase, Bacillus licheniformis subtilisin, Bacillus licheniformis beta-lactamase, Bacillus stearothermophilus neutral proteases (nprT, nprS, nprM), and Bacillus subtilis prsA. Further signal peptides are described by Simonen and Palva, 1993, Microbiological Reviews 57: 109-137.

The control sequence may also be a propeptide coding region that codes for an amino acid sequence positioned at the amino terminus of a polypeptide. The resultant polypeptide is known as a proenzyme or propolypeptide (or a zymogen in some cases). A propolypeptide is generally inactive and can be converted to a mature active polypeptide by catalytic or autocatalytic cleavage of the propeptide from the propolypeptide. The propeptide coding region may be obtained from the genes for Bacillus subtilis alkaline protease (aprE) and Bacillus subtilis neutral protease (nprT).

Where both signal peptide and propeptide regions are present at the amino terminus of a polypeptide, the propeptide region is positioned next to the amino terminus of a polypeptide and the signal peptide region is positioned next to the amino terminus of the propeptide region.

It may also be desirable to add regulatory sequences that allow the regulation of the expression of a biologically active substance relative to the growth of the host cell. Examples of regulatory systems are those that cause the expression of the gene to be turned on or off in response to a chemical or physical stimulus, including the presence of a regulatory compound. Regulatory systems in prokaryotic systems include the lac, tac, and trp operator systems. Other examples of regulatory sequences are those that allow for gene amplification. In eukaryotic systems, these include the dihydrofolate reductase gene that is amplified in the presence of methotrexate, and the metallothionein genes that are amplified with heavy metals. In these cases, the nucleotide sequence encoding the biologically active substance would be operably linked with the regulatory sequence.

Expression Vectors

The present invention also relates to recombinant expression vectors comprising an isolated polynucleotide of the present invention, a promoter, and transcriptional and translational stop signals. The various nucleic acid and control sequences described above may be joined together to produce a recombinant expression vector that may include one or more (several) convenient restriction sites to allow for insertion or substitution of the nucleotide sequence encoding the polypeptide at such sites. Alternatively, a polynucleotide of the present invention may be expressed by inserting the nucleotide sequence or a nucleic acid construct comprising the sequence into an appropriate vector for expression. In creating the expression vector, the coding sequence is located in the vector so that the coding sequence is operably linked with the appropriate control sequences for expression.

The recombinant expression vector may be any vector (e.g., a plasmid or virus) that can be conveniently subjected to recombinant DNA procedures and can bring about the expression of a polynucleotide of the present invention. The choice of the vector will typically depend on the compatibility of the vector with the host cell into which the vector is to be introduced. The vectors may be linear or closed circular plasmids.

The vector may be an autonomously replicating vector, i.e., a vector that exists as an extrachromosomal entity, the replication of which is independent of chromosomal replication, e.g., a plasmid, an extrachromosomal element, a minichromosome, or an artificial chromosome. The vector may contain any means for assuring self-replication. Alternatively, the vector may be one that, when introduced into the host cell, is integrated into the genome and replicated together with the chromosome(s) into which it has been integrated. Furthermore, a single vector or plasmid or two or more vectors or plasmids that together contain the total DNA to be introduced into the genome of the host cell, or a transposon may be used.

The vectors of the present invention preferably contain one or more (several) selectable markers that permit easy selection of transformed cells. A selectable marker is a gene the product of which provides for biocide or viral resistance, resistance to heavy metals, prototrophy to auxotrophs, and the like.

Examples of bacterial selectable markers are the dal genes from Bacillus subtilis or Bacillus licheniformis , or markers that confer antibiotic resistance such as ampicillin, kanamycin, chloramphenicol or tetracycline resistance.

The vectors of the present invention preferably contain an element(s) that permits integration of the vector into the host cell's genome or autonomous replication of the vector in the cell independent of the genome.

For integration into the host cell genome, the vector may rely on portions of the sequence of the gene or any other element of the vector for integration of the vector into the genome by homologous or nonhomologous recombination. Alternatively, the vector may contain additional nucleotide sequences for directing integration by homologous recombination into the genome of the host cell. The additional nucleotide sequences enable the vector to be integrated into the host cell genome at a precise location(s) in the chromosome(s). To increase the likelihood of integration at a precise location, the integrational elements should preferably contain a sufficient number of nucleotides, such as 100 to 10,000 base pairs, preferably 400 to 10,000 base pairs, and most preferably 800 to 10,000 base pairs, which are highly homologous with the corresponding target sequence to enhance the probability of homologous recombination. The integrational elements may be any sequence that is homologous with the target sequence in the genome of the host cell. Furthermore, the integrational elements may be non-encoding or encoding nucleotide sequences. On the other hand, the vector may be integrated into the genome of the host cell by non-homologous recombination.

For autonomous replication, the vector may further comprise an origin of replication enabling the vector to replicate autonomously in the host cell in question. The origin of replication may be any plasmid replicator mediating autonomous replication that functions in a cell. The term “origin of replication” or “plasmid replicator” is defined herein as a sequence that enables a plasmid or vector to replicate in vivo. Examples of bacterial origins of replication are the origins of replication of plasmids pBR322, pUC19, pACYC177, and pACYC184 permitting replication in E. coli , and pUB110, pE194, pTA1060, and pAMβ1 permitting replication in Bacillus.

More than one copy of a polynucleotide of the present invention may be inserted into the host cell to increase production of the polynucleotide product. An increase in the copy number of the polynucleotide can be obtained by integrating at least one additional copy of the sequence into the host cell genome or by including an amplifiable selectable marker gene with a polynucleotide of the present invention where cells containing amplified copies of the selectable marker gene, and thereby additional copies of the polynucleotide of the present invention, can be selected for by cultivating the cells in the presence of the appropriate selectable agent.

The procedures used to ligate the elements described above to construct the recombinant expression vectors of the present invention are well known to one skilled in the art (see, e.g., Sambrook et al., 1989, supra).

Host Cells

The present invention also relates to recombinant host cells, comprising an isolated polynucleotide of the present invention, where the host cells are advantageously used in the recombinant production of a biologically active substance encoded by the polynucleotide. A vector comprising a polynucleotide of the present invention is introduced into a host cell so that the vector is maintained as a chromosomal integrant or as a self-replicating extra-chromosomal vector as described earlier. The term “host cell” encompasses any progeny of a parent cell that is not identical to the parent cell due to mutations that occur during replication. The choice of a host cell will to a large extent depend upon the polynucleotide encoding the biologically active substance and its source.

The host cell may be any unicellular microorganism, e.g., a prokaryote, or a non-unicellular microorganism, e.g., a eukaryote.

The bacterial host cell may be any Gram positive bacterium or a Gram negative bacterium. Gram positive bacteria include, but not limited to, Bacillus, Streptococcus, Streptomyces, Staphylococcus, Enterococcus, Lactobacillus, Lactococcus, Clostridium, Geobacillus , and Oceanobacillus . Gram negative bacteria include, but not limited to, E. coli, Pseudomonas, Salmonella, Campylobacter, Helicobacter, Flavobacterium, Fusobacterium, Hyobacter, Neisseria , and Ureaplasma.

The bacterial host cell may be any Bacillus cell. Bacillus cells useful in the practice of the present invention include, but are not limited to, Bacillus alkalophilus, Bacillus amyloliquefaciens, Bacillus brevis, Bacillus circulans, Bacillus clausii, Bacillus coagulans, Bacillus firmus, Bacillus lautus, Bacillus lentus, Bacillus licheniformis, Bacillus megaterium, Bacillus pumilus, Bacillus stearothermophilus, Bacillus subtilis , and Bacillus thuringiensis cells.

In a preferred aspect, the bacterial host cell is a Bacillus amyloliquefaciens, Bacillus lentus, Bacillus licheniformis, Bacillus stearothermophilus or Bacillus subtilis cell. In a more preferred aspect, the bacterial host cell is a Bacillus amyloliquefaciens cell. In another more preferred aspect, the bacterial host cell is a Bacillus clausii cell. In another more preferred aspect, the bacterial host cell is a Bacillus licheniformis cell. In another more preferred aspect, the bacterial host cell is a Bacillus subtilis cell.

The bacterial host cell may also be any Streptococcus cell. Streptococcus cells useful in the practice of the present invention include, but are not limited to, Streptococcus equisimilis, Streptococcus pyogenes, Streptococcus uberis , and Streptococcus equi subsp. Zooepidemicus.

In a preferred aspect, the bacterial host cell is a Streptococcus equisimilis cell. In another preferred aspect, the bacterial host cell is a Streptococcus pyogenes cell. In another preferred aspect, the bacterial host cell is a Streptococcus uberis cell. In another preferred aspect, the bacterial host cell is a Streptococcus equi subsp. Zooepidemicus cell.

The bacterial host cell may also be any Streptomyces cell. Streptomyces cells useful in the practice of the present invention include, but are not limited to, Streptomyces achromogenes, Streptomyces avermitilis, Streptomyces coelicolor, Streptomyces griseus , and Streptomyces lividans.

In a preferred aspect, the bacterial host cell is a Streptomyces achromogenes cell. In another preferred aspect, the bacterial host cell is a Streptomyces avermitilis cell. In another preferred aspect, the bacterial host cell is a Streptomyces coelicolor cell. In another preferred aspect, the bacterial host cell is a Streptomyces griseus cell. In another preferred aspect, the bacterial host cell is a Streptomyces lividans cell.

The introduction of DNA into a Bacillus cell may, for instance, be effected by protoplast transformation (see, e.g., Chang and Cohen, 1979, Molecular General Genetics 168: 111-115), by using competent cells (see, e.g., Young and Spizizen, 1961, Journal of Bacteriology 81: 823-829, or Dubnau and Davidoff-Abelson, 1971, Journal of Molecular Biology 56: 209-221), by electroporation (see, e.g., Shigekawa and Dower, 1988, Biotechniques 6: 742-751), or by conjugation (see, e.g., Koehler and Thorne, 1987, Journal of Bacteriology 169: 5271-5278). The introduction of DNA into an E. coli cell may, for instance, be effected by protoplast transformation (see, e.g., Hanahan, 1983, J. Mol. Biol. 166: 557-580) or electroporation (see, e.g., Dower et al., 1988, Nucleic Acids Res. 16: 6127-6145). The introduction of DNA into a Streptomyces cell may, for instance, be effected by protoplast transformation and electroporation (see, e.g., Gong et al., 2004, Folia Microbiol . (Praha) 49: 399-405), by conjugation (see, e.g., Mazodier et al., 1989, J. Bacteriol. 171: 3583-3585), or by transduction (see, e.g., Burke et al., 2001, Proc. Natl. Acad. Sci. USA 98:6289-6294). The introduction of DNA into a Pseudomonas cell may, for instance, be effected by electroporation (see, e.g., Choi et al., 2006, J. Microbiol. Methods 64: 391-397) or by conjugation (see, e.g., Pinedo and Smets, 2005, Appl. Environ. Microbiol. 71: 51-57). The introduction of DNA into a Streptococcus cell may, for instance, be effected by natural competence (see, e.g., Perry and Kuramitsu, 1981, Infect. Immun. 32: 1295-1297), by protoplast transformation (see, e.g., Catt and Jollick, 1991, Microbios. 68: 189-2070, by electroporation (see, e.g., Buckley et al., 1999, Appl. Environ. Microbiol. 65: 3800-3804) or by conjugation (see, e.g., Clewell, 1981 , Microbiol. Rev. 45: 409-436). However, any method known in the for introducing DNA into a host cell can be used.

Methods of Production

The present invention also relates to methods for producing a biologically active substance of the present invention comprising (a) cultivating a strain, which in its wild-type form is capable of producing the biologically active substance, under conditions conducive for production of the biologically active substance; and (b) recovering the biologically active substance. Preferably, the strain is of the genus Bacillus , and more preferably Bacillus licheniformis.

The present invention also relates to methods for producing a biologically active substance of the present invention comprising (a) cultivating a host cell under conditions conducive for production of the biologically active substance; and (b) recovering the biologically active substance.

The present invention also relates to methods for producing a biologically active substance of the present invention comprising (a) cultivating a host cell under conditions conducive for production of the biologically active substance, wherein the host cell comprises a mutant polynucleotide comprising at least one mutation in the coding region of any of SEQ ID NOs: 2-4876, wherein the mutant polynucleotide encodes a biologically active substance that consists of SEQ ID NOs: 4877-9751, respectively, and (b) recovering the biologically active substance.

In the production methods of the present invention, the cells are cultivated in a nutrient medium suitable for production of the biologically active substance using methods known in the art. For example, the cell may be cultivated by shake flask cultivation, and small-scale or large-scale fermentation (including continuous, batch, fed-batch, or solid state fermentations) in laboratory or industrial fermentors performed in a suitable medium and under conditions allowing the biologically active substance to be expressed and/or isolated. The cultivation takes place in a suitable nutrient medium comprising carbon and nitrogen sources and inorganic salts, using procedures known in the art. Suitable media are available from commercial suppliers or may be prepared according to published compositions (e.g., in catalogues of the American Type Culture Collection). If the biologically active substance is secreted into the nutrient medium, the biologically active substance can be recovered directly from the medium. If the biologically active substance is not secreted, it can be recovered from cell lysates.

The biologically active substances may be detected using methods known in the art that are specific for the polypeptides. These detection methods may include use of specific antibodies, formation of an enzyme product, or disappearance of an enzyme substrate. For example, an enzyme assay may be used to determine the activity of an enzyme. See, for example, Enzyme Nomenclature , Academic Press, Inc., New York, 2007.

The resulting biologically active substances may be recovered by methods known in the art. For example, the biologically active substances may be recovered from the nutrient medium by conventional procedures including, but not limited to, centrifugation, filtration, extraction, spray-drying, evaporation, or precipitation.

The biologically active substances of the present invention may be purified by a variety of procedures known in the art including, but not limited to, chromatography (e.g., ion exchange, affinity, hydrophobic, chromatofocusing, and size exclusion), electrophoretic procedures (e.g., preparative isoelectric focusing), differential solubility (e.g., ammonium sulfate precipitation), SDS-PAGE, or extraction (see, e.g., Protein Purification, J.-C. Janson and Lars Ryden, editors, VCH Publishers, New York, 1989).

Plants

The present invention also relates to a transgenic plant, plant part, or plant cell, which has been transformed with a polynucleotide encoding a biologically active substance of the present invention so as to express and produce the biologically active substance in recoverable quantities. The biologically active substance may be recovered from the plant or plant part. Alternatively, the plant or plant part containing the recombinant biologically active substance may be used as such for improving the quality of a food or feed, e.g., improving nutritional value, palatability, and rheological properties, or to destroy an antinutritive factor.

The transgenic plant can be dicotyledonous (a dicot) or monocotyledonous (a monocot). Examples of monocot plants are grasses, such as meadow grass (blue grass, Poa ), forage grass such as festuca, lolium , temperate grass, such as Agrostis , and cereals, e.g., wheat, oats, rye, barley, rice, sorghum, and maize (corn).

Examples of dicot plants are tobacco, legumes, such as lupins, potato, sugar beet, pea, bean and soybean, and cruciferous plants (family Brassicaceae), such as cauliflower, rape seed, and the closely related model organism Arabidopsis thaliana.

Examples of plant parts are stem, callus, leaves, root, fruits, seeds, and tubers as well as the individual tissues comprising these parts, e.g., epidermis, mesophyll, parenchyme, vascular tissues, meristems. In the present context, also specific plant cell compartments, such as chloroplast, apoplast, mitochondria, vacuole, peroxisomes and cytoplasm are considered to be a plant part. Furthermore, any plant cell, whatever the tissue origin, is considered to be a plant part. Likewise, plant parts such as specific tissues and cells isolated to facilitate the utilisation of the invention are also considered plant parts e.g. embryos, endosperms, aleurone and seeds coats.

Also included within the scope of the present invention are the progeny of such plants, plant parts, and plant cells.

The transgenic plant or plant cell expressing a biologically active substance of the present invention may be constructed in accordance with methods known in the art. Briefly, the plant or plant cell is constructed by incorporating one or more (several) expression constructs encoding a biologically active substance of the present invention into the plant host genome and propagating the resulting modified plant or plant cell into a transgenic plant or plant cell.

The expression construct is conveniently a nucleic acid construct that comprises a polynucleotide encoding a biologically active substance of the present invention operably linked with appropriate regulatory sequences required for expression of the nucleotide sequence in the plant or plant part of choice. Furthermore, the expression construct may comprise a selectable marker useful for identifying host cells into which the expression construct has been integrated and DNA sequences necessary for introduction of the construct into the plant in question (the latter depends on the DNA introduction method to be used).

The choice of regulatory sequences, such as promoter and terminator sequences and optionally signal or transit sequences is determined, for example, on the basis of when, where, and how the biologically active substance is desired to be expressed. For instance, the expression of the polynucleotide encoding a biologically active substance of the present invention may be constitutive or inducible, or may be developmental, stage or tissue specific, and the gene product may be targeted to a specific tissue or plant part such as seeds or leaves. Regulatory sequences are, for example, described by Tague et al., 1988, Plant Physiology 86: 506.

For constitutive expression the 35S-CaMV, the maize ubiquitin 1 and the rice actin 1 promoter may be used (Franck et al., 1980 . Cell 21: 285-294, Christensen A H, Sharrock R A and Quail, 1992, Plant Mo. Biol. 18: 675-689.; Zhang W, McElroy D. and Wu R., 1991, Plant Cell 3: 1155-1165). Organ-specific promoters may be, for example, a promoter from storage sink tissues such as seeds, potato tubers, and fruits (Edwards and Coruzzi, 1990, Ann. Rev. Genet. 24: 275-303), or from metabolic sink tissues such as meristems (Ito et al., 1994, Plant Mol. Biol. 24: 863-878), a seed specific promoter such as the glutelin, prolamin, globulin, or albumin promoter from rice (Wu et al., 1998 , Plant and Cell Physiology 39: 885-889), a Vicia faba promoter from the legumin B4 and the unknown seed protein gene from Vicia faba (Conrad et al., 1998, Journal of Plant Physiology 152: 708-711), a promoter from a seed oil body protein (Chen et al., 1998, Plant and Cell Physiology 39: 935-941), the storage protein napA promoter from Brassica napus , or any other seed specific promoter known in the art, e.g., as described in WO 91/14772. Furthermore, the promoter may be a leaf specific promoter such as the rbcs promoter from rice or tomato (Kyozuka et al., 1993, Plant Physiology 102: 991-1000, the chlorella virus adenine methyltransferase gene promoter (Mitra and Higgins, 1994, Plant Molecular Biology 26: 85-93), or the aldP gene promoter from rice (Kagaya et al., 1995, Molecular and General Genetics 248: 668-674), or a wound inducible promoter such as the potato pin2 promoter (Xu et al., 1993, Plant Molecular Biology 22: 573-588). Likewise, the promoter may inducible by abiotic treatments such as temperature, drought or alterations in salinity or induced by exogenously applied substances that activate the promoter, e.g., ethanol, oestrogens, plant hormones like ethylene, abscisic acid and gibberellic acid and heavy metals.

A promoter enhancer element may also be used to achieve higher expression of the enzyme in the plant. For instance, the promoter enhancer element may be an intron that is placed between the promoter and the nucleotide sequence encoding a biologically active substance of the present invention. For instance, Xu et al., 1993, supra disclose the use of the first intron of the rice actin 1 gene to enhance expression. The selectable marker gene and any other parts of the expression construct may be chosen from those available in the art.

The nucleic acid construct is incorporated into the plant genome according to conventional techniques known in the art, including Agrobacterium -mediated transformation, virus-mediated transformation, microinjection, particle bombardment, biolistic transformation, and electroporation (Gasser et al., 1990, Science 244: 1293; Potrykus, 1990, Bio/Technology 8: 535; Shimamoto et al., 1989, Nature 338: 274).

Presently, Agrobacterium tumefaciens -mediated gene transfer is the method of choice for generating transgenic dicots (for a review, see Hooykas and Schilperoort, 1992, Plant Molecular Biology 19: 15-38). However it can also be used for transforming monocots, although other transformation methods are generally preferred for these plants. Presently, the method of choice for generating transgenic monocots is particle bombardment (microscopic gold or tungsten particles coated with the transforming DNA) of embryonic calli or developing embryos (Christou, 1992, Plant Journal 2: 275-281; Shimamoto, 1994, Current Opinion Biotechnology 5: 158-162; Vasil et al., 1992 , Bio/Technology 10: 667-674). An alternative method for transformation of monocots is based on protoplast transformation as described by Omirulleh et al., 1993, Plant Molecular Biology 21: 415-428.

Following transformation, the transformants having incorporated therein the expression construct are selected and regenerated into whole plants according to methods well-known in the art. Often the transformation procedure is designed for the selective elimination of selection genes either during regeneration or in the following generations by using, for example, co-transformation with two separate T-DNA constructs or site specific excision of the selection gene by a specific recombinase.

The present invention also relates to methods for producing a biologically active substance of the present invention comprising (a) cultivating a transgenic plant or a plant cell comprising a polynucleotide encoding a biologibally active substance of the present invention under conditions conducive for production of the biologically active substance; and (b) recovering the biologically active substance.

Removal or Reduction of Biologically Active Substance

The present invention also relates to methods for producing a mutant of a parent cell, which comprises disrupting or deleting all or a portion of a polynucleotide encoding a biologically active substance of the present invention, which results in the mutant cell producing less of the biologically active substance than the parent cell when cultivated under the same conditions.

The mutant cell may be constructed by reducing or eliminating expression of a gene encoding or regulatory synthesis of a biologically active substance of the present invention using methods well known in the art, for example, insertions, disruptions, replacements, or deletions. The gene to be modified or inactivated may be, for example, the coding region or a part thereof essential for activity, or a regulatory element of the gene required for the expression of the coding region. An example of such a regulatory or control sequence may be a promoter sequence or a functional part thereof, i.e., a part that is sufficient for affecting expression of the gene. Other control sequences for possible modification include, but are not limited to, a leader, propeptide sequence, signal peptide sequence, transcription terminator, and transcriptional activator.

Modification or inactivation of the gene may be performed by subjecting the parent cell to mutagenesis and selecting for mutant cells in which expression of the gene has been reduced or eliminated. The mutagenesis, which may be specific or random, may be performed, for example, by use of a suitable physical or chemical mutagenizing agent, by use of a suitable oligonucleotide, or by subjecting the DNA sequence to PCR generated mutagenesis. Furthermore, the mutagenesis may be performed by use of any combination of these mutagenizing agents.

Examples of a physical or chemical mutagenizing agent suitable for the present purpose include ultraviolet (UV) irradiation, hydroxylamine, N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), O-methyl hydroxylamine, nitrous acid, ethyl methane sulphonate (EMS), sodium bisulphite, formic acid, and nucleotide analogues.

When such agents are used, the mutagenesis is typically performed by incubating the parent cell to be mutagenized in the presence of the mutagenizing agent of choice under suitable conditions, and screening and/or selecting for mutant cells exhibiting reduced or no expression of the gene.

Modification or inactivation of the nucleotide sequence may be accomplished by introduction, substitution, or removal of one or more (several) nucleotides in the gene or a regulatory element required for the transcription or translation thereof. For example, nucleotides may be inserted or removed so as to result in the introduction of a stop codon, the removal of the start codon, or a change in the open reading frame. Such modification or inactivation may be accomplished by site-directed mutagenesis or PCR generated mutagenesis in accordance with methods known in the art. Although, in principle, the modification may be performed in vivo, i.e., directly on the cell expressing the nucleotide sequence to be modified, it is preferred that the modification be performed in vitro as exemplified below.

An example of a convenient way to eliminate or reduce expression of a nucleotide sequence by a cell of choice is based on techniques of gene replacement, gene deletion, or gene disruption. For example, in the gene disruption method, a nucleic acid sequence corresponding to the endogenous nucleotide sequence is mutagenized in vitro to produce a defective nucleic acid sequence that is then transformed into the parent cell to produce a defective gene. By homologous recombination, the defective nucleic acid sequence replaces the endogenous nucleotide sequence. It may be desirable that the defective nucleotide sequence also encodes a marker that may be used for selection of transformants in which the nucleotide sequence has been modified or destroyed. In a particularly preferred aspect, the nucleotide sequence is disrupted with a selectable marker such as those described herein.

Alternatively, modification or inactivation of the nucleotide sequence may be performed by established anti-sense or RNA interference (RNAi) techniques using a sequence complementary to the nucleotide sequence. More specifically, expression of the nucleotide sequence by a cell may be reduced or eliminated by introducing a sequence complementary to the nucleic acid sequence of the gene that may be transcribed in the cell and is capable of hybridizing to the mRNA produced in the cell. Under conditions allowing the complementary anti-sense nucleotide sequence to hybridize to the mRNA, the amount of protein translated is thus reduced or eliminated.

The present invention further relates to a mutant cell of a parent cell that comprises a disruption or deletion of a nucleotide sequence encoding the biologically active substance or a control sequence thereof, which results in the mutant cell producing less of the biologically active substance than the parent cell.

The biologically active substance-deficient mutant cells so created are particularly useful as host cells for the expression of homologous and/or heterologous substances, such as polypeptides. Therefore, the present invention further relates to methods for producing a homologous or heterologous substance comprising (a) cultivating the mutant cell under conditions conducive for production of the substance; and (b) recovering the substance. The term “heterologous substances” is defined herein as substances that are not native to the host cell, a native substance in which modifications have been made to alter the native sequence, or a native substance whose expression is quantitatively altered as a result of a manipulation of the host cell by recombinant DNA techniques.

In a further aspect, the present invention relates to a method for producing a protein product essentially free of a biologically active substance by fermentation of a cell that produces both a biologically active substance of the present invention as well as the protein product of interest by adding an effective amount of an agent capable of inhibiting activity of the biologically active substance to the fermentation broth before, during, or after the fermentation has been completed, recovering the product of interest from the fermentation broth, and optionally subjecting the recovered product to further purification.

In accordance with this aspect of the invention, it is possible to remove at least 60%, preferably at least 75%, more preferably at least 85%, still more preferably at least 95%, and most preferably at least 99% of the biologically active substance. Complete removal of biologically active substance may be obtained by use of this method.

The methods used for cultivation and purification of the product of interest may be performed by methods known in the art.

The methods of the present invention for producing an essentially biologically active substance-free product is of particular interest in the production of prokaryotic polypeptides, in particular bacterial proteins such as enzymes. The enzyme may be selected from, e.g., an amylolytic enzyme, lipolytic enzyme, proteolytic enzyme, cellulytic enzyme, oxidoreductase, or plant cell-wall degrading enzyme. Examples of such enzymes include an aminopeptidase, amylase, amyloglucosidase, carbohydrase, carboxypeptidase, catalase, cellulase, chitinase, cutinase, cyclodextrin glycosyltransferase, deoxyribonuclease, esterase, galactosidase, beta-galactosidase, glucoamylase, glucose oxidase, glucosidase, haloperoxidase, hemicellulase, invertase, isomerase, laccase, ligase, lipase, lyase, mannosidase, oxidase, pectinolytic enzyme, peroxidase, phytase, phenoloxidase, polyphenoloxidase, proteolytic enzyme, ribonuclease, transferase, transglutaminase, or xylanase. The biologically active substance-deficient cells may also be used to express heterologous proteins of pharmaceutical interest such as hormones, growth factors, receptors, polymers, e.g., hyaluronic acid and elastin, and the like.

It will be understood that the term “prokaryotic polypeptides” includes not only native polypeptides, but also those polypeptides, e.g., enzymes, which have been modified by amino acid substitutions, deletions or additions, or other such modifications to enhance activity, thermostability, pH tolerance and the like.

In a further aspect, the present invention relates to a product of a protein or substance essentially free of a biologically active substance of the invention, produced by a method of the present invention.

Methods of Inhibiting Expression of a Polypeptide

The present invention also relates to methods of inhibiting the expression of a biological substance in a cell, comprising administering to the cell or expressing in the cell a double-stranded RNA (dsRNA) molecule, wherein the dsRNA comprises a subsequence of a polynucleotide of the present invention. In a preferred aspect, the dsRNA is about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more duplex nucleotides in length.

The dsRNA is preferably a small interfering RNA (siRNA) or a micro RNA (miRNA). In a preferred aspect, the dsRNA is small interfering RNA (siRNAs) for inhibiting transcription. In another preferred aspect, the dsRNA is micro RNA (miRNAs) for inhibiting translation.

The present invention also relates to such double-stranded RNA (dsRNA) molecules, comprising a portion of the coding sequence of any of SEQ ID NOs: 2-4876 for inhibiting expression of a biological substance in a cell. While the present invention is not limited by any particular mechanism of action, the dsRNA can enter a cell and cause the degradation of a single-stranded RNA (ssRNA) of similar or identical sequences, including endogenous mRNAs. When a cell is exposed to dsRNA, mRNA from the homologous gene is selectively degraded by a process called RNA interference (RNAi).

The dsRNAs of the present invention can be used in gene-silencing therapeutics. In one aspect, the invention provides methods to selectively degrade RNA using the dsRNAis of the present invention. The process may be practiced in vitro, ex vivo or in vivo. In one aspect, the dsRNA molecules can be used to generate a loss-of-function mutation in a cell, an organ or an animal. Methods for making and using dsRNA molecules to selectively degrade RNA are well known in the art, see, for example, U.S. Pat. No. 6,506,559; U.S. Pat. No. 6,511,824; U.S. Pat. No. 6,515,109; and U.S. Pat. No. 6,489,127.

Compositions

The present invention also relates to compositions comprising a biologically active substance of the present invention. Preferably, the compositions are enriched in the biologically active substance. The term “enriched” indicates that the biologically active substance of the composition has been increased, e.g., with an enrichment factor of 1.1

The composition may comprise a biologically active substance of the invention as the major component, e.g., a mono-component composition. Alternatively, the composition may comprise multiple biologically active substances, for example, multiple enzymes, such as an aminopeptidase, amylase, carbohydrase, carboxypeptidase, catalase, cellulase, chitinase, cutinase, cyclodextrin glycosyltransferase, deoxyribonuclease, esterase, alpha-galactosidase, beta-galactosidase, glucoamylase, alpha-glucosidase, beta-glucosidase, haloperoxidase, invertase, laccase, lipase, mannosidase, oxidase, pectinolytic enzyme, peptidoglutaminase, peroxidase, phytase, polyphenoloxidase, proteolytic enzyme, ribonuclease, transglutaminase, or xylanase.

The compositions may be prepared in accordance with methods known in the art and may be in the form of a liquid or a dry composition. For instance, the composition may be in the form of a granulate or a microgranulate. The biologically active substance to be included in the composition may be stabilized in accordance with methods known in the art.

Methods for Using the Bacillus licheniformis Chromosome

The present invention also relates to methods for using the Bacillus licheniformis chromosome.

The chromosome of Bacillus licheniformis serves as a reservoir of useful genes/proteins that have environmental, energy, health, and industrial applications (e.g., enzymes, antibiotics, biochemicals). A clear extension of this is that the newly discovered molecules can be used as starting points for further improvements via well-established gene shuffling, directed evolution, and protein engineering methods. Additionally, regions or motifs (e.g., signal peptides, active sites, substrate-binding regions) from the newly discovered molecules may be employed to derive novel chimeras with industrially advantageous properties.

The 5′ and 3′ untranslated regions that are located upstream and downstream, respectively, of the chromosomal genes contain promoters, terminators, and other regulatory elements that control transcription and translation of the adjacent coding DNA sequences (CDSs). These elements may be used to construct novel vectors for efficient expression of homologous and heterologous genes in Bacillus licheniformis and other Bacillus species.

The chromosomal DNA sequence may be used for selecting integration sites for stable inheritance and expression of inserted vector constructs. These constructs may be targeted to specific chromosomal locations using homologous recombination between vector and chromosomal DNA molecules.

The genes encoded in the chromosome may be used for monitoring global gene expression during the life cycle of the organism or during industrial fermentations (e.g., implemented on DNA microarrays). By monitoring global gene expression, for example, improved processes for industrial fermentation can be implemented with greater efficiency and economy.

The genes of Bacillus licheniformis SJ1904 may be employed to improve industrial fermentation strains via selective breeding, conjugative mating, bacteriophage-mediated transduction, and DNA-mediated transformation. In addition, the chromosome of Bacillus licheniformis SJ1904 may be useful, in whole or in part, to construct new microbial cell factories via synthetic biology approaches (Danchin, A. 2004. The bag or the spindle: the cell factory at the time of systems' biology. Microb. Cell Fact. 3: 13).

The chromosome is useful in comparative evolutionary and ecological studies. For example, dozens of Bacillus licheniformis isolates can be readily compared on a global scale by hybridization of their genomic DNAs to a microarray fabricated from the reference strain presented herein (so-called comparative genomic hybridization). Using this method, one can compare various isolates to look for similarities/differences among geographical and environmental niches or among biocontrol strains versus saprophytic isolates.

The chromosome sequence may be used to construct the metabolic blueprint for Bacillus licheniformis that includes all catabolic and anabolic pathways, signaling pathways, regulatory networks, growth substrates, biochemical intermediates, end products, electron donors/acceptors and others. In doing so, it is possible to modify the metabolic machinery of the organism by deleting unwanted pathways and/or adding enzymes/pathways from other organisms to generate useful chemicals and intermediates.

The pathways and components that contribute to production of extracellular and surface proteins in Bacillus licheniformis can be extracted from the chromosomal sequence. This affords opportunities for improved production of extracellular proteins by genetic manipulation of the secretion machinery.

The chromosome data allows deduction of the essential genes for Bacillus licheniformis (either by comparison to related bacteria such as Bacillus subtilis or by systematic gene-by-gene knock outs). Thus it has become possible to design custom-made strains that contain only the genes that are essential for production of specific proteins or metabolites (so-called cell factory concept).

The chromosome data may be used to construct interspecies hybrids between Bacillus licheniformis and other bacteria. Venter et al., 2003, Proc. Nat. Acad. Sci. USA 100, 15440-15445 have shown that it is possible to construct an entire virus genome from smaller DNA segments. Thus, segments of the Bacillus licheniformis chromosome may be employed to derive novel chromosomal segments or even entire chimeric chromosomes for specific applications.

In a preferred aspect, methods for using the Bacillus licheniformis chromosome include host improvement, e.g., secretion of a protein or metabolite, genome shuffling, construction of new genomes, metabolic engineering and pathway reconstruction, carrier for heterologous expression vectors, microarrays as described herein, identification of polypeptides in proteomics analyses, and comparative genomics with other Bacillus species or related organisms.

Methods for Isolating Genes

The present invention also relates to methods for isolating a polynucleotide encoding a biologically active substance from a microbial strain. The method comprises first the addition of a mixture of first labeled nucleic acid probes, isolated from a microbial strain cultured on medium without an inducing substrate, and a mixture of second labeled nucleic acid probes, isolated from the microbial strain cultured on medium with the inducing substrate, to an array of Bacillus licheniformis polynucleotides selected from the group consisting of the polynucleotides of SEQ ID NOs: 2-4876, full-length complementary strands of SEQ ID NOs: 2-4876, and fragments of SEQ ID NOs: 2-4876, under conditions where the labeled nucleic acid probes hybridize to complementary sequences of the Bacillus licheniformis polynucleotides on the array. The first nucleic acid probes are labeled with a first reporter and the second nucleic acid probes are labeled with a second reporter. The array is then examined under conditions wherein the relative expression of the genes of the microbial strain is determined by the observed hybridization reporter signal of each spot on the array in which (i) the Bacillus licheniformis polynucleotides on the array that hybridize to the first nucleic acid probes produce a distinct first hybridization reporter signal or to the second nucleic acid probes produce a distinct second hybridization reporter signal, and (ii) the Bacillus licheniformis polynucleotides on the array that hybridize to both the first and second nucleic acid probes produce a distinct combined hybridization reporter signal. The probe is then sequenced to isolate from the microbial strain the corresponding gene that encodes an enzyme that degrades or converts the substrate.

Enzymes. The gene of interest may encode any enzyme including an oxidoreductase, transferase, hydrolase, lyase, isomerase, or ligase. In a preferred aspect, the enzyme is an acylase, alpha-glucosidase, amidase, aminopeptidase, amylase, carbohydrase, carboxypeptidase, catalase, cellulase, chitinase, cutinase, cyclodextrin glycosyltransferase, deoxyribonuclease, dextrinase, endoglucanase, esterase, galactanase, alpha-galactosidase, beta-galactosidase, glucoamylase, glucanase, glucocerebrosidase, alpha-glucosidase, beta-glucosidase, hemicellulase, invertase, laccase, lignase, lipase, lysin, mannosidase, mutanase, oxidase, pectinolytic enzyme, peroxidase, phosphatase, phospholipase, phytase, polyphenoloxidase, proteolytic enzyme, pullulanase, ribonuclease, transglutaminase, urokinase, or xylanase.

Inducing Substrate. The inducing substrate may be any substrate that is subject to the action of an enzyme, i.e., that degrades or converts the substrate. In a preferred aspect, the inducing substrate is lignin or a lignin-containing material. In a more preferred aspect, the lignin-containing material is lignocellulose. In another preferred aspect, the inducing substrate is cellulose. In another preferred aspect, the inducing substrate is hemicellulose. In another preferred aspect, the inducing substrate is pectin. In another preferred aspect, the inducing substrate is a lipid. In another preferred aspect, the inducing substrate is phospholipid. In another preferred aspect, the inducing substrate is phytic acid. In another preferred aspect, the inducing substrate is protein. In another preferred aspect, the inducing substrate is a starch. In another preferred aspect, the inducing substrate is a medium that is low in nutrients such as amino acids, carbon, nitrogen, phosphate, or iron.

In a more preferred aspect, the protein substrate is blood, casein, egg, gelatin, gluten, milk protein, or soy protein. In another more preferred aspect, the lignin-containing material is hardwood thermomechanical pulp. In another more preferred aspect, the lignocellulose is corn stover. In another more preferred aspect, the lignocellulose is white poplar. In another more preferred aspect, the lignocellulose is rice straw. In another more preferred aspect, the lignocellulose is switch grass.

Microbial Strains. In the methods of the present invention, the microbial strain may be any microbial strain. The strain is cultured on a suitable nutrient medium with and without a substrate of interest. The strain cultured on medium without the substrate is used as a reference for identifying differences in expression of the same or similar complement of genes in the strain cultured on medium with substrate. The strain may be a wild-type, mutant, or recombinant strain.

In the methods of the present invention, the microbial strain is preferably a bacterium. In a more preferred aspect, the bacterium is a Bacillus, Pseudomonas, Streptococcus , or Streptomyces strain or E. coli.

The Bacillus strain may be any Bacillus strain. In a preferred aspect, the Bacillus strain is Bacillus alkalophilus, Bacillus amyloliquefaciens, Bacillus brevis, Bacillus cereus, Bacillus circulans, Bacillus clausii, Bacillus coagulans, Bacillus fastidiosus, Bacillus firmus, Bacillus lautus, Bacillus lentus, Bacillus licheniformis, Bacillus macerans, Bacillus megaterium, Bacillus methanolicus, Bacillus pumilus, Bacillus sphaericus, Bacillus stearothermophilus, Bacillus subtilis , or Bacillus thuringiensis . It will be understood that the term “ Bacillus ” also encompasses relatives of Bacillus such as Paenibacillus, Oceanobacillus , and the like.

The Pseudomonas strain may be any Pseudomonas strain. In a preferred aspect, the Pseudomonas strain is Pseudomonas acidovorans, Pseudomonas aeruginosa, Pseudomonas alcaligenes, Pseudomonas anguilliseptica, Pseudomonas abtimicrobica, Pseudomonas aurantiaca, Pseudomonas aureofaciens, Pseudomonas beijerinckii, Pseudomonas boreopolis, Pseudomonas chlororaphis, Pseudomonas citronellolis, Pseudomonas cocovenenans, Pseudomonas diminuta, Pseudomonas doudoroffii, Pseudomonas echinoides, Pseudomonas elongate, Pseudomonas fluorescens, Pseudomonas fragi, Pseudomonas halophobica, Pseudomonas huttiensis, Pseudomonas indigofera, Pseudomonas lanceolate, Pseudomonas lemoignei, Pseudomonas lundensis, Pseudomonas mendocina, Pseudomonas mephitica, Pseudomonas mucidolens, Pseudomonas oleovorans, Pseudomonas phenazinium, Pseudomonas pictorium, Pseudomonas putida, Pseudomonas resinovorans, Pseudomonas saccharophila, Pseudomonas stanieri, Pseudomonas stutzeri, Pseudomonas taetrolens, or Pseudomonas vesicularis.

The Streptococcus strain may be any Streptococcus strain. In a preferred aspect, the Streptococcus strain is a Streptococcus equisimilis cell. In another preferred aspect, the Streptococcus strain is a Streptococcus pyogenes cell. In another preferred aspect, the Streptococcus strain is a Streptococcus uberis cell. In another preferred aspect, the Streptococcus strain is a Streptococcus equi subsp. Zooepidemicus cell.

The Streptomyces strain may be any Streptomyces strain. In a preferred aspect, the Streptomyces strain is a Streptomyces achromogenes cell. In another preferred aspect, the Streptomyces strain is a Streptomyces avermitilis cell. In another preferred aspect, the Streptomyces strain is a Streptomyces coelicolor cell. In another preferred aspect, the Streptomyces strain is a Streptomyces griseus cell. In a preferred aspect, the Streptomyces strain is Streptomyces lividans . In another preferred aspect, the Streptomyces strain is Streptomyces murinus.

Microarrays. The term “an array of Bacillus licheniformis polynucleotides” is defined herein as a linear or two-dimensional array of preferably discrete elements of an array of Bacillus licheniformis polynucleotides selected from the group consisting of SEQ ID NOs: 2-4876, full-length complementary strands of SEQ ID NOs: 2-4876, and fragments of SEQ ID NOs: 2-4876 (e.g., synthetic oligonucleotides of, for example, 20-60 nucleotides), wherein each discrete element has a finite area, formed on the surface of a solid support. It is understood herein that the term “ Bacillus licheniformis polynucleotides” encompasses the polynucleotides of SEQ ID NOs: 2-4876, full-length complementary strands of SEQ ID NOs: 2-4876, and fragments of SEQ ID NOs: 2-4876.

The term “microarray” is defined herein as an array of Bacillus licheniformis polynucleotide elements having a density of discrete of Bacillus licheniformis polynucleotide elements of at least about 100/cm ² , and preferably at least about 1000/cm ² . The Bacillus licheniformis polynucleotide elements in a microarray have typical dimensions, e.g., diameters, in the range of between about 10 to about 250 μm, preferably in the range of between about 10 to about 200 μm, more preferably in the range of between about 20 to about 150 μm, even more preferably in the range of between about 20 to about 100 μm, most preferably in the range of between about 50 to about 100 μm, and even most preferably in the range of between about 80 to about 100 μm, and are separated from other polynucleotide elements in the microarray by about the same distance.

Methods and instruments for forming microarrays on the surface of a solid support are well known in the art. See, for example, U.S. Pat. No. 5,807,522; U.S. Pat. No. 5,700,637; and U.S. Pat. No. 5,770,151. The instrument may be an automated device such as described in U.S. Pat. No. 5,807,522.

The term “a substrate containing an array of Bacillus licheniformis polynucleotides” is defined herein as a solid support having deposited on the surface of the support one or more (several) of a plurality of Bacillus licheniformis polynucleotides, as described herein, for use in detecting binding of labeled nucleic acids to the Bacillus licheniformis polynucleotides.

The substrate may, in one aspect, be a glass support (e.g., glass slide) having a hydrophilic or hydrophobic coating on the surface of the support, and an array of distinct random nucleic acid fragments bound to the coating, where each distinct random nucleic acid fragment is disposed at a separate, defined position.

Each microarray in the substrate preferably contains at least 10 ³ distinct Bacillus licheniformis in a surface area of less than about 5 or 6 cm ² . Each distinct Bacillus licheniformis polynucleotide (i) is disposed at a separate, defined position on the array, (ii) has a length of at least 50 bp, and (iii) is present in a defined amount between about 0.1 femtomoles and 100 nanomoles or higher if necessary.

For a hydrophilic coating, the glass slide is coated by placing a film of a polycationic polymer with a uniform thickness on the surface of the slide and drying the film to form a dried coating. The amount of polycationic polymer added should be sufficient to form at least a monolayer of polymers on the glass surface. The polymer film is bound to the surface via electrostatic binding between negative silyl-OH groups on the surface and charged cationic groups in the polymers. Such polycationic polymers include, but are not limited to, polylysine and polyarginine.

Another coating strategy employs reactive aldehydes to couple DNA to the slides (Schena et al., 1996 , Proceedings of the National Academy of Science USA 93: 10614-10619; Heller at al., 1997 , Proceedings of the National Academy of Science USA 94: 2150-2155).

Alternatively, the surface may have a relatively hydrophobic character, i.e., one that causes aqueous medium deposited on the surface to bead. A variety of known hydrophobic polymers, such as polystyrene, polypropylene, or polyethylene, have desirable hydrophobic properties, as do glass and a variety of lubricant or other hydrophobic films that may be applied to the support surface. A support surface is “hydrophobic” if an aqueous droplet applied to the surface does not spread out substantially beyond the area size of the applied droplet, wherein the surface acts to prevent spreading of the droplet applied to the surface by hydrophobic interaction with the droplet.

In another aspect, the substrate may be a multi-cell substrate where each cell contains a microarray of Bacillus licheniformis and preferably an identical microarray, formed on a porous surface. For example, a 96-cell array may typically have array dimensions between about 12 and 244 mm in width and 8 and 400 mm in length, with the cells in the array having width and length dimension of 1/12 and ⅛ the array width and length dimensions, respectively, i.e., between about 1 and 20 in width and 1 and 50 mm in length.

The solid support may include a water-impermeable backing such as a glass slide or rigid polymer sheet, or other non-porous material. Formed on the surface of the backing is a water-permeable film, which is formed of porous material. Such porous materials include, but are not limited to, nitrocellulose membrane nylon, polypropylene, and polyvinylidene difluoride (PVDF) polymer. The thickness of the film is preferably between about 10 and 1000 μm. The film may be applied to the backing by spraying or coating, or by applying a preformed membrane to the backing.

Alternatively, the solid support may be simply a filter composed of nitrocellulose, nylon, polypropylene, or polyvinylidene difluoride (PVDF) polymer, or, for that matter, any material suitable for use.

The film surface may be partitioned into a desirable array of cells by water-impermeable grid lines typically at a distance of about 100 to 2000 μm above the film surface. The grid lines can be formed on the surface of the film by laying down an uncured flowable resin or elastomer solution in an array grid, allowing the material to infiltrate the porous film down to the backing, and then curing the grid lines to form the cell-array substrate.

The barrier material of the grid lines may be a flowable silicone, wax-based material, thermoset material (e.g., epoxy), or any other useful material. The grid lines may be applied to the solid support using a narrow syringe, printing techniques, heat-seal stamping, or any other useful method known in the art.

Each well preferably contains a microarray of distinct Bacillus licheniformis polynucleotides. “Distinct Bacillus licheniformis polynucleotides” as applied to the polynucleotides forming a microarray is defined herein as an array member that is distinct from other array members on the basis of a different Bacillus licheniformis polynucleotide sequence or oligo sequence thereof, and/or different concentrations of the same or distinct Bacillus licheniformis polynucleotides and/or different mixtures of distinct Bacillus licheniformis polynucleotides or different-concentrations of Bacillus licheniformis polynucleotides. Thus an array of “distinct Bacillus licheniformis polynucleotides” may be an array containing, as its members, (i) distinct Bacillus licheniformis genes that may have a defined amount in each member, (ii) different, graded concentrations of a specific Bacillus licheniformis polynucleotide, and/or (iii) different-composition mixtures of two or more distinct Bacillus licheniformis polynucleotides.

It will be understood, however, that in the methods of the present invention, any type of substrate known in the art may be used.

The delivery of a known amount of a selected Bacillus licheniformis polynucleotide to a specific position on the support surface is preferably performed with a dispensing device equipped with one or more (several) tips for insuring reproducible deposition and location of the Bacillus licheniformis polynucleotides and for preparing multiple arrays. Any dispensing device known in the art may be used in the methods of the present invention. See, for example, U.S. Pat. No. 5,807,522.

For liquid-dispensing on a hydrophilic surface, the liquid will have less of a tendency to bead, and the dispensed volume will be more sensitive to the total dwell time of the dispenser tip in the immediate vicinity of the support surface.

For liquid-dispensing on a hydrophobic surface, flow of fluid from the tip onto the support surface will continue from the dispenser onto the support surface until it forms a liquid bead. At a given bead size, i.e., volume, the tendency of liquid to flow onto the surface will be balanced by the hydrophobic surface interaction of the bead with the support surface, which acts to limit the total bead area on the surface, and by the surface tension of the droplet, which tends toward a given bead curvature. At this point, a given bead volume will have formed, and continued contact of the dispenser tip with the bead, as the dispenser tip is being withdrawn, will have little or no effect on bead volume.

The desired deposition volume, i.e., bead volume, formed is preferably in the range 2 μl (picoliters) to 2 nl (nanoliters), although volumes as high as 100 nl or more may be dispensed. It will be appreciated that the selected dispensed volume will depend on (i) the “footprint” of the dispenser tip(s), i.e., the size of the area spanned by the tip(s), (ii) the hydrophobicity of the support surface, and (iii) the time of contact with and rate of withdrawal of the tip(s) from the support surface. In addition, bead size may be reduced by increasing the viscosity of the medium, effectively reducing the flow time of liquid from the dispensing device onto the support surface. The drop size may be further constrained by depositing the drop in a hydrophilic region surrounded by a hydrophobic grid pattern on the support surface.

At a given tip size, bead volume can be reduced in a controlled fashion by increasing surface hydrophobicity, reducing time of contact of the tip with the surface, increasing rate of movement of the tip away from the surface, and/or increasing the viscosity of the medium. Once these parameters are fixed, a selected deposition volume in the desired picoliter to nanoliter range can be achieved in a repeatable fashion.

After depositing a liquid droplet of a Bacillus licheniformis polynucleotide sample at one selected location on a support, the tip may be moved to a corresponding position on a second support, the Bacillus licheniformis polynucleotide sample is deposited at that position, and this process is repeated until the random nucleic acid fragment sample has been deposited at a selected position on a plurality of supports.

This deposition process may then be repeated with another random nucleic acid fragment sample at another microarray position on each of the supports.

The diameter of each Bacillus licheniformis polynucleotide region is preferably between about 20-200 μm. The spacing between each region and its closest (non-diagonal) neighbor, measured from center-to-center, is preferably in the range of about 20-400 μm. Thus, for example, an array having a center-to-center spacing of about 250 μm contains about 40 regions/cm or 1,600 regions/cm ² . After formation of the array, the support is treated to evaporate the liquid of the droplet forming each region, to leave a desired array of dried, relatively flat Bacillus licheniformis polynucleotide or oligo thereof regions. This drying may be done by heating or under vacuum. The DNA can also be UV-crosslinked to the polymer coating.

Nucleic Acid Probes. In the methods of the present invention, the strains are cultivated in a nutrient medium with and without a substrate using methods well known in the art for isolation of nucleic acids to be used as probes. For example, the strains may be cultivated by shake flask cultivation, small-scale or large-scale fermentation (including continuous, batch, fed-batch, or solid state fermentations) in laboratory or industrial fermentors performed in a suitable medium. The cultivation takes place in a suitable nutrient medium comprising carbon and nitrogen sources and inorganic salts, using procedures known in the art. Suitable media are available from commercial suppliers or may be prepared according to published compositions (e.g., in catalogues of the American Type Culture Collection).

The nucleic acid probes from the microbial strains cultured on medium with and without substrate may be any nucleic acid including genomic DNA, cDNA, and RNA, and may be isolated using standard methods known in the art.

The populations of isolated nucleic acid probes may be labeled with detection reporters such as colorimetric, radioactive for example, ³² P, ³³ P, or ³⁵ S), fluorescent reporters, or other reporters using methods known in the art (Chen et al., 1998 , Genomics 51: 313-324; DeRisi et al., 1997, Science 278: 680-686; U.S. Pat. No. 5,770,367).

In a preferred aspect, the probes are labeled with fluorescent reporters. For example, the DNA probes may be labeled during reverse transcription from the respective RNA pools by incorporation of fluorophores as dye-labeled nucleotides (DeRisi et al., 1997, supra), e.g., Cy5-labeled deoxyuridine triphosphate, or the isolated cDNAs may be directly labeled with different fluorescent functional groups. Fluorescent-labeled nucleotides include, but are not limited to, fluorescein conjugated nucleotide analogs (green fluorescence), lissamine nucleotide analogs (red fluorescence). Fluorescent functional groups include, but are not limited to, Cy3 (a green fluorescent dye) and Cy5 (red fluorescent dye).

Array Hybridization. The labeled nucleic acids from the two strains cultivated with and without substrate are then added to an array of Bacillus licheniformis polynucleotides under conditions where the nucleic acid pools from the two strains hybridize to complementary sequences of the Bacillus licheniformis polynucleotides on the array. For purposes of the present invention, hybridization indicates that the labeled nucleic acids from the two strains hybridize to the Bacillus licheniformis polynucleotides under very low to very high stringency conditions.

A small volume of the labeled nucleic acids mixture is loaded onto the substrate. The solution will spread to cover the entire microarray. In the case of a multi-cell substrate, one or more (several) solutions are loaded into each cell that stop at the barrier elements.

For nucleic acid probes of at least about 100 nucleotides in length, miroarray hybridization conditions described by Eisen and Brown, 1999 , Methods of Enzymology 303: 179-205, may be used. Hybridization is conducted under a cover slip at 65° C. in 3×SSC for 4-16 hours followed by post-hybridization at room temperature after removal of the cover slip in 2×SSC, 0.1% SDS by washing the array two or three times in the solution, followed by successive washes in 1×SSC for 2 minutes and 0.2×SSC wash for two or more minutes.

Conventional conditions of very low to very high stringency conditions may also be used. Very low to very high stringency conditions are defined as prehybridization and hybridization at 42° C. in 5×SSPE, 0.3% SDS, 200 μg/ml sheared and denatured salmon sperm DNA, and either 25% formamide for very low and low stringencies, 35% formamide for medium and medium-high stringencies, or 50% formamide for high and very high stringencies, following standard Southern blotting procedures.

The carrier material is finally washed three times each for 15 minutes using 2×SSC, 0.2% SDS preferably at least at 45° C. (very low stringency), more preferably at least at 50° C. (low stringency), more preferably at least at 55° C. (medium stringency), more preferably at least at 60° C. (medium-high stringency), even more preferably at least at 65° C. (high stringency), and most preferably at least at 70° C. (very high stringency).

For shorter nucleic acid probes that are less than 50 nucleotides, microarray hybridization conditions described by Kane et al., 2000, Nucleic Acids Research 28: 4552-4557, may be used. Hybridization is conducted under a supported coverslip at 42° C. for 16-18 hours at high humidity in 50% formamide, 4.1×Denhardt's solution, 4.4×SSC, and 100 μg/ml of herring sperm DNA. Arrays are washed after removal of the coverslip in 4×SSC by immersion into 1×SSC, 0.1% SDS for 10 minutes, 0.1×SSC, 0.1% SDS twice for 10 minutes, and 0.1×SSC twice for 10 minutes.

For shorter nucleic acid probes that are about 50 nucleotides to about 100 nucleotides in length, conventional stringency conditions may be used. Such stringency conditions are defined as prehybridization, hybridization, and washing post-hybridization at 5° C. to 10° C. below the calculated T _m , using the calculation according to Bolton and McCarthy (1962 , Proceedings of the National Academy of Sciences USA 48:1390) in 0.9 M NaCl, 0.09 M Tris-HCl pH 7.6, 6 mM EDTA, 0.5% NP-40, 1×Denhardt's solution, 1 mM sodium pyrophosphate, 1 mM sodium monobasic phosphate, 0.1 mM ATP, and 0.2 mg of yeast RNA per ml following standard Southern blotting procedures.

The carrier material is finally washed once in 6×SSC plus 0.1% SDS for 15 minutes and twice each for 15 minutes using 6×SSC at 5° C. to 10° C. below the calculated T _m .

The choice of hybridization conditions will depend on the degree of homology between the Bacillus licheniformis polynucleotides and the nucleic acid probes obtained from the strain cultured with and without inducing substrate. For example, where the nucleic acid probes and the Bacillus licheniformis polynucleotides are obtained from identical strains, high stringency conditions may be most suitable. Where the strains are from a genus or species different from which the Bacillus licheniformis polynucleotides were obtained, low or medium stringency conditions may be more suitable.

In a preferred aspect, the hybridization is conducted under low stringency conditions. In a more preferred aspect, the hybridization is conducted under medium stringency conditions. In a most preferred aspect, the hybridization is conducted under high stringency conditions.

The entire solid support is then reacted with detection reagents if needed and analyzed using standard colorimetric, radioactive, or fluorescent detection means. All processing and detection steps are performed simultaneously to all of the microarrays on the solid support ensuring uniform assay conditions for all of the microarrays on the solid support.

Detection. The most common detection method is laser-induced fluorescence detection using confocal optics (Cheung et al., 1998 , Nat. Genet. 18: 225-230). The array is examined under fluorescence excitation conditions such that (i) the Bacillus licheniformis polynucleotides on the array that hybridize to the first nucleic acid probes obtained from the strain cultured without inducing substrate and to the second nucleic acid probes obtained from the strain cultured with inducing substrate produce a distinct first fluorescence emission color and a distinct second fluorescence emission color, respectively, and (ii) the Bacillus licheniformis polynucleotides on the array that hybridize to substantially equal numbers of nucleic acid probes obtained from the strain cultured without inducing substrate and from the strain cultured with inducing substrate produce a distinct combined fluorescence emission color; wherein the relative expression of the genes in the strains can be determined by the observed fluorescence emission color of each spot on the array.

The fluorescence excitation conditions are based on the selection of the fluorescence reporters. For example, Cy3 and Cy5 reporters are detected with solid state lasers operating at 532 nm and 632 nm, respectively.

However, other methods of detection well known in the art may be used such as standard photometric, colorimetric, or radioactive detection means, as described earlier.

Data Analysis. The data obtained from the scanned image may then be analyzed using any of the commercially available image analysis software. The software preferably identifies array elements, subtracts backgrounds, deconvolutes multi-color images, flags or removes artifacts, verifies that controls have performed properly, and normalizes the signals (Chen et al., 1997, Journal of Biomedical Optics 2: 364-374).

Several computational methods have been described for the analysis and interpretation of microarray-based expression profiles including cluster analysis (Eisen et al., 1998, Proc. Nat. Acad. Sci. USA 95: 14863-14868), paraMetric ordering of genes (Spellman et al., 1998 , Mol. Biol. Ce 119: 3273-3297), and supervised clustering methods based on representative hand-picked or computer-generated expression profiles (Chu et al., 1998 . Science 282: 699-705). Preferred methods for evaluating the results of the microarrays employ statistical analysis to determine the significance of the differences in expression levels. In the methods of the present invention, the difference in the detected expression level is at least about 10% or greater, preferably at least about 20% or greater, more preferably at least about 50% or greater, even more preferably at least about 75% or greater; and most preferably at least about 100% or greater.

One such preferred system is the Significance Analysis of Microarrays (SAM) (Tusher et al., 2001, Proc. Natl. Acad. Sci. USA 98: 5116-5121). Statistical analysis allows the determination of significantly altered expression of levels of about 50% or even less. The PAM (or predictive analysis for microarrays) represents another approach for analyzing the results of the microarrays (Tibshirani et al., 2002, Proc. Natl. Acad. Sci. USA 99: 6567-6572).

Cluster algorithms may also be used to analyze microarray expression data. From the analysis of the expression profiles it is possible to identify co-regulated genes that perform common metabolic or biosynthetic functions. Hierarchical clustering has been employed in the analysis of microarray expression data in order to place genes into clusters based on sharing similar patterns of expression (Eisen et al., 1998, supra). This method yields a graphical display that resembles a kind of phylogenetic tree where the relatedness of the expression behavior of each gene to every other gene is depicted by branch lengths. The programs Cluster and TreeView, both written by Michael Eisen (Eisen et al., 1998 Proc. Nat. Acad. Sci. USA 95: 14863-14868) are freely available. Genespring is a commercial program available for such analysis (Silicon Genetics, Redwood City, Calif.).

Self-organizing maps (SOMs), a non-hierarchical method, have also been used to analyze microarray expression data (Tamayo et al., 1999, Proc. Natl. Acad. Sci. USA 96: 2907-2912). This method involves selecting a geometry of nodes, where the number of nodes defines the number of clusters. Then, the number of genes analyzed and the number of experimental conditions that were used to provide the expression values of these genes are subjected to an iterative process (20,000-50,000 iterations) that maps the nodes and data points into multidimensional gene expression space. After the identification of significantly regulated genes, the expression level of each gene is normalized across experiments. As a result, the expression profile of the genome is highlighted in a manner that is relatively independent of each gene's expression magnitude. Software for the “GENECLUSTER” SOM program for microarray expression analysis can be obtained from the Whitehead/MIT Center for Genome Research. SOMs can also be constructed using the GeneSpring software package.

Isolation of Genes. Probes containing genes or portions thereof identified to be induced by the present of substrate in the medium are characterized by determining the sequence of the probe. Based on the sequence, the gene can then be isolated using methods well known in the art.

The techniques used to isolate or clone a gene include isolation from genomic DNA, preparation from cDNA, or a combination thereof. The cloning of the gene from such genomic DNA can be effected, e.g., by using the well known polymerase chain reaction (PCR) or antibody screening of expression libraries to detect cloned DNA fragments with shared structural features. See, e.g., Innis et al., 1990, PCR: A Guide to Methods and Application , Academic Press, New York. Other nucleic acid amplification procedures such as ligase chain reaction (LCR), ligated activated transcription (LAT) and nucleic acid sequence-based amplification (NASBA) may be used. The gene may be cloned from the strain of interest, or another or related organism and thus, for example, may be a species variant of the gene.

Methods for Monitoring Differential Expression of a Plurality of Genes

The present invention also relates to methods for monitoring differential expression of a plurality of genes in a first bacterial cell relative to expression of the same genes in one or more (several) second bacterial cells, comprising:

(a) adding a mixture of detection reporter-labeled nucleic acids isolated from the bacterial cells to a substrate containing an array of Bacillus licheniformis polynucleotides selected from the group consisting of SEQ ID NOs: 2-4876, full-length complementary strands of SEQ ID NOs: 2-4876, and fragments of SEQ ID NOs: 2-4876, under conditions where the detection reporter-labeled nucleic acids hybridize to complementary sequences of the Bacillus licheniformis polynucleotides on the array, wherein the nucleic acids from the first bacterial cell and the one or more (several) second bacterial cells are labeled with a first detection reporter and one or more (several) different second detection reporters, respectively; and

(b) examining the array under conditions wherein the relative expression of the genes in the bacterial cells is determined by the observed detection signal of each spot on the array in which (i) the Bacillus licheniformis polynucleotides on the array that hybridize to the nucleic acids obtained from either the first or the one or more (several) second bacterial cells produce a distinct first detection signal or one or more (several) second detection signals, respectively, and (ii) the Bacillus licheniformis polynucleotides on the array that hybridize to the nucleic acids obtained from both the first and one or more (several) second bacterial produce a distinct combined detection signal.

The methods of the present invention may be used to monitor global expression of a plurality of genes from a Bacillus cell, discover new genes, identify possible functions of unknown open reading frames, and monitor gene copy number variation and stability. For example, the global view of changes in expression of genes may be used to provide a picture of the way in which Bacillus cells adapt to changes in culture conditions, environmental stress, or other physiological provocation. Other possibilities for monitoring global expression include spore morphogenesis, recombination, metabolic or catabolic pathway engineering.

The methods of the present invention are particularly advantageous since one spot on an array equals one gene or open reading frame because extensive follow-up characterization is unnecessary since sequence information is available, and the Bacillus licheniformis microarrays can be organized based on function of the gene products.

Bacterial Cells. In the methods of the present invention, the two or more Bacillus cells may be any Bacillus cell where one of the cells is used as a reference for identifying differences in expression of the same or similar complement of genes in the other cell(s). In one aspect, the two or more cells are the same cell. For example, they may be compared under different growth conditions, e.g., oxygen limitation, nutrition, and/or physiology. In another aspect, one or more (several) cells are mutants of the reference cell. For example, the mutant(s) may have a different phenotype. In a further aspect, the two or more cells are of different species (e.g., Bacillus clausii and Bacillus subtilis ). In another further aspect, the two or more cells are of different genera. In an even further aspect, one or more (several) cells are transformants of the reference cell, wherein the one or more (several) transformants exhibit a different property. For example, the transformants may have an improved phenotype relative to the reference cell and/or one of the other transformants. The term “phenotype” is defined herein as an observable or outward characteristic of a cell determined by its genotype and modulated by its environment. Such improved phenotypes may include, but are not limited to, improved secretion or production of a protein or compound, reduced or no secretion or production of a protein or compound, improved or reduced expression of a gene, desirable morphology, an altered growth rate under desired conditions, relief of over-expression mediated growth inhibition, or tolerance to low oxygen conditions.

The Bacillus cells may be any Bacillus cells, but preferably Bacillus alkalophilus, Bacillus amyloliquefaciens, Bacillus brevis, Bacillus cereus, Bacillus circulans, Bacillus clausii, Bacillus coagulans, Bacillus fastidiosus, Bacillus firmus, Bacillus lautus, Bacillus lentus, Bacillus licheniformis, Bacillus macerans, Bacillus megaterium, Bacillus methanolicus, Bacillus pumilus, Bacillus sphaericus, Bacillus stearothermophilus, Bacillus subtilis , or Bacillus thuringiensis cells.

In a preferred aspect, the Bacillus cells are Bacillus alkalophilus cells. In another preferred aspect, the Bacillus cells are Bacillus amyloliquefaciens cells. In another preferred aspect, the Bacillus cells are Bacillus brevis cells. In another preferred aspect, the Bacillus cells are Bacillus cereus cells. In another preferred aspect, the Bacillus cells are Bacillus circulans cells. In another preferred aspect, the Bacillus cells are Bacillus clausii cells. In another preferred aspect, the Bacillus cells are Bacillus coagulans cells. In another preferred aspect, the Bacillus cells are Bacillus fastidiosus cells. In another preferred aspect, the Bacillus cells are Bacillus firmus cells. In another preferred aspect, the Bacillus cells are Bacillus lautus cells. In another preferred aspect, the Bacillus cells are Bacillus lentus cells. In another preferred aspect, the Bacillus cells are Bacillus licheniformis cells. In another preferred aspect, the Bacillus cells are Bacillus macerans cells. In another preferred aspect, the Bacillus cells are Bacillus megaterium cells. In another preferred aspect, the Bacillus cells are Bacillus methanolicus cells. In another preferred aspect, the Bacillus cells are Bacillus pumilus cells. In another preferred aspect, the Bacillus cells are Bacillus sphaericus cells. In another preferred aspect, the Bacillus cells are Bacillus stearothermophilus cells. In another preferred aspect, the Bacillus cells are Bacillus subtilis cells. In another preferred aspect, the Bacillus cells are Bacillus thuringiensis cells.

In a more preferred aspect, the Bacillus cells are Bacillus licheniformis cells. In a most preferred aspect, the Bacillus licheniformis cells are Bacillus licheniformis SJ1904 cells.

In another more preferred aspect, the Bacillus cells are Bacillus clausii cells. In another most preferred aspect, the Bacillus clausii cells are Bacillus clausii NCIB 10309 cells.

It will be understood that the term “ Bacillus ” also encompasses relatives of Bacillus such as Paenibacillus, Oceanobacillus , and the like.

In the methods of the present invention, the cells are cultivated in a nutrient medium suitable for growth using methods well known in the art for isolation of the nucleic acids to be used as probes. For example, the cells may be cultivated by shake flask cultivation, small-scale or large-scale fermentation (including continuous, batch, fed-batch, or solid state fermentations) in laboratory or industrial fermentors performed in a suitable medium. The cultivation takes place in a suitable nutrient medium comprising carbon and nitrogen sources and inorganic salts, using procedures known in the art. Suitable media are available from commercial suppliers or may be prepared according to published compositions (e.g., in catalogues of the American Type Culture Collection).

Nucleic Acid Probes. The nucleic acid probes from the two or more Bacillus cells may be any nucleic acid including genomic DNA, cDNA, and RNA, and may be isolated using standard methods known in the art, as described herein. The populations of isolated nucleic acid probes may be labeled with colorimetric, radioactive, fluorescent reporters, or other reporters using methods described herein.

In a preferred aspect, the probes are labeled with fluorescent reporters, e.g., Cy3 (a green fluorescent dye) and Cy5 (red fluorescent dye), as described herein.

Array Hybridization. The labeled nucleic acids from the two or more Bacillus cells are then added to a substrate containing an array of Bacillus licheniformis polynucleotides under conditions, as described herein, where the nucleic acid pools from the two or more Bacillus cells hybridize to complementary sequences of the Bacillus licheniformis polynucleotides on the array.

Detection and Data Analysis. The same methods as described herein are used for detection and data analysis.

Computer Readable Media and Computer-Based Systems

The Bacillus licheniformis chromosome and its polynucleotides (genes) described herein may be “provided” in a variety of media to facilitate their use. The term “provided” refers to a manufacture comprising an array of Bacillus licheniformis polynucleotides. Such manufactures provide the Bacillus licheniformis polynucleotides in a form that allows one skilled in the art to examine the manufacture using means not directly applicable to examining the chromosome or a subset thereof as it exists in nature or in purified form.

Thus, the present invention also relates to such a manufacture in the form of a computer readable medium comprising an array of Bacillus licheniformis polynucleotides selected from the group consisting of SEQ ID NOs: 2-4876, full-length complementary strands of SEQ ID NOs: 2-4876, and fragments of SEQ ID NOs: 2-4876.

In one application of this aspect, the Bacillus licheniformis polynucleotides of the present invention can be recorded on computer readable media. The term “computer readable media” is defined herein as any medium that can be read and accessed by a computer. Such computer readable media include, but are not limited to, magnetic storage media, e.g., floppy discs, hard disc storage medium, and magnetic tape; optical storage media, e.g., CD-ROM, DVD; electrical storage media, e.g., RAM and ROM; and hybrids of these categories, e.g., magnetic/optical storage media. One skilled in the art can readily appreciate how any of the presently known computer readable media can be used to create a manufacture comprising computer readable medium having recorded thereon a nucleotide sequence of the present invention. Likewise, it will be clear to those of skill how additional computer readable media that may be developed also can be used to create analogous manufactures having recorded thereon a nucleotide sequence of the present invention.

As used herein, “recorded” refers to a process for storing information on computer readable medium. One skilled in the art can readily adopt any of the presently known methods for recording information on computer readable medium to generate manufactures comprising the nucleotide sequence information of the present invention.

A variety of data storage structures are available for creating a computer readable medium having recorded thereon a nucleotide sequence of the present invention. The choice of the data storage structure will generally be based on the means chosen to access the stored information. In addition, a variety of data processor programs and formats can be used to store the nucleotide sequence information of the present invention on computer readable medium. The sequence information can be represented in a word processing text file, formatted in commercially-available software such as WordPerfect and Microsoft Word, or represented in the form of an ASCII file, stored in a database application, such as DB2, Sybase, Oracle, or the like. A skilled artisan can readily adapt any number of data-processor structuring formats (e.g., text file or database) in order to obtain computer readable medium having recorded thereon the nucleotide sequence information of the present invention.

Various computer software programs are publicly available that allow a skilled artisan to access sequence information provided in a computer readable medium. Thus, by providing in computer readable form an array of Bacillus licheniformis polynucleotides selected from the group consisting of SEQ ID NOs: 2-4876, full-length complementary strands of SEQ ID NOs: 2-4876, and fragments of SEQ ID NOs: 2-4876, enables one skilled in the art to routinely access the provided sequence information for a wide variety of purposes.

Software utilizing the BLAST (Altschul et al., 1990, supra), BLAZE (Brutlag et al., 1993, Comp. Chem. 17: 203-207), GENEMARK (Lukashin and Borodovsky, 1998, Nucleic Acids Research 26: 1107-1115), GENSCAN (Burge and Karlin, 1997, Journal of Molecular Biology 268: 78-94), GLIMMER (Salzberg et al., 1998, Nucleic Acids Research 26: 544-548), and GRAIL (Xu et al., 1994, Comput. Appl. Biosci. 10: 613-623) search algorithms may be used to identify open reading frames (ORFs) within a genome of interest, which contain homology to ORFs or proteins from both Bacillus licheniformis and Bacillus clausii and from other organisms. Among the ORFs discussed herein are protein encoding fragments of the Bacillus licheniformis and Bacillus clausii genomes useful in producing commercially important proteins, such as enzymes used in fermentation reactions and in the production of commercially useful metabolites.

The present invention further provides systems, particularly computer-based systems, which contain the sequence information described herein. Such systems are designed to identify, among other things, genes and gene products—many of which could be products themselves or used to genetically modify an industrial expression host through increased or decreased expression of a specific gene sequence(s).

The term “a computer-based system” is herein defined as the hardware means, software means, and data storage means used to analyze the nucleotide sequence information of the present invention. The minimum hardware means of the computer-based systems of the present invention comprises a central processing unit (CPU), input means, output means, and data storage means. One skilled in the art can readily appreciate that any currently available computer-based system is suitable for use in the present invention.

As stated above, the computer-based systems of the present invention comprise a data storage means having stored therein a nucleotide sequence of the present invention and the necessary hardware means and software means for supporting and implementing a search means.

The term “data storage means” is defined herein as memory that can store nucleotide sequence information of the present invention, or a memory access means that can access manufactures having recorded thereon the nucleotide sequence information of the present invention.

The term “search means” refers is defined herein as one or more (several) programs that are implemented on the computer-based system to compare a target sequence or target structural motif with the sequence information stored within the data storage means. Search means are used to identify fragments or regions of the present genomic sequences that match a particular target sequence or target motif. A variety of known algorithms are disclosed publicly and a variety of commercially available software for conducting search means are and can be used in the computer-based systems of the present invention. Examples of such software includes, but is not limited to, MacPattern (Fuchs, 1991, Comput. Appl. Biosci. 7: 105-106), BLASTN and BLASTX National Center for Biotechnology Information (NCBI). One skilled in the art can readily recognize that any one of the available algorithms or implementing software packages for conducting homology searches can be adapted for use in the present computer-based systems.

The term “target sequence” is defined here as any DNA (genomic DNA, cDNA) or amino acid sequence of six or more nucleotides or two or more amino acids. One skilled in the art can readily recognize that the longer a target sequence is, the less likely a target sequence will be present as a random occurrence in the database. The most preferred sequence length of a target sequence is from about 10 to 100 amino acids or from about 30 to 300 nucleotide residues. However, it is well recognized that searches for commercially important fragments, such as sequence fragments involved in gene expression and protein processing, may be of shorter length.

The term “a target structural motif” or “target motif” is defined herein as any rationally selected sequence or combination of sequences in which the sequence(s) are chosen based on a three-dimensional configuration that is formed upon the folding of the target motif. There are a variety of target motifs known in the art. Protein target motifs include, but are not limited to, enzyme active sites and signal sequences, substrate and cofactor binding domains, transmembrane domains, and sites for post-translational modifications. Nucleic acid target motifs include, but are not limited to, promoter sequences, hairpin structures and inducible expression elements (protein binding sequences), repeats, palindromes, dyad symmetries, and transcription and translation start and stop sites.

A variety of structural formats for the input and output means can be used to input and output the information in the computer-based systems of the present invention. A preferred format for an output means ranks fragments of the Bacillus licheniformis or Bacillus clausii genomic sequences possessing varying degrees of homology to the target sequence or target motif. Such presentation provides one skilled in the art with a ranking of sequences that contain various amounts of the target sequence or target motif and identifies the degree of homology contained in the identified fragment.

A variety of comparing means can be used to compare a target sequence or target motif with the data storage means to identify sequence fragments of the Bacillus licheniformis and Bacillus clausii genomes. For example, implementing software that utilize the BLAST and BLAZE algorithms, described in Altschul et al., 1990, supra, may be used to identify open reading frames within the Bacillus licheniformis or Bacillus clausii genome or the genomes of other organisms. A skilled artisan can readily recognize that any one of the publicly available homology search programs can be used as the search means for the computer-based systems of the present invention. Suitable proprietary systems that may be known to those of skill also may be employed in this regard.

Codon Usage Table

The present invention further relates to methods for preparing a synthetic gene, comprising (a) generating a codon usage table based on codons used in one or more (several) open reading frames or portions thereof of SEQ ID NO: 1, (b) constructing a synthetic gene or portion thereof that contains in place of one or more (several) native codons one or more (several) preferred codons from the codon usage table, and (c) recovering the synthetic gene. In a preferred aspect, the codon usage table is Table 5. The Bacillus licheniformis chromosomal sequence of SEQ ID NO: 1 or portions thereof can be used to generate codon usage tables to design synthetic genes for their efficient heterologous expression in Bacillus licheniformis host cells. The codon usage tables can be based on (1) the codon used in all the open reading frames, (2) selected open reading frames, (3) fragments of the open reading frames, or (4) fragments of selected open reading frames. With a codon usage table, synthetic genes can be designed with only the most preferred codon for each amino acid; with a number of common codons for each amino acid; or with the same or a similar statistical average of codon usages found in the table of choice.

The synthetic gene can be constructed using any method such as site-directed mutagenesis or PCR generated mutagenesis in accordance with methods known in the art. Although, in principle, the modification may be performed in vivo, i.e., directly on the cell expressing the nucleotide sequence to be modified, it is preferred that the modification is performed in vitro.

The synthetic gene can be further modified by operably linking the synthetic gene to one or more (several) control sequences that direct the expression of the coding sequence in a suitable host cell under conditions compatible with the control sequences using the methods described herein. Nucleic acid constructs, recombinant expression vectors, and recombinant host cells comprising the synthetic gene can also be prepared using the methods described herein.

The present invention also relates to methods for producing a polypeptide encoded by such a synthetic gene comprising (a) cultivating a host cell comprising the synthetic gene under conditions conducive for production of the polypeptide; and (b) recovering the polypeptide.

The present invention is further described by the following examples that should not be construed as limiting the scope of the invention.

EXAMPLES

Example 1

DNA Sequencing and Genome Assembly

The genome of Bacillus licheniformis SJ1904 was sequenced by a combination of the whole genome shotgun method described by Wilson, R. K. and Mardis, E. R., 1997 , In Genome Analysis: A Laboratory Manual , Vol. 1, eds. Birren, B., Green, E. D., Meyers, R. M., and Roskams, J. (Cold Spring Harbor Press, Cold Spring Harbor, N.Y.), pp. 397-454, and by the highly parallel pyrosequencing method described by Margulies et al., 2005, Genome sequencing in microfabricated high-density picolitre reactors. Nature 437: 376-380.

Genomic DNA of Bacillus licheniformis SJ1904 was isolated using the following method: A single colony was used to inoculate 20 ml of LB broth (Davis, R. W., Botstein, D., and Roth, J. R. 1980, Advanced Bacterial Genetics , Cold Spring Harbor Press, Cold Spring Harbor, N.Y.) in a sterile 125 ml Erlenmeyer flask. The culture was incubated at 37° C. overnight with agitation at 240 rpm. The resulting cells were collected by centrifugation in a 45 ml screw-cap tube for 10 minutes at 6000×g, and the cell pellet was resuspended in 5 ml of Tris-glucose buffer (50 mM Tris-HCl, pH 8.0, 50 mM glucose, 10 mM EDTA). Lysozyme was added to a final concentration of 50 μg/ml and the suspension was incubated in a 37° C. water bath for 25 minutes. Next, 200 μl of 10% SDS was added and the tube was gently inverted several times. Five milliliters of a second detergent mixture (1% BRIJ®, 1% deoxycholate, 50 mM EDTA, pH 7.5) was added, and the tube was inverted several times while incubating for 20 minutes at room temperature. An equal volume of phenol:chloroform (1:1 v/v) was added and the tube was inverted gently at room temperature for 20-30 minutes. The tube was centrifuged for 20 minutes at 12,000×g, 4° C. The top aqueous layer was carefully removed with a wide-bore pipette and placed in a clean 45 ml screw-cap tube. The phenol; chloroform extraction was repeated and 1/10 volume of 3 M sodium acetate pH 5.2 was added to the aqueous layer. Two volumes of cold ethanol were carefully layered on top and the DNA was spooled from the solution onto a sterile glass rod. Spooled DNA was carefully rinsed in 70% ethanol and resuspended in a suitable amount of TE buffer (10 mM Tris-HCl, pH 8.0, 1 mM EDTA).

Plasmid libraries were constructed using randomly-sheared and Nhe I-digested genomic DNA that was enriched for 2-3 kb fragments by preparative agarose gel electrophoresis (Berka, R. M., Schneider, P., Golightly, E. J., Brown, S. H., Madden, M., Brown, K. M., Halkier, T., Mondorf, K., and Xu, F., 1997, Appl. Environ. Microbiol. 63: 3151-3157). Approximately 24,000 random clones were sequenced using dye-terminator chemistry (Applied Biosystems, Foster City, Calif.) with ABI 377, ABI 3700, and ABI 3130XL automated sequencers yielding approximately 2× coverage of the genome. For highly parallel pyrosequencing pools of random DNA fragments were generated by shearing genomic DNA and isolating single DNA molecules by limiting dilution (Margulies et al., 2005, supra). Overall sequencing coverage from this method was approximately 20×. High quality contigs were assembled from the raw pyrosequencing data using computer software described by Margulies et al. (2005).

A combination of methods was employed for gap closure including primer walking on selected clones, and PCR-amplified DNA fragments. Sequences from dye-terminator reactions were base-called using TraceTuner 2.0 (Paracel, Inc., Pasadena, Calif.) and assembled using Phrap (Gordon D., Abajian C., and Green P., 1998, Genome Res. 8: 195-202). Phrap, Crossmatch, and Consed were used for sequence finishing (Gordon D., Abajian C., and Green P., 1998, Genome Res. 8: 195-202).

Example 2

Identification and Annotation of Open Reading Frames (ORFs)

Protein coding regions in the assembled genome sequence data were identified using Glimmer version 3.0 (Delcher, A, L., Harmon, D., Kasif, S., White, O. and Salzberg, S. L., 1999, Nucleic Acids Res. 27, 4636-4641), and post-processed using TiCO version 2.0 (Tech M, Morgenstern B, and Meinicke P., 2006, Nucleic Acids Res. 34 (Web Server issue): W588-90). Predicted proteins were compared to the non-redundant database Uniref100 (Bairoch A, Apweiler R, Wu C H, Barker W C, Boeckmann B, Ferro S, Gasteiger E, Huang H, Lopez R, Magrane M, Martin M J, Natale D A, O′Donovan C, Redaschi N, Yeh L S. 2005. The Universal Protein Resource [UniProt]. Nucleic Acids Res. 33: D154-159) and the Bacillus subtilis genome (SubtilList) using BLASTP with an E-value threshold of 1×10 ⁻⁵ . InterProScan version 3.3 with database release 13.0 was used to predict function (Zdobnov, E. M. and Apweiler, R., 2001, Bioinformatics 17, 847-848). The InterPro analysis included comparison to Pfam (Bateman, A., Coin, L., Durbin, R., Finn, R. D., Hollich, V., Griffiths-Jones, S., Khanna, A., Sonnhammer, E. L. et al., 2004, Nucleic Acids Res. 32, D138-D141), TIGRfam (Haft, D. J., Selengut, J. D. and White, O., 2003 , Nucleic Acids Res. 31: 371-373), Interpro (Apweiler, R., Attwood, T. K., Bairock, A., Bateman, A., Birney, E., Biswas, M., Bucher, P., Cerutti, L., Corpet, F., Croning, M. D., et al., 2001, Nucleic Acids Res. 29: 37-40), signal peptide prediction using SignalP version 3.0 (Nielsen, H., Engelbrecht, J., Brunak, S., and von Heijne, G., 1997 , Protein Engineering 10:1-6), and trans-membrane domain prediction using TMHMM version 2.0 (Krogh, A., Larsson, B., von Heijne, G. and Sonnhammer, E. L. L., 2000, J. Mol. Biol. 305, 567-580). These coding sequences (CDSs) were assigned to functional categories based on the Cluster of Orthologous Groups (COG) database (Tatusov, R. L., Natale, D. A., Garkavtsev, I. V., Tatusova, T. A., Shankavarum, U. T., Rao, B. S., Kiryutin, B., Galperin, M. Y., Federova, N. D., and Koonin, E. V. 2001. The COG database: new developments in phylogenetic classification of proteins from complete genomes. Nucleic Acids Res. 29: 22-28) with manual verification as described (Tatusov, R. L., Koonin, E. V. and Lipman, D. J., 1997, Science 278: 631-637; Koonin, E. V. and Galperin, M. Y., 2002, Sequence Evolution-Function: Computational Approaches in Comparative Genomics (Kluwer, Boston)). Transfer RNA genes were identified using tRNAscan-SE version 1.21 (Lowe, T. M. and Eddy, S. R., 1997, Nucleic Acids Res. 25: 955-964).

Example 3

General Features of the Bacillus licheniformis SJ1904 Genome

The genome of Bacillus licheniformis SJ1904 was determined to consist of a circular molecule of 4,345,159 by with an average % G+C content of 46.7% (Table 2). No plasmids were found during the genome analysis, and none were found by agarose gel electrophoresis.

Using a combination of several gene-finding algorithms, 4875 protein coding CDSs and pseudogenes with an average size of 789 by were identified. Among the predicted CDSs, 4225 (86%) have significant similarity (E≦1.0E-05) to proteins in Uniref100 (UniProt). The number of hypothetical and conserved hypothetical proteins in the Bacillus licheniformis SJ1904 genome with hits in the Uniref100 database was 1532. There are 650 CDSs that are unique to the genome of Bacillus licheniformis SJ1904 (no homologues found in the Uniref100 database). There are 72 tRNA genes representing all 20 amino acids and 7 rRNA operons.

The likely origin of replication was identified by homology to the corresponding region in the Bacillus licheniformis ATCC 14580 origin (Rey, M. W, Ramaiya, P, Nelson, B. A., Brody-Karpin, S. D., Zaretsky, E. J., Tang, M., Lopez de Leon, A., Xiang, H., Gusti, V., Clausen, I. G., Olsen, P. B., Rasmussen, M. D., Andersen, J. T., Jorgensen, P. L., Larsen, T. S., Sorokin, A., Bolotin, A., Lapidus, A., Galleron, N., Ehrlich, S. D., and Berka, R. M., 2004, Complete genome sequence of the industrial bacterium Bacillus licheniformis and comparisons with closely related Bacillus species. Genome Biol. 5: R77).

Extracellular proteins: In the Bacillus licheniformis genome, 625 of the 4875 gene models have signal peptides as forecasted by SignalP version 3.0 (Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites. Henrik Nielsen, Jacob Engelbrecht, Soren Brunak and Gunnar von Heijne, 1997, Protein Engineering 10:1-6) and/or PSORTb version 2.0 (J. L. Gardy, M. R. Laird, F. Chen, S. Rey, C. J. Walsh, M. Ester, and F. S. L. Brinkman (2005) PSORTb v.2.0: expanded prediction of bacterial protein subcellular localization and insights gained from comparative proteome analysis, Bioinformatics 21: 617-623). Of these, 304 either have no trans-membrane domain as predicted with TMHMM version 2.0 (A. Krogh, B. Larsson, G. von Heijne, and E. L. L. Sonnhammer, 2000, Journal of Molecular Biology 305: 567-580) or a possible transmembrane domain that overlaps a predicted signal peptide. Based on manual examination, 204 were determined to encode probable secreted proteins and enzymes. Of these 78 (38%) are hypothetical or conserved hypothetical proteins. The sequence ID numbers for each of these genes encoding likely extracellular proteins are listed in Table 4.

Genes found in Bacillus licheniformis SJ1904 that are not predicted in Bacillus licheniformis ATCC 14580: There are 673 gene models in the Bacillus licheniformis SJ 1904 chromosome that were not predicted in the Bacillus licheniformis ATCC 14580 chromosome data (GENBANK® accession number CP000002). The vast majority of the Bacillus licheniformis SJ1904 specific gene models encode hypothetical proteins of unknown or unassigned function (see Table 3). Among those gene models that share similarity to protein sequences in the UniRef100 database, most encode functions that can be ascribed to bacteriophages, transposons, and other mobile genetic elements.

Example 4

Codon Usage Table

The evolution of codon bias, the unequal usage of synonomous codons, is thought to be due to natural selection for the use of preferred codons that match the most abundant species of isoaccepting tRNAs, resulting in increased translational efficiency and accuracy. The practical applications for utilizing codon bias information include optimizing expression of heterologous and mutant genes (Jiang and Mannervik, 1999 , Protein Expression and Purification 15: 92-98), site-directed mutagenesis to derive variant polypeptides from a given gene (Wong et al., 1995, J. Immunol. 154: 3351-3358; Kaji, H. et al., 1999, J. Biochem. 126: 769-775), design and synthesis of synthetic genes (Libertini and Di Donato, 1992 , Protein Engineering 5: 821-825; Feng et al., 2000, Biochem. 39: 15399-15409), and fine-tuning or reducing of translation efficiency of specific genes by introduction of non-preferred codons (Crombie et al., 1992, J. Mol. Biol. 228: 7-12; Carlini and Stephan, 2003, Genetics 163: 239-243).

A codon usage table (Table 5) was generated from SEQ ID NO: 1 with Artemis, a software package created by the Wellcome Trust Sanger Institute (K. Rutherford, J. Parkhill, J. Crook, T. Horsnell, P. Rice, M-A. Rajandream and B. Barrell. 2000. Artemis: sequence visualisation and annotation. Bioinformatics 16: 944-945) on all the predicted protein-coding genes of the Bacillus licheniformis SJ1904 chromosome. Artemis read the coding sequences and calculated the Codon frequency table shown in Table 5. The codon usage data presented in Table 5 comprises the collective frequencies of each codon among the 4875 protein-coding gene models. Some noteworthy observations include (a) CTA and AGT codons are used infrequently, and (b) in several instances where two codon alternatives exist (e.g., Asp, Glu, Phe and Lys), codons with an A or T in the wobble position are preferred.

TABLE 1
Predicted functions
SEQ ID	Gene Name & Product	Uniref100 Hit Description	Uniref100 Accession	Hit Organism
2	dnaA DnaA	Hypothetical protein dnaA [ Bacillus licheniformis DSM 13]	UniRef100_Q65PM2	Bacillus licheniformis DSM 13
3	dnaN DNA polymerase III (beta subunit)	DnaN [ Bacillus licheniformis DSM 13]	UniRef100_Q65PM1	Bacillus licheniformis DSM 13
4	yaaA conserved protein YaaA	YaaA [ Bacillus licheniformis DSM 13]	UniRef100_Q65PM0	Bacillus licheniformis DSM 13
5	recF DNA repair RecF	Hypothetical protein recF [ Bacillus licheniformis DSM 13]	UniRef100_Q65PL9	Bacillus licheniformis DSM 13
6	yaaB YaaB	Hypothetical protein yaaB [ Bacillus licheniformis DSM 13]	UniRef100_Q65PL8	Bacillus licheniformis DSM 13
7	gyrB DNA gyrase (subunit B)	DNA gyrase [ Bacillus licheniformis DSM 13]	UniRef100_Q630A8	Bacillus licheniformis DSM 13
8	gyrA DNA gyrase (subunit A)	DNA gyrase subunit A [ Bacillus licheniformis ]	UniRef100_Q65PL6	Bacillus licheniformis
9	yaaC conserved protein YaaC	YaaC [ Bacillus licheniformis DSM 13]	UniRef100_Q65PL5	Bacillus licheniformis DSM 13
10	guaB inosine-monophosphate dehydrogenase	GuaB [ Bacillus licheniformis DSM 13]	UniRef100_Q65PL4	Bacillus licheniformis DSM 13
11	dacA D-alanyl-D-alanine carboxypeptidase (penicillin-	DacA [ Bacillus licheniformis DSM 13]	UniRef100_Q65PL3	Bacillus licheniformis DSM 13
	binding protein 5)
12	pdx1 Vitamin B6 biosynthesis protein	YaaD [ Bacillus licheniformis DSM 13]	UniRef100_Q65PL2	Bacillus licheniformis DSM 13
13	pdxT SNO glutamine amidotransferase	YaaE [ Bacillus licheniformis DSM 13]	UniRef100_Q65PL1	Bacillus licheniformis DSM 13
14	serS seryl-tRNA synthetase	SerS [ Bacillus licheniformis DSM 13]	UniRef100_Q65PL0	Bacillus licheniformis DSM 13
15	glxK Glycerate kinase GlxK	Glycerate kinase [ Bacillus licheniformis DSM 13]	UniRef100_Q630A0	Bacillus licheniformis DSM 13
16	BLP00015 Putative gluconate transporter	YojA [ Bacillus licheniformis DSM 13]	UniRef100_Q65PK9	Bacillus licheniformis DSM 13
17	BLP00016 Putative sugar diacid recognition protein	YsfB [ Bacillus licheniformis DSM 13]	UniRef100_Q65PK8	Bacillus licheniformis DSM 13
18	BLP00017 conserved Hypothetical Heavy metal	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65PK7	Bacillus licheniformis DSM 13
	transport_detoxification protein
19	dck deoxyadenosine_deoxycytidine kinase	Dck [ Bacillus licheniformis DSM 13]	UniRef100_Q65PK6	Bacillus licheniformis DSM 13
20	dgk deoxyguanosine kinase	Dgk [ Bacillus licheniformis DSM 13]	UniRef100_Q65PK5	Bacillus licheniformis DSM 13
21	yaaH Glycoside hydrolase, family 18, YaaH	YdhD [ Bacillus licheniformis DSM 13]	UniRef100_Q65PK4	Bacillus licheniformis DSM 13
22	yaaI putative Isochorismatase hydrolase YaaI	YaaI [ Bacillus licheniformis DSM 13]	UniRef100_Q65PK3	Bacillus licheniformis DSM 13
23	yaaJ putative Cytidine_deoxycytidylate deaminase,	YaaJ [ Bacillus licheniformis DSM 13]	UniRef100_Q65PK2	Bacillus licheniformis DSM 13
	zinc-binding region YaaJ
24	dnaX DNA polymerase III (gamma and tau subunits)	DnaX [ Bacillus licheniformis DSM 13]	UniRef100_Q65PK1	Bacillus licheniformis DSM 13
25	yaaK conserved hypothetical YaaK
26	recR DNA repair protein RecR	Hypothetical protein recR [ Bacillus licheniformis DSM 13]	UniRef100_Q65PJ9	Bacillus licheniformis DSM 13
27	yaaL conserved hypothetical protein YaaL	Hypothetical protein yaaL [ Bacillus licheniformis DSM 13]	UniRef100_Q65PJ8	Bacillus licheniformis DSM 13
28	bofA BofA	Hypothetical protein bofA [ Bacillus licheniformis DSM 13]	UniRef100_Q65PJ7	Bacillus licheniformis DSM 13
29	csfB CsfB	Hypothetical protein csfB [ Bacillus licheniformis DSM 13]	UniRef100_Q62ZY6	Bacillus licheniformis DSM 13
30	xpaC XpaC	Hypothetical protein xpaC [ Bacillus licheniformis DSM 13]	UniRef100_Q65PJ6	Bacillus licheniformis DSM 13
31	yaaN putative Toxic anion resistance protein YaaN	YaaN [ Bacillus licheniformis DSM 13]	UniRef100_Q65PJ5	Bacillus licheniformis DSM 13
32	yaaO putative Orn_Lys_Arg decarboxylase, C-	YaaO [ Bacillus licheniformis DSM 13]	UniRef100_Q65PJ4	Bacillus licheniformis DSM 13
	terminal YaaO
33	tmk thymidylate kinase	Tmk [ Bacillus licheniformis DSM 13]	UniRef100_Q65PJ3	Bacillus licheniformis DSM 13
34	yaaQ YaaQ	Hypothetical protein yaaQ [ Bacillus licheniformis DSM 13]	UniRef100_Q65PJ2	Bacillus licheniformis DSM 13
35	yaaR conserved hypothetical protein YaaR	YaaR [ Bacillus licheniformis DSM 13]	UniRef100_Q65PJ1	Bacillus licheniformis DSM 13
36	holB DNA polymerase III (delta′ subunit)	HolB [ Bacillus licheniformis DSM 13]	UniRef100_Q65PJ0	Bacillus licheniformis DSM 13
37	yaaT putative signal peptidase II YaaT	YaaT [ Bacillus licheniformis DSM 13]	UniRef100_Q65PI9	Bacillus licheniformis DSM 13
38	yabA DnaA and DnaN interacting protein containing	Hypothetical protein yabA [ Bacillus licheniformis DSM 13]	UniRef100_Q65PI8	Bacillus licheniformis DSM 13
	domain DUF972-YabA
39	yabB conserved hypothetical protein containing SAM	YabB (SAM (And some other nucleotide) binding motif)	UniRef100_Q65PI7	Bacillus licheniformis DSM 13
	(and some other nucleotide) binding motif YabB	[ Bacillus licheniformis DSM 13]
40	yazA putative Excinuclease ABC, C subunit, N-	YazA [ Bacillus licheniformis DSM 13]	UniRef100_Q65PI6	Bacillus licheniformis DSM 13
	terminal YazA
41	yabC putative methyltransferase YabC containing	YabC [ Bacillus licheniformis DSM 13]	UniRef100_Q65PI5	Bacillus licheniformis DSM 13
	domain UPF0011
42	abrB transcriptional regulator AbrB	AbrB [ Bacillus licheniformis DSM 13]	UniRef100_Q65PI4	Bacillus licheniformis DSM 13
43	metS methionyl-tRNA synthetase MetS	MetS [ Bacillus licheniformis DSM 13]	UniRef100_Q65PI3	Bacillus licheniformis DSM 13
44	yabD putative TatD-related deoxyribonuclease YabD	YabD [ Bacillus licheniformis DSM 13]	UniRef100_Q65PI2	Bacillus licheniformis DSM 13
45	yabE conserved hypothetical containing domain	YabE [ Bacillus licheniformis DSM 13]	UniRef100_Q65PI1	Bacillus licheniformis DSM 13
	DUF348 YabE
46	mmV ribonuclease M5	RnmV [ Bacillus licheniformis DSM 13]	UniRef100_Q65PI0	Bacillus licheniformis DSM 13
47	ksgA dimethyladenosine transferase	KsgA [ Bacillus licheniformis DSM 13]	UniRef100_Q65PH9	Bacillus licheniformis DSM 13
48	yabG spore coat assembly Peptidase U57, YabG	Peptidase U57, YabG [ Bacillus licheniformis DSM 13]	UniRef100_Q65PH8	Bacillus licheniformis DSM 13
49	veg Veg	Hypothetical protein veg [ Bacillus licheniformis DSM 13]	UniRef100_Q65PH7	Bacillus licheniformis DSM 13
50	BLP04682 hypothetical protein
51	sspF small acid-soluble spore protein (alpha_beta-	SspF [ Bacillus licheniformis DSM 13]	UniRef100_Q65PH6	Bacillus licheniformis DSM 13
	type SASP)
52	ispE 4-diphosphocytidyl-2-C-methyl-D-erythritol	4-diphosphocytidyl-2-C-methyl-D-erythritol kinase [ Bacillus	UniRef100_Q62ZW4	Bacillus licheniformis DSM 13
	kinase	licheniformis DSM 13]
53	purR transcriptional regulator	PurR [ Bacillus licheniformis DSM 13]	UniRef100_Q65PH4	Bacillus licheniformis DSM 13
54	yabJ putative regulator of purine operon, putative	YabJ [ Bacillus licheniformis DSM 13]	UniRef100_Q65PH3	Bacillus licheniformis DSM 13
	translation initiation inhibitor
55	BLP00052 hypothetical protein
56	spoVG Stage V sporulation protein G	Hypothetical protein spoVG [ Bacillus licheniformis DSM 13]	UniRef100_Q65PH2	Bacillus licheniformis DSM 13
57	gcaD UDP-N-acetylglucosamine pyrophosphorylase	GcaD [ Bacillus licheniformis DSM 13]	UniRef100_Q65PH1	Bacillus licheniformis DSM 13
58	prs phosphoribosylpyrophosphate synthetase	Prs [ Bacillus licheniformis DSM 13]	UniRef100_Q65PH0	Bacillus licheniformis DSM 13
59	ctc general stress protein	Ctc [ Bacillus licheniformis DSM 13]	UniRef100_Q65PG9	Bacillus licheniformis DSM 13
60	spoVC peptidyl-tRNA hydrolase	SpoVC [ Bacillus licheniformis DSM 13]	UniRef100_Q65PG8	Bacillus licheniformis DSM 13
61	yabK conserved hypothetical YabK	Hypothetical protein yabK [ Bacillus licheniformis DSM 13]	UniRef100_Q65PG7	Bacillus licheniformis DSM 13
62	mfd transcription-repair coupling factor	Mfd [ Bacillus licheniformis DSM 13]	UniRef100_Q65PG6	Bacillus licheniformis DSM 13
63	spoVT transcriptional regulator	SpoVT [ Bacillus licheniformis DSM 13]	UniRef100_Q65PG5	Bacillus licheniformis DSM 13
64	yabM putative Polysaccharide biosynthesis protein	YabM [ Bacillus licheniformis DSM 13]	UniRef100_Q65PG4	Bacillus licheniformis DSM 13
	YabM
65	yabN putative phosphatase and methylase	YabN [ Bacillus licheniformis DSM 13]	UniRef100_Q65PG3	Bacillus licheniformis DSM 13
66	yabO putative RNA-binding S4 protein YabO	YabO [ Bacillus licheniformis DSM 13]	UniRef100_Q65PG2	Bacillus licheniformis DSM 13
67	yabP conserved hypothetical protein YabP	Hypothetical protein yabP [ Bacillus licheniformis DSM 13]	UniRef100_Q65PG1	Bacillus licheniformis DSM 13
68	yabQ essential protein for formation of the spore	Hypothetical protein yabQ [ Bacillus licheniformis DSM 13]	UniRef100_Q65PG0	Bacillus licheniformis DSM 13
	cortex YabQ
69	divIC cell-division initiation protein	DivIC [ Bacillus licheniformis DSM 13]	UniRef100_Q65PF9	Bacillus licheniformis DSM 13
70	yabR putative Nucleic acid-binding OB-fold	YabR [ Bacillus licheniformis DSM 13]	UniRef100_Q65PF8	Bacillus licheniformis DSM 13
	protein, contains S1 domain
71	spoIIE seine phosphatase	SpoIIE [ Bacillus licheniformis DSM 13]	UniRef100_Q65PF7	Bacillus licheniformis DSM 13
72	yabS YabS	YabS [ Bacillus licheniformis DSM 13]	UniRef100_Q65PF6	Bacillus licheniformis DSM 13
73	yabT putative serine_threonine-protein kinase	YabT [ Bacillus licheniformis DSM 13]	UniRef100_Q65PF5	Bacillus licheniformis DSM 13
74	tilS tRNA(Ile)-lysidine synthetase	YacA [ Bacillus licheniformis DSM 13]	UniRef100_Q65PF4	Bacillus licheniformis DSM 13
75	hprT hypoxanthine-guanine	HprT [ Bacillus licheniformis DSM 13]	UniRef100_Q65PF3	Bacillus licheniformis DSM 13
	phosphoribosyltransferase
76	ftsH cell-division protein and general stress protein	FtsH [ Bacillus licheniformis DSM 13]	UniRef100_Q65PF2	Bacillus licheniformis DSM 13
	(class III heat-shock)
77	BLP00074 hypothetical protein
78	yacB conserved hypothetical protein YacB	Bordetella pertussis Bvg accessory factor [ Bacillus	UniRef100_Q62ZU0	Bacillus licheniformis DSM 13
		licheniformis DSM 13]
79	hslO putative chaperone protein HslO	YacC [ Bacillus licheniformis DSM 13]	UniRef100_Q65PF0	Bacillus licheniformis DSM 13
80	yacD putative PpiC-type peptidyl-prolyl cis-trans	YacD [ Bacillus licheniformis DSM 13]	UniRef100_Q65PE9	Bacillus licheniformis DSM 13
	isomerase
81	cysK cysteine synthetase A	CysK [ Bacillus licheniformis DSM 13]	UniRef100_Q65PE8	Bacillus licheniformis DSM 13
82	BLP04683 hypothetical protein
83	pabB para-aminobenzoate synthase (subunit A)	PabB [ Bacillus licheniformis DSM 13]	UniRef100_Q65PE7	Bacillus licheniformis DSM 13
84	pabA para-aminobenzoate synthase glutamine	PabA (Para-aminobenzoate synthase glutamine	UniRef100_Q65PE6	Bacillus licheniformis DSM 13
	amidotransferase (subunit B) and anthranilate	amidotransferase (Subunit B) and anthranilate synthase)
	synthase (subunit II)	[ Bacillus licheniformis DSM 13]
85	pabC aminodeoxychorismate lyase	PabC [ Bacillus licheniformis DSM 13]	UniRef100_Q65PE5	Bacillus licheniformis DSM 13
86	sul dihydropteroate synthase	Sul [ Bacillus licheniformis DSM 13]	UniRef100_Q65PE4	Bacillus licheniformis DSM 13
87	folB dihydroneopterin aldolase	FolB [ Bacillus licheniformis DSM 13]	UniRef100_Q65PE3	Bacillus licheniformis DSM 13
88	folK 7,8-dihydro-6-hydroxymethylpterin	FolK [ Bacillus licheniformis DSM 13]	UniRef100_Q65PE2	Bacillus licheniformis DSM 13
	pyrophosphokinase
89	dus1 putative Dihydrouridine synthase TIM-barrel	YacF [ Bacillus licheniformis DSM 13]	UniRef100_Q65PE1	Bacillus licheniformis DSM 13
	protein
90	lysS lysyl-tRNA synthetase	LysS [ Bacillus licheniformis DSM 13]	UniRef100_Q65PE0	Bacillus licheniformis DSM 13
91	BLP00087 hypothetical protein
92	ctsR transcriptional regulator	CtsR [ Bacillus licheniformis DSM 13]	UniRef100_Q65PD9	Bacillus licheniformis DSM 13
93	mcsA McsA	Hypothetical protein mcsA [ Bacillus licheniformis DSM 13]	UniRef100_Q65PD8	Bacillus licheniformis DSM 13
94	mcsB McsB	Hypothetical protein mcsB [ Bacillus licheniformis DSM 13]	UniRef100_Q65PD7	Bacillus licheniformis DSM 13
95	clpC class III stress response-related ATPase	ClpC [ Bacillus licheniformis DSM 13]	UniRef100_Q65PD6	Bacillus licheniformis DSM 13
96	radA DNA repair protein RadA	RadA [ Bacillus licheniformis DSM 13]	UniRef100_Q65PD5	Bacillus licheniformis DSM 13
97	yacK putative DNA binding protein YacK	YacK (H+-transporting two-sector ATPase, delta (OSCP)	UniRef100_Q65PD4	Bacillus licheniformis DSM 13
		subunit) [ Bacillus licheniformis DSM 13]
98	BLP00094 hypothetical protein
99	yacL conserved hypothetical protein YacL	YacL [ Bacillus licheniformis DSM 13]	UniRef100_Q65PD3	Bacillus licheniformis DSM 13
100	ispD 4-diphosphocytidyl-2C-methyl-D-erythritol	YacM [ Bacillus licheniformis DSM 13]	UniRef100_Q65PD2	Bacillus licheniformis DSM 13
	synthase
101	ispF 2-C-methyl-D-erythritol 2,4-cyclodiphosphate	YacN [ Bacillus licheniformis DSM 13]	UniRef100_Q65PD1	Bacillus licheniformis DSM 13
	synthase
102	gltX glutamyl-tRNA synthetase	GltX [ Bacillus licheniformis DSM 13]	UniRef100_Q65PD0	Bacillus licheniformis DSM 13
103	BLP04684 hypothetical protein
104	cysE serine acetyltransferase	CysE [ Bacillus licheniformis DSM 13]	UniRef100_Q65PC9	Bacillus licheniformis DSM 13
105	cysS cysteinyl-tRNA synthetase	CysS [ Bacillus licheniformis DSM 13]	UniRef100_Q65PC8	Bacillus licheniformis DSM 13
106	yazC putative Ribonuclease III, conserved	YazC [ Bacillus licheniformis DSM 13]	UniRef100_Q65PC7	Bacillus licheniformis DSM 13
	hypothetical YazC protein
107	yacO putative tRNA_rRNA methyltransferase YacO	YacO [ Bacillus licheniformis DSM 13]	UniRef100_Q65PC6	Bacillus licheniformis DSM 13
108	yacP conserved hypothetical protein YacP	Hypothetical protein yacP [ Bacillus licheniformis DSM 13]	UniRef100_Q65PC5	Bacillus licheniformis DSM 13
109	sigH RNA polymerase sigma-30 factor (sigma-H)	RNA polymerase sigma-H factor [ Bacillus licheniformis ]	UniRef100_P02964	Bacillus licheniformis
110	rpmGB 50S ribosomal protein L33 2	RpmGB [ Bacillus licheniformis DSM 13]	UniRef100_Q65PC3	Bacillus licheniformis DSM 13
111	secE preprotein translocase subunit	Preprotein translocase secE subunit [ Bacillus licheniformis ]	UniRef100_P38381	Bacillus licheniformis
112	nusG transcription antitermination factor	NusG [ Bacillus licheniformis DSM 13]	UniRef100_Q65PC1	Bacillus licheniformis DSM 13
113	rplK ribosomal protein L11	RplK [ Bacillus licheniformis DSM 13]	UniRef100_Q65PC0	Bacillus licheniformis DSM 13
114	rplA ribosomal protein L1 (BL1)	RplA [ Bacillus licheniformis DSM 13]	UniRef100_Q65PB9	Bacillus licheniformis DSM 13
115	rplJ ribosomal protein L10 (BL5)	Ribosomal protein L10 [ Bacillus licheniformis DSM 13]	UniRef100_Q62ZQ7	Bacillus licheniformis DSM 13
116	rplL ribosomal protein L12 (BL9)	Ribosomal protein L12 [ Bacillus licheniformis DSM 13]	UniRef100_Q62ZQ6	Bacillus licheniformis DSM 13
117	ybxB hypothetical protein with SAM binding motif	YbxB (SAM (And some other nucleotide) binding motif)	UniRef100_Q65PB6	Bacillus licheniformis DSM 13
		[ Bacillus licheniformis DSM 13]
118	rpoB RNA polymerase (beta subunit)	RNA polymerase beta subunit [ Bacillus licheniformis ]	UniRef100_Q65PB5	Bacillus licheniformis
119	rpoC RNA polymerase (beta subunit)	RpoC [ Bacillus licheniformis DSM 13]	UniRef100_Q65PB4	Bacillus licheniformis DSM 13
120	ybxF putative ribosomal protein L7AE family	YbxF [ Bacillus licheniformis DSM 13]	UniRef100_Q65PB3	Bacillus licheniformis DSM 13
121	rpsL ribosomal protein S12 (BS12)	RpsL [ Bacillus licheniformis DSM 13]	UniRef100_Q65PB2	Bacillus licheniformis DSM 13
122	rpsG ribosomal protein S7 (BS7)	RpsG [ Bacillus licheniformis DSM 13]	UniRef100_Q65PB1	Bacillus licheniformis DSM 13
123	fusA elongation factor G	FusA [ Bacillus licheniformis DSM 13]	UniRef100_Q65PB0	Bacillus licheniformis DSM 13
124	tufA elongation factor Tu	TufA [ Bacillus licheniformis DSM 13]	UniRef100_Q65PA9	Bacillus licheniformis DSM 13
125	BLP04685 hypothetical protein
126	rpsJ ribosomal protein RpsJ	30S ribosomal protein S10 [ Bacillus halodurans ]	UniRef100_Q9Z9L5	Bacillus halodurans
127	rplC ribosomal protein L3 (BL3)	RplC [ Bacillus licheniformis DSM 13]	UniRef100_Q65PA7	Bacillus licheniformis DSM 13
128	rplD ribosomal protein L4	RplD [ Bacillus licheniformis DSM 13]	UniRef100_Q65PA6	Bacillus licheniformis DSM 13
129	rplW ribosomal protein L23	RplW [ Bacillus licheniformis DSM 13]	UniRef100_Q65PA5	Bacillus licheniformis DSM 13
130	rplB ribosomal protein L2 (BL2)	RplB [ Bacillus licheniformis DSM 13]	UniRef100_Q65PA4	Bacillus licheniformis DSM 13
131	rpsS ribosomal protein RpsS	RpsS [ Bacillus licheniformis DSM 13]	UniRef100_Q65PA3	Bacillus licheniformis DSM 13
132	rplV ribosomal protein RplV	RplV [ Bacillus licheniformis DSM 13]	UniRef100_Q65PA2	Bacillus licheniformis DSM 13
133	rpsC ribosomal protein S3 (BS3)	RpsC [ Bacillus licheniformis DSM 13]	UniRef100_Q65PA1	Bacillus licheniformis DSM 13
134	rplP ribosomal protein L16	RplP [ Bacillus licheniformis DSM 13]	UniRef100_Q65PA0	Bacillus licheniformis DSM 13
135	rpmC ribosomal protein L29
136	rpsQ ribosomal protein S17 (BS16)	RpsQ [ Bacillus licheniformis DSM 13]	UniRef100_Q65P98	Bacillus licheniformis DSM 13
137	rplN ribosomal protein RplN	RplN [ Bacillus licheniformis DSM 13]	UniRef100_Q65P97	Bacillus licheniformis DSM 13
138	rplX ribosomal protein L24 (BL23) (histone-like protein	RplX [ Bacillus licheniformis DSM 13]	UniRef100_Q65P96	Bacillus licheniformis DSM 13
	HPB12)
139	rplE ribosomal protein L5 (BL6)	RplE [ Bacillus licheniformis DSM 13]	UniRef100_Q65P95	Bacillus licheniformis DSM 13
140	rpsN 30S ribosomal protein S14	RpsN [ Bacillus licheniformis DSM 13]	UniRef100_Q65P94	Bacillus licheniformis DSM 13
141	rpsH ribosomal protein S8 (BS8)	RpsH [ Bacillus licheniformis DSM 13]	UniRef100_Q65P93	Bacillus licheniformis DSM 13
142	rplF ribosomal protein L6 (BL8)	Ribosomal protein L6 [ Bacillus licheniformis DSM 13]	UniRef100_Q62ZN1	Bacillus licheniformis DSM 13
143	rplR ribosomal protein L18	Ribosomal protein L18 [ Bacillus licheniformis DSM 13]	UniRef100_Q62ZN0	Bacillus licheniformis DSM 13
144	rpsE ribosomal protein S5	RpsE [ Bacillus licheniformis DSM 13]	UniRef100_Q65P90	Bacillus licheniformis DSM 13
145	rpmD ribosomal protein L30 (BL27)	RpmD [ Bacillus licheniformis DSM 13]	UniRef100_Q65P89	Bacillus licheniformis DSM 13
146	rplO ribosomal protein L15	RplO [ Bacillus licheniformis DSM 13]	UniRef100_Q65P88	Bacillus licheniformis DSM 13
147	secY preprotein translocase subunit	SecY [ Bacillus licheniformis DSM 13]	UniRef100_Q65P87	Bacillus licheniformis DSM 13
148	adk adenylate kinase	Adk [ Bacillus licheniformis DSM 13]	UniRef100_Q65P86	Bacillus licheniformis DSM 13
149	map methionine aminopeptidase	Map [ Bacillus licheniformis DSM 13]	UniRef100_Q65P85	Bacillus licheniformis DSM 13
150	BLP00139 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P84	Bacillus licheniformis DSM 13
151	infA Translation initiation factor IF-1 InfA	InfA [ Bacillus licheniformis DSM 13]	UniRef100_Q65P83	Bacillus licheniformis DSM 13
152	rpmJ ribosomal protein L36 (ribosomal protein B)	50S ribosomal protein L36 [ Bacillus subtilis ]	UniRef100_P20278	Bacillus subtilis
153	rpsM Ribosomal protein S13 RpsM	RpsM [ Bacillus licheniformis DSM 13]	UniRef100_Q65P81	Bacillus licheniformis DSM 13
154	rpsK ribosomal protein S11 (BS11)	RpsK [ Bacillus licheniformis DSM 13]	UniRef100_Q65P80	Bacillus licheniformis DSM 13
155	rpoA RNA polymerase (alpha subunit)	RpoA [ Bacillus licheniformis DSM 13]	UniRef100_Q65P79	Bacillus licheniformis DSM 13
156	rplQ ribosomal protein L17 (BL15)	RplQ [ Bacillus licheniformis DSM 13]	UniRef100_Q65P78	Bacillus licheniformis DSM 13
157	cbiO ABC transporter	YbxA [ Bacillus licheniformis DSM 13]	UniRef100_Q65P77	Bacillus licheniformis DSM 13
158	ybaE ABC transport system ATP-binding protein	YbaE [ Bacillus licheniformis DSM 13]	UniRef100_Q65P76	Bacillus licheniformis DSM 13
159	ybaF Cobalt transport protein	YbaF [ Bacillus licheniformis DSM 13]	UniRef100_Q65P75	Bacillus licheniformis DSM 13
160	truA pseudouridylate synthase I	TruA [ Bacillus licheniformis DSM 13]	UniRef100_Q65P74	Bacillus licheniformis DSM 13
161	rplM ribosomal protein L13	RplM [ Bacillus licheniformis DSM 13]	UniRef100_Q65P73	Bacillus licheniformis DSM 13
162	rpsI ribosomal protein S9	RpsI [ Bacillus licheniformis DSM 13]	UniRef100_Q65P72	Bacillus licheniformis DSM 13
163	BLP00148 Lambda integrase-like protein(phage	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KT3	Bacillus licheniformis DSM 13
	related)
164	BLP04812 phage related protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62W79	Bacillus licheniformis DSM 13
165	yonS conserved hypothetical phage protein YonS	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KT1	Bacillus licheniformis DSM 13
166	BLP00149 conserved hypothetical phage protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KT0	Bacillus licheniformis DSM 13
167	BLP00150 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KS9	Bacillus licheniformis DSM 13
168	yqaE probable transcriptional regulator (phage-	YqaE [ Bacillus licheniformis DSM 13]	UniRef100_Q65KS8	Bacillus licheniformis DSM 13
	related)
169	BLP00152 Putative transcriptional regulator	Transcriptional regulator, Cro/Cl family [ Enterococcus	UniRef100_Q832S7	Enterococcus faecalis
		faecalis ]
170	BLP00153 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KS7	Bacillus licheniformis DSM 13
171	BLP00154 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KS6	Bacillus licheniformis DSM 13
172	BLP00155 putative phage protein	77ORF010 [Bacteriophage 77]	UniRef100_Q6R854	Bacteriophage 77
173	BLP00156 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KS4	Bacillus licheniformis DSM 13
174	BLP04687 hypothetical protein
175	BLP04842 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62W68	Bacillus licheniformis DSM 13
176	BLP00157 phage related protein	Orf178 [ Staphylococcus aureus temperate phage phiSLT]	UniRef100_Q9B0G4	Staphylococcus aureus temperate
				phage phiSLT
177	BLP00158 conserved hypothetical phage protein	Hypothetical protein [ Enterococcus faecalis ]	UniRef100_Q833D2	Enterococcus faecalis
178	BLP00159 conserved hypothetical phage protein
179	BLP00160 hypothetical protein
180	BLP04686 hypothetical protein
181	BLP00161 hypothetical protein
182	BLP00162 conserved hypothetical phage protein	Hypothetical protein [ Bacillus anthracis ]	UniRef100_Q81XU9	Bacillus anthracis
183	BLP00163 hypothetical protein	DNA replication protein DnaC [ Clostridium acetobutylicum ]	UniRef100_Q97HS5	Clostridium acetobutylicum
184	yqaO phage related protein YqaO	YqaO [ Bacillus licheniformis DSM 13]	UniRef100_Q65KR7	Bacillus licheniformis DSM 13
185	BLP00166 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KR6	Bacillus licheniformis DSM 13
186	BLP00167 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KR5	Bacillus licheniformis DSM 13
187	BLP00168 hypothetical protein
188	BLP00169 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KR2	Bacillus licheniformis DSM 13
189	BLP00170 phage related protein	Prophage Lp1 protein 30 [ Lactobacillus plantarum ]	UniRef100_Q88YU0	Lactobacillus plantarum
190	yqaN phage related protein YqaN	YqaN [ Bacillus licheniformis DSM 13]	UniRef100_Q65KQ9	Bacillus licheniformis DSM 13
191	BLP00172 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62W56	Bacillus licheniformis DSM 13
192	BLP00173 hypothetical protein
193	BLP00174 conserved Ssb-homolog protein	Ssb [ Bacillus licheniformis DSM 13]	UniRef100_Q65CP4	Bacillus licheniformis DSM 13
194	BLP00175 hypothetical protein
195	BLP00175 hypothetical protein
196	BLP00177 hypothetical protein
197	ssb single-strand DNA-binding protein	Single-strand DNA-binding protein [ Bacillus licheniformis	UniRef100_Q62W55	Bacillus licheniformis DSM 13
		DSM 13]
198	BLP04690 hypothetical protein
199	BLP00179 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KQ7	Bacillus licheniformis DSM 13
200	BLP00180 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KQ6	Bacillus licheniformis DSM 13
201	BLP00181 conserved hypothetical protein	YqaQ [ Bacillus licheniformis DSM 13]	UniRef100_Q65KQ3	Bacillus licheniformis DSM 13
202	BLP00182 phage related protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KQ1	Bacillus licheniformis DSM 13
203	BLP00183 hypothetical protein
204	BLP00184 putative terminase small subunit protein	Putative terminase small subunit TerS [Bacteriophage	UniRef100_Q7Y5U8	Bacteriophage Aaphi23
		Aaphi23]
205	BLP00185 putative phage terminase, large subunit,	UPI00003CC57A UniRef100 entry	UniRef100_UPI00003CC57A
	PBSX family
206	BLP00186 hypothetical protein
207	BLP00187 putative Phage portal protein, A118 family	UPI00003CC5A4 UniRef100 entry	UniRef100_UPI00003CC5A4
208	BLP00189 putative Gp4-like protein	UPI00003CC514 UniRef100 entry	UniRef100_UPI00003CC514
209	BLP00190 hypothetical protein
210	BLP00191 hypothetical protein
211	BLP00192 conserved hypothetical phage protein	Pas24 [Actinoplanes phage phiAsp2]	UniRef100_Q6J807	Actinoplanes phage phiAsp2
212	BLP00193 conserved hypothetical phage-like protein	Hypothetical protein SPs0635 [ Streptococcus pyogenes ]	UniRef100_Q879B4	Streptococcus pyogenes
213	BLP00194 conserved phage protein	Lin2390 protein [ Listeria innocua ]	UniRef100_Q928Z0	Listeria innocua
214	BLP00195 conserved phage protein
215	BLP00196 conserved phage protein	UPI00003CC51A UniRef100 entry	UniRef100_UPI00003CC51A
216	BLP04843 conserved hypothetical phage protein	UPI00003CA3DF UniRef100 entry	UniRef100_UPI00003CA3DF
217	BLP00197 hypothetical protein
218	BLP00198 hypothetical protein	UPI00003CC51D UniRef100 entry	UniRef100_UPI00003CC51D
219	BLP04691 hypothetical protein
220	BLP00199 hypothetical protein	UPI00003CC51E UniRef100 entry	UniRef100_UPI00003CC51E
221	BLP00200 hypothetical protein	UPI00003CC549 UniRef100 entry	UniRef100_UPI00003CC549
222	BLP00201 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KN3	Bacillus licheniformis DSM 13
223	BLP00203 hypothetical protein	UPI00003CC2A0 UniRef100 entry	UniRef100_UPI00003CC2A0
224	BLP00204 phage related protein	Hypothetical Phage minor structural protein, N-terminal	UniRef100_Q65KN1	Bacillus licheniformis DSM 13
		[ Bacillus licheniformis DSM 13]
225	BLP00205 hypothetical protein	Complete nucleotide sequence [Bacteriophage SPP1]	UniRef100_O48465	Bacteriophage SPP1
226	BLP00206 hypothetical protein
227	BLP00207 hypothetical protein
228	BLP00208 hypothetical protein
229	BLP00209 hypothetical protein
230	BLP00210 hypothetical protein
231	BLP00211 N-acetylmuramoyl-L-alanine amidase	Complete nucleotide sequence [Bacteriophage SPP1]	UniRef100_O48471	Bacteriophage SPP1
232	BLP00212 hypothetical protein	YizA [ Bacillus licheniformis DSM 13]	UniRef100_Q65P71	Bacillus licheniformis DSM 13
233	ybaK conserved hypothetical protein YbaK	Hypothetical protein ybaK [ Bacillus licheniformis DSM 13]	UniRef100_Q65P70	Bacillus licheniformis DSM 13
234	cwlD N-acetylmuramoyl-L-alanine amidase	CwlD [ Bacillus licheniformis DSM 13]	UniRef100_Q65P69	Bacillus licheniformis DSM 13
235	mrp putative ATP-binding protein Mrp	YbaL [ Bacillus licheniformis DSM 13]	UniRef100_Q65P68	Bacillus licheniformis DSM 13
236	gerD GerD	Hypothetical protein gerD [ Bacillus licheniformis DSM 13]	UniRef100_Q65P67	Bacillus licheniformis DSM 13
237	BLP04692 hypothetical protein
238	kbaA kinB signaling pathway activation protein KbaA	Hypothetical protein kbaA [ Bacillus licheniformis DSM 13]	UniRef100_Q65P66	Bacillus licheniformis DSM 13
239	ybaN Polysaccharide deacetylase, Carbohydrate	YbaN [ Bacillus licheniformis DSM 13]	UniRef100_Q65P65	Bacillus licheniformis DSM 13
	Esterase Family 4
240	BLP00219 putative integrase	UPI00003CB8B4 UniRef100 entry	UniRef100_UPI00003CB8B4
241	BLP00220 hypothetical protein
242	BLP00221 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65KE2	Bacillus licheniformis DSM 13
243	BLP00222 hypothetical protein
244	BLP04911 conserved hyopothetical protein
245	BLP04912 hypothetical protein
246	BLP04693 hypothetical protein
247	BLP04913 hypothetical protein
248	BLP00223 hypothetical protein
249	BLP04914 hypothetical protein
250	BLP00224 hypothetical protein
251	BLP04915 hypothetical protein
252	BLP00225 hypothetical protein	Hypothetical protein [ Bacillus cereus ZK]	UniRef100_Q633V9	Bacillus cereus ZK
253	BLP04916 hypothetical protein
254	BLP00226 hypothetical protein
255	BLP00227 hypothetical protein
256	BLP04917 hypothetical protein
257	BLP04918 hypothetical protein
258	BLP00228 hypothetical protein	Transposase, IS256 family [ Enterococcus faecalis ]	UniRef100_Q833S8	Enterococcus faecalis
259	BLP04694 hypothetical protein	Very-short-patch-repair endonuclease [ Oceanobacillus	UniRef100_Q8EL90	Oceanobacillus iheyensis
		iheyensis ]
260	BLP00229 hypothetical protein	Hypothetical protein OB3334 [ Oceanobacillus iheyensis ]	UniRef100_Q8EL97	Oceanobacillus iheyensis
261	BLP04813 conserved hypothetical	Hypothetical protein [ Bacillus cereus ZK]	UniRef100_Q636X5	Bacillus cereus ZK
262	BLP00230 Modification methylase, Cytosine-specific	Cytosine-specific DNA-methyltransferase [ Oceanobacillus	UniRef100_Q8EL98	Oceanobacillus iheyensis
	methyltransferase	iheyensis ]
263	BLP00231 hypothetical protein
264	BLP00232 hypothetical protein
265	BLP00233 hypothetical protein
266	BLP04695 hypothetical protein	DNA-binding protein [ Listeria monocytogenes ]	UniRef100_Q723Z9	Listeria monocytogenes
267	BLP00234 hypothetical protein
268	pbpX penicillin-binding protein	PbpX [ Bacillus licheniformis DSM 13]	UniRef100_Q65P64	Bacillus licheniformis DSM 13
269	BLP00236 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P63	Bacillus licheniformis DSM 13
270	ybaS Bile acid:sodium symporter	YbaS [ Bacillus licheniformis DSM 13]	UniRef100_Q65P62	Bacillus licheniformis DSM 13
271	yxaJ conserved hypothetical protein YxaJ	YxaJ [ Bacillus licheniformis DSM 13]	UniRef100_Q65P61	Bacillus licheniformis DSM 13
272	BLP00239 Phenazine biosynthesis PhzC_PhzF	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P60	Bacillus licheniformis DSM 13
	protein, Aminoacyl-tRNA synthetase, class I
273	ybbC conserved hypothetical protein YbbC	YbbC [ Bacillus licheniformis DSM 13]	UniRef100_Q65P59	Bacillus licheniformis DSM 13
274	ybbD Glycoside hydrolase, family 3	YbbD [ Bacillus licheniformis DSM 13]	UniRef100_Q65P58	Bacillus licheniformis DSM 13
275	ybbE putative beta-lactamase YbbE	YbbE [ Bacillus licheniformis DSM 13]	UniRef100_Q65P57	Bacillus licheniformis DSM 13
276	BLP00243 hypothetical protein
277	ybbF Phosphotransferase system PTS, EIIB	YbbF [ Bacillus licheniformis DSM 13]	UniRef100_Q65P56	Bacillus licheniformis DSM 13
	domain, Phosphotransferase system, EIIC
278	ybbH probable transcriptional regulator YbbH	YbbH [ Bacillus licheniformis DSM 13]	UniRef100_Q65P55	Bacillus licheniformis DSM 13
279	ybbI putative sugar phosphate isomerase YbbI	YbbI [ Bacillus licheniformis DSM 13]	UniRef100_Q65P54	Bacillus licheniformis DSM 13
280	ybbK conserved hypothetical protein YbbK	YbbK [ Bacillus licheniformis DSM 13]	UniRef100_Q65P53	Bacillus licheniformis DSM 13
281	rocF arginase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P52	Bacillus licheniformis DSM 13
282	sigW RNA polymerase ECF(extracytoplasmic	SigW (RNA polymerase ECF(Extracytoplasmic function)-type	UniRef100_Q65P51	Bacillus licheniformis DSM 13
	function)-type sigma factor (sigma-W)	sigma factor) [ Bacillus licheniformis DSM 13]
283	rsiW antisigma factor RsiW	Hypothetical protein ybbM [ Bacillus licheniformis DSM 13]	UniRef100_Q65P50	Bacillus licheniformis DSM 13
284	ybbP conserved hypothetical containing domain	Hypothetical protein ybbP [ Bacillus licheniformis DSM 13]	UniRef100_Q62ZI8	Bacillus licheniformis DSM 13
	DUF147 YbbP
285	ybbR conserved hypothetical protein YbbR	Hypothetical protein ybbR [ Bacillus licheniformis DSM 13]	UniRef100_Q65P48	Bacillus licheniformis DSM 13
286	glmM putative Phosphoglucosamine mutase GlmM	YbbT [ Bacillus licheniformis DSM 13]	UniRef100_Q65P47	Bacillus licheniformis DSM 13
287	BLP00254 hypothetical protein
288	glmS L-glutamine-D-fructose-6-phosphate	GlmS [ Bacillus licheniformis DSM 13]	UniRef100_Q65P46	Bacillus licheniformis DSM 13
	amidotransferase
289	BLP00256 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P45	Bacillus licheniformis DSM 13
290	BLP00257 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P44	Bacillus licheniformis DSM 13
291	BLP00258 ABC transporter, ATP_GTP-binding site	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P43	Bacillus licheniformis DSM 13
	motif A (P-loop)
292	BLP00259 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P42	Bacillus licheniformis DSM 13
293	BLP00260 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P41	Bacillus licheniformis DSM 13
294	ybcL probable transporter	YbcL [ Bacillus licheniformis DSM 13]	UniRef100_Q65P40	Bacillus licheniformis DSM 13
295	BLP00262 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P39	Bacillus licheniformis DSM 13
296	yvcC ABC transporter	YvcC [ Bacillus licheniformis DSM 13]	UniRef100_Q65P38	Bacillus licheniformis DSM 13
297	ywbO DSBA oxidoreductase YwbO	YwbO [ Bacillus licheniformis DSM 13]	UniRef100_Q65P37	Bacillus licheniformis DSM 13
298	BLP04696 hypothetical protein
299	BLP00265 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P36	Bacillus licheniformis DSM 13
300	BLP00266 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P35	Bacillus licheniformis DSM 13
301	aadK aminoglycoside 6-adenylyltransferase	AadK [ Bacillus licheniformis DSM 13]	UniRef100_Q65P34	Bacillus licheniformis DSM 13
302	BLP00268 conserved hypothetical kinase-like protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P33	Bacillus licheniformis DSM 13
303	yfnB HAD-superfamily hydrolase, subfamily IA, variant	YfnB [ Bacillus licheniformis DSM 13]	UniRef100_Q65P32	Bacillus licheniformis DSM 13
	1 YfnB
304	ybxG Amino acid permease YbxG	YbxG [ Bacillus licheniformis DSM 13]	UniRef100_Q65P31	Bacillus licheniformis DSM 13
305	BLP00271 hypothetical protein
306	BLP00272 hypothetical protein
307	citM secondary transporter of divalent metal	CitM [ Bacillus licheniformis DSM 13]	UniRef100_Q65P30	Bacillus licheniformis DSM 13
	ions_citrate complexes
308	BLP00274 hypothetical protein
309	yflP YflP	YflP [ Bacillus licheniformis DSM 13]	UniRef100_Q65P29	Bacillus licheniformis DSM 13
310	citT two-component response regulator	CitT [ Bacillus licheniformis DSM 13]	UniRef100_Q65P28	Bacillus licheniformis DSM 13
311	citS two-component sensor histidine kinase	CitS [ Bacillus licheniformis DSM 13]	UniRef100_Q65P27	Bacillus licheniformis DSM 13
312	cisL transcriptional activator of the cysJI operon	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P26	Bacillus licheniformis DSM 13
313	BLP00279 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P25	Bacillus licheniformis DSM 13
314	BLP00280 Sugar transporter superfamily	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P24	Bacillus licheniformis DSM 13
315	csgA sporulation-specific SASP protein	CsgA [ Bacillus licheniformis DSM 13]	UniRef100_Q65P23	Bacillus licheniformis DSM 13
316	ybxH conserved hypothetical protein YbxH	Hypothetical protein ybxH [ Bacillus licheniformis DSM 13]	UniRef100_Q65P22	Bacillus licheniformis DSM 13
317	BLP00283 hypothetical protein
318	ybyB conserved hypothetical protein YbyB	Hypothetical protein ybyB [ Bacillus licheniformis DSM 13]	UniRef100_Q62ZG0	Bacillus licheniformis DSM 13
319	yyaL conserved protein YyaL	YyaL [ Bacillus licheniformis DSM 13]	UniRef100_Q65P20	Bacillus licheniformis DSM 13
320	ydeG Major facilitator superfamily	YdeG [ Bacillus licheniformis DSM 13]	UniRef100_Q65P12	Bacillus licheniformis DSM 13
321	BLP00287 SAM (and some other nucleotide) binding	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P11	Bacillus licheniformis DSM 13
	motif, Generic methyltransferase
322	BLP00288 conserved hypothetical, putative	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P10	Bacillus licheniformis DSM 13
	epimerase
323	BLP04697 hypothetical protein
324	BLP00289 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P09	Bacillus licheniformis DSM 13
325	BLP00290 Na_Pi cotransporter II-related protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P08	Bacillus licheniformis DSM 13
326	yubF conserved protein YubF	YubF [ Bacillus licheniformis DSM 13]	UniRef100_Q65P07	Bacillus licheniformis DSM 13
327	BLP00292 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P06	Bacillus licheniformis DSM 13
328	BLP00293 hypothetical protein	YbfF [ Bacillus licheniformis DSM 13]	UniRef100_Q65P05	Bacillus licheniformis DSM 13
329	BLP00294 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P04	Bacillus licheniformis DSM 13
330	BLP00295 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65P03	Bacillus licheniformis DSM 13
331	ybfH conserved hypothetical membrane protein YbfH	Hypothetical protein ybfH [ Bacillus licheniformis DSM 13]	UniRef100_Q65P02	Bacillus licheniformis DSM 13
332	ybfI conserved hypothetical protein YbfI	YbfI protein [ Bacillus subtilis ]	UniRef100_O31449	Bacillus subtilis
333	BLP00298 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NZ9	Bacillus licheniformis DSM 13
334	BLP00299 conserved hypothetical DNA-binding	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NZ8	Bacillus licheniformis DSM 13
	protein
335	BLP00300 Hypothetical Bipartite response regulator,	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NZ7	Bacillus licheniformis DSM 13
	C-terminal effector
336	BLP00301 putative Iron-containing alcohol	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NZ6	Bacillus licheniformis DSM 13
	dehydrogenase
337	yvaQ putative transmembrane receptor taxis protein	YvaQ [ Bacillus licheniformis DSM 13]	UniRef100_Q65NZ5	Bacillus licheniformis DSM 13
	YvaQ
338	BLP00303 putative ribose ABC transporter (ribose-	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NZ4	Bacillus licheniformis DSM 13
	binding protein)
339	BLP00304 putative lytic transglycosylase YomI	Hypothetical protein yomI [ Bacillus licheniformis DSM 13]	UniRef100_Q65NZ3	Bacillus licheniformis DSM 13
340	BLP00305 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NZ2	Bacillus licheniformis DSM 13
341	BLP00306 putative soluble quinoprotein glucose	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NZ1	Bacillus licheniformis DSM 13
	dehydrogenase protein
342	ycbP conserved hypothetical protein YcbP	YcbP [ Bacillus licheniformis DSM 13]	UniRef100_Q65NZ0	Bacillus licheniformis DSM 13
343	ybgF Amino acid permease YbgF	YbgF [ Bacillus licheniformis DSM 13]	UniRef100_Q65NY9	Bacillus licheniformis DSM 13
344	ybgG Homocysteine S-methyltransferase YbgG	YbgG [ Bacillus licheniformis DSM 13]	UniRef100_Q65NY8	Bacillus licheniformis DSM 13
345	BLP00310 Hypothetical YdjC-like protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NY7	Bacillus licheniformis DSM 13
346	BLP00311 phosphotransferase system (PTS) N-	Hypothetical protein (Phosphotransferase system (PTS) N-	UniRef100_Q65NY6	Bacillus licheniformis DSM 13
	acetylglucosamine-specific enzyme IICB component	acetylglucosamine-specific enzyme IICB component) [ Bacillus
		licheniformis DSM 13]
347	mtaA transcriptional regulator	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NY5	Bacillus licheniformis DSM 13
348	BLP00313 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NY4	Bacillus licheniformis DSM 13
349	BLP00314 putative carbonic anhyrdase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NY3	Bacillus licheniformis DSM 13
350	BLP00315 hypothetical protein
351	yjgA conserved hypothetical protein YjgA	YjgA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NY2	Bacillus licheniformis DSM 13
352	BLP00317 Sodium:alanine symporter	Sodium:alanine symporter, Sodium:alanine symporter	UniRef100_Q62ZC8	Bacillus licheniformis DSM 13
		[ Bacillus licheniformis DSM 13]
353	ybgJ Glutaminase YbgJ	YbgJ [ Bacillus licheniformis DSM 13]	UniRef100_Q65NY1	Bacillus licheniformis DSM 13
354	BLP00319 hypothetical protein
355	ycbA Two component Histidine kinase YcbA	YcbA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NY0	Bacillus licheniformis DSM 13
356	glnL, ycbB Sensory transduction protein GlnL	YcbB [ Bacillus licheniformis DSM 13]	UniRef100_Q65NX9	Bacillus licheniformis DSM 13
357	ynaD GCN5-related N-acetyltransferase	YnaD [ Bacillus licheniformis DSM 13]	UniRef100_Q65NX8	Bacillus licheniformis DSM 13
358	blaRI Penicillin-binding protein, transpeptidase	Regulatory protein blaR1 [ Bacillus licheniformis DSM 13]	UniRef100_Q65NX7	Bacillus licheniformis DSM 13
	domain, Peptidase M56, BlaR1
359	blaI putative beta-lactamase repressor protein	Penicillinase repressor [ Bacillus licheniformis DSM 13]	UniRef100_Q65NX6	Bacillus licheniformis DSM 13
360	BLP00325 hypothetical protein
361	BLP00326 hypothetical protein
362	penP beta-lactamase precursor	PenP [ Bacillus licheniformis DSM 13]	UniRef100_Q65NX5	Bacillus licheniformis DSM 13
363	BLP00328 hypothetical protein
364	phoD phosphodiesterase_alkaline phosphatase D	Phosphodiesterase/alkaline phosphatase D [ Bacillus	UniRef100_Q62ZC0	Bacillus licheniformis DSM 13
		licheniformis DSM 13]
365	tatAD component of the twin-arginine pre-protein	TatAD [ Bacillus licheniformis DSM 13]	UniRef100_Q65NX3	Bacillus licheniformis DSM 13
	translocation pathway
366	tatCD component of the twin-arginine pre-protein	TatCD [ Bacillus licheniformis DSM 13]	UniRef100_Q65NX2	Bacillus licheniformis DSM 13
	translocation pathway
367	BLP00332 hypothetical protein
368	kdgD Probable 5-dehydro-4-deoxyglucarate	YcbC [ Bacillus licheniformis DSM 13]	UniRef100_Q65NX1	Bacillus licheniformis DSM 13
	dehydratase KdgD
369	ybcD Aldehyde dehydrogenase YbcD	YcbD [ Bacillus licheniformis DSM 13]	UniRef100_Q65NX0	Bacillus licheniformis DSM 13
370	gudP D-galactonate transporter	YcbE [ Bacillus licheniformis DSM 13]	UniRef100_Q65NW9	Bacillus licheniformis DSM 13
371	gudD Mandelate racemase_muconate lactonizing	YcbF [ Bacillus licheniformis DSM 13]	UniRef100_Q65NW8	Bacillus licheniformis DSM 13
	enzyme
372	ycbG putative regulatory protein YcbG	YcbG [ Bacillus licheniformis DSM 13]	UniRef100_Q65NW7	Bacillus licheniformis DSM 13
373	garD D-galactarate dehydratase_Altronate hydrolase,	YcbH [ Bacillus licheniformis DSM 13]	UniRef100_Q65NW6	Bacillus licheniformis DSM 13
	N-terminal, D-galactarate dehydratase_Altronate
	hydrolase, C-terminal
374	ycbL YcbL	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NW5	Bacillus licheniformis DSM 13
375	ycbM putative sensor histidine kinase	HPr serine phosphorylation site [ Bacillus licheniformis DSM	UniRef100_Q62ZB0	Bacillus licheniformis DSM 13
		13]
376	ycbN ABC transporter YcbN	YcbN [ Bacillus licheniformis DSM 13]	UniRef100_Q65NW2	Bacillus licheniformis DSM 13
377	ycbO conserved hypothetical protein YcbO	YcbO [ Bacillus licheniformis DSM 13]	UniRef100_Q65NW1	Bacillus licheniformis DSM 13
378	ycbO2 conserved hypothetical protein YcbO
379	yetN conserved hypothetical protein YetN	Hypothetical protein yetN [ Bacillus licheniformis DSM 13]	UniRef100_Q65NV9	Bacillus licheniformis DSM 13
380	ybdO conserved hypothetical protein YbdO	YbdO [ Bacillus licheniformis DSM 13]	UniRef100_Q65NV8	Bacillus licheniformis DSM 13
381	BLP00347 hypothetical protein
382	ycbJ putative Macrolide 2′-phosphotransferase	YcbJ [ Bacillus licheniformis DSM 13]	UniRef100_Q65NV7	Bacillus licheniformis DSM 13
383	ywhA putative transcriptional regulator	YwhA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NV6	Bacillus licheniformis DSM 13
384	ydaB AMP-dependent synthetase and ligase	YdaB [ Bacillus licheniformis DSM 13]	UniRef100_Q65NV5	Bacillus licheniformis DSM 13
385	BLP00351 putative Proteinase inhibititor I4, serpin	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NV4	Bacillus licheniformis DSM 13
386	BLP00352 unassigned	YbdN [ Bacillus licheniformis DSM 13]	UniRef100_Q65NV3	Bacillus licheniformis DSM 13
387	BLP00353 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NV2	Bacillus licheniformis DSM 13
388	mtaB transcriptional regulator (MerR family)	Mta [ Bacillus licheniformis DSM 13]	UniRef100_Q65NV1	Bacillus licheniformis DSM 13
389	BLP00355 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NV0	Bacillus licheniformis DSM 13
390	BLP00356 putative DNA binding protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NU9	Bacillus licheniformis DSM 13
391	BLP00357 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NU8	Bacillus licheniformis DSM 13
392	rtpA inhibitor of TRAP, regulated by T-BOX (trp)	YczA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NU7	Bacillus licheniformis DSM 13
	sequence RtpA
393	ycbK hypothetical membrane protein YcbK	YcbK [ Bacillus licheniformis DSM 13]	UniRef100_Q65NU6	Bacillus licheniformis DSM 13
394	yczC conserved membrane protein YczC	RDD [ Bacillus licheniformis DSM 13]	UniRef100_Q62Z92	Bacillus licheniformis DSM 13
395	yccF conserved hypothetical protein YccF	YccF [ Bacillus licheniformis DSM 13]	UniRef100_Q65NU4	Bacillus licheniformis DSM 13
396	spaF ABC transporter SpaF	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NU3	Bacillus licheniformis DSM 13
397	spaE SpaE	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NU2	Bacillus licheniformis DSM 13
398	spaG SpaG	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NU1	Bacillus licheniformis DSM 13
399	spaR SpaR	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NU0	Bacillus licheniformis DSM 13
400	spaK two-component sensor histidine kinase SpaK	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NT9	Bacillus licheniformis DSM 13
401	ytlI transcription regulatory protein YtlI	YtlI [ Bacillus licheniformis DSM 13]	UniRef100_Q65NT8	Bacillus licheniformis DSM 13
402	yusQ 4-oxalocrotonate tautomerase YusQ	YusQ [ Bacillus licheniformis DSM 13]	UniRef100_Q65NT7	Bacillus licheniformis DSM 13
403	yusR putative Short-chain dehydrogenase_reductase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NT6	Bacillus licheniformis DSM 13
	YusR
404	BLP00370 putative methyltransferase	Hypothetical protein (Hypothetical SAM (And some other	UniRef100_Q65NT5	Bacillus licheniformis DSM 13
		nucleotide) binding motif, Generic methyltransferase) [ Bacillus
		licheniformis DSM 13]
405	ycdA putative lipoprotein YcdA	YcdA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NT4	Bacillus licheniformis DSM 13
406	ycgA C4-dicarboxylate anaerobic carrier YcgA	YcgA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NT3	Bacillus licheniformis DSM 13
407	hipO Peptidase M20D, amidohydrolase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NT2	Bacillus licheniformis DSM 13
408	yvbK GCN5-related N-acetyltransferase	YvbK [ Bacillus licheniformis DSM 13]	UniRef100_Q65NT1	Bacillus licheniformis DSM 13
409	BLP00375 glutamyl-tRNA(Gln) amidotransferase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NT0	Bacillus licheniformis DSM 13
	(subunit A)
410	BLP00376 neutral zinc metallopeptidase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NS9	Bacillus licheniformis DSM 13
411	BLP00377 conserved membrane protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NS8	Bacillus licheniformis DSM 13
412	BLP00378 penicillin-binding protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NS7	Bacillus licheniformis DSM 13
413	ysfD 4Fe-4S ferredoxin, iron-sulfur binding domain	YsfD [ Bacillus licheniformis DSM 13]	UniRef100_Q65NS6	Bacillus licheniformis DSM 13
414	ysfC Glycolate oxidase subunit GlcD	YsfC [ Bacillus licheniformis DSM 13]	UniRef100_Q65NS5	Bacillus licheniformis DSM 13
415	BLP00381 hypothetical protein
416	ydhM Phosphotransferase system,	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NS4	Bacillus licheniformis DSM 13
	lactose_cellobiose-specific IIB subunit
417	BLP00383 phosphotransferase system (PTS)	Hypothetical protein (Phosphotransferase system (PTS)	UniRef100_Q65NS3	Bacillus licheniformis DSM 13
	lichenan-specific enzyme IIA component	lichenan-specific enzyme IIA component) [ Bacillus
		licheniformis DSM 13]
418	BLP00384 PTS lactose_cellobiose IIC	YwbA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NS2	Bacillus licheniformis DSM 13
	component, PTS system cellobiose-specific IIC
	component
419	BLP00385 Glycoside Hydrolase Family 4	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NS1	Bacillus licheniformis DSM 13
420	BLP00386 transcriptional regulator, GntR family,	YurK [ Bacillus licheniformis DSM 13]	UniRef100_Q65NS0	Bacillus licheniformis DSM 13
	conserved hypothetical protein
421	BLP00387 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NR9	Bacillus licheniformis DSM 13
422	BLP00388 hypothetical protein
423	yvbX conserved protein, Glycoside Hydrolase Family	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NR8	Bacillus licheniformis DSM 13
	18, YvbX
424	BLP00390 Chitinase precursor, Glycoside Hydrolase	Chitodextrinase [ Bacillus licheniformis ]	UniRef100_Q65NR7	Bacillus licheniformis
	Family 18
425	mpr Glutamyl Endo peptidase	Glutamyl endopeptidase precursor [ Bacillus licheniformis ]	UniRef100_P80057	Bacillus licheniformis
426	ycdF Glucose 1-dehydrogenase II YcdF	YcdF [ Bacillus licheniformis DSM 13]	UniRef100_Q65NR5	Bacillus licheniformis DSM 13
427	BLP00393 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NR4	Bacillus licheniformis DSM 13
428	ycdC conserved hypothetical protein YcdC	YcdC [ Bacillus licheniformis DSM 13]	UniRef100_Q65NR3	Bacillus licheniformis DSM 13
429	BLP00395 Thiosulfate sulfurtransferase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NR2	Bacillus licheniformis DSM 13
430	cwlJ cell wall hydrolase	Hypothetical protein cwlJ [ Bacillus licheniformis DSM 13]	UniRef100_Q65NR1	Bacillus licheniformis DSM 13
431	yceB putative monooxygenase YceB	Luciferase-like [ Bacillus licheniformis DSM 13]	UniRef100_Q62Z57	Bacillus licheniformis DSM 13
432	BLP00398 hypothetical protein
433	yvcE putative peptidoglycan hydrolase, DL-	YvcE [ Bacillus licheniformis DSM 13]	UniRef100_Q65NQ9	Bacillus licheniformis DSM 13
	endopeptidase II family
434	BLP00400 putative permease	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NQ8	Bacillus licheniformis DSM 13
435	BLP00401 ABC transporter	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NQ7	Bacillus licheniformis DSM 13
436	BLP00402 transcriptional regulator	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NQ6	Bacillus licheniformis DSM 13
437	BLP00403 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NQ5	Bacillus licheniformis DSM 13
438	BLP00404 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NQ4	Bacillus licheniformis DSM 13
439	BLP00405 transcriptional regulator	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NQ3	Bacillus licheniformis DSM 13
440	yceC putative stress response protein YceC	YceC [ Bacillus licheniformis DSM 13]	UniRef100_Q65NQ2	Bacillus licheniformis DSM 13
441	yceD putative stress response protein YceD	YceD [ Bacillus licheniformis DSM 13]	UniRef100_Q65NQ1	Bacillus licheniformis DSM 13
442	yceE putative stress response protein YceE	YceE [ Bacillus licheniformis DSM 13]	UniRef100_Q65NQ0	Bacillus licheniformis DSM 13
443	yceF Integral membrane protein TerC family, YceF	YceF [ Bacillus licheniformis DSM 13]	UniRef100_Q65NP9	Bacillus licheniformis DSM 13
444	BLP00410 Putative ATP_GTP-binding protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NP8	Bacillus licheniformis DSM 13
445	BLP00411 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NP7	Bacillus licheniformis DSM 13
446	yceG conserved hypothetical protein YceG	YceG [ Bacillus licheniformis DSM 13]	UniRef100_Q65NP6	Bacillus licheniformis DSM 13
447	yceH putative signal peptide binding protein YceH	YceH (Signal peptide binding (SRP54) M-domain) [ Bacillus	UniRef100_Q65NP5	Bacillus licheniformis DSM 13
		licheniformis DSM 13]
448	BLP00414 integral membrane protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NP4	Bacillus licheniformis DSM 13
449	BLP00415 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NP3	Bacillus licheniformis DSM 13
450	mtaC transcriptional regulator	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NP2	Bacillus licheniformis DSM 13
451	nasA nitrate transporter	NasA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NP1	Bacillus licheniformis DSM 13
452	ldh L-lactate dehydrogenase	Ldh [ Bacillus licheniformis DSM 13]	UniRef100_Q65NP0	Bacillus licheniformis DSM 13
453	lctP L-lactate permease	LctP [ Bacillus licheniformis DSM 13]	UniRef100_Q65NN9	Bacillus licheniformis DSM 13
454	ycgF Lysine exporter protein YcgF	YcgF [ Bacillus licheniformis DSM 13]	UniRef100_Q65NN8	Bacillus licheniformis DSM 13
455	ycgH Amino acid_polyamine transporter I YcgH	YcgH [ Bacillus licheniformis DSM 13]	UniRef100_Q65NN7	Bacillus licheniformis DSM 13
456	nadE NH3-dependent NAD synthetase	NadE [ Bacillus licheniformis DSM 13]	UniRef100_Q65NN6	Bacillus licheniformis DSM 13
457	aroK shikimate kinase	AroK [ Bacillus licheniformis DSM 13]	UniRef100_Q65NN5	Bacillus licheniformis DSM 13
458	ycgL conserved hypothetical protein YcgL	YcgL [ Bacillus licheniformis DSM 13]	UniRef100_Q65NN4	Bacillus licheniformis DSM 13
459	ycgM putative proline dehydrogenase YcgM	YcgM [ Bacillus licheniformis DSM 13]	UniRef100_Q65NN3	Bacillus licheniformis DSM 13
460	ycgN delta-1-pyrroline-5-carboxylate dehydrogenase	YcgN [ Bacillus licheniformis DSM 13]	UniRef100_Q65NN2	Bacillus licheniformis DSM 13
	2 YcgN
461	ycgO Na_solute symporter YcgO	Na+/solute symporter [ Bacillus licheniformis DSM 13]	UniRef100_Q62Z29	Bacillus licheniformis DSM 13
462	ycgP YcgP	YcgP [ Bacillus licheniformis DSM 13]	UniRef100_Q65NN0	Bacillus licheniformis DSM 13
463	ycgQ YcgQ	YcgQ [ Bacillus licheniformis DSM 13]	UniRef100_Q65NM9	Bacillus licheniformis DSM 13
464	ycgR putative permease YcgR	Predicted permease [ Bacillus licheniformis DSM 13]	UniRef100_Q62Z26	Bacillus licheniformis DSM 13
465	cah cephalosporin C deacetylase, Carbohydrate	Cah [ Bacillus licheniformis DSM 13]	UniRef100_Q65NM7	Bacillus licheniformis DSM 13
	Esterase Family 7
466	BLP00432 putative transcriptional regulator	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NM6	Bacillus licheniformis DSM 13
467	BLP00433 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NM5	Bacillus licheniformis DSM 13
468	BLP00434 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NM4	Bacillus licheniformis DSM 13
469	BLP00435 hypothetical protein
470	yckA Amino acid ABC transporter, permease protein	YckA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NM3	Bacillus licheniformis DSM 13
	YckA
471	yckB putative extracellular solute-binding protein	YckB [ Bacillus licheniformis DSM 13]	UniRef100_Q65NM2	Bacillus licheniformis DSM 13
	YckB
472	BLP00438 hypothetical protein
473	BLP00439 NAD(P)H dehydrogenase	Hypothetical protein (NAD(P)H dehydrogenase) [ Bacillus	UniRef100_Q65NM1	Bacillus licheniformis DSM 13
		licheniformis DSM 13]
474	BLP00440 ABC transporter	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NM0	Bacillus licheniformis DSM 13
475	yckE putative Glycosyl Hydrolase Family 1 YckE	YckE [ Bacillus licheniformis DSM 13]	UniRef100_Q65NL9	Bacillus licheniformis DSM 13
476	nin Nin	Hypothetical protein nin [ Bacillus licheniformis DSM 13]	UniRef100_Q62Z16	Bacillus licheniformis DSM 13
477	nucA nuclease NucA	NucA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NL7	Bacillus licheniformis DSM 13
478	BLP00444 hypothetical protein
479	tlpC Methyl-accepting chemotaxis protein tlpC TlpC
480	ycqG Endoplasmic reticulum targeting sequence	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NL2	Bacillus licheniformis DSM 13
	YcqG
481	BLP00447 Hydantoin utilization protein A	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NL1	Bacillus licheniformis DSM 13
482	BLP00448 Hydantoin utilization protein B	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NL0	Bacillus licheniformis DSM 13
483	BLP00449 putative extracellular solute-binding protein	Extracellular solute-binding protein, family 1 [ Bacillus	UniRef100_Q62Z10	Bacillus licheniformis DSM 13
		licheniformis DSM 13]
484	BLP00450 multiple sugar-binding transport ATP-	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NK8	Bacillus licheniformis DSM 13
	binding protein
485	BLP00451 Binding-protein-dependent transport	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NK7	Bacillus licheniformis DSM 13
	systems inner membrane component
486	BLP00452 Binding-protein-dependent transport	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NK6	Bacillus licheniformis DSM 13
	systems inner membrane component
487	BLP00453 hypothetical protein
488	BLP04698 hypothetical protein
489	lchAA lichenysin synthetase A	Lichenysin synthetase A [ Bacillus licheniformis DSM 13]	UniRef100_Q65NK5	Bacillus licheniformis DSM 13
490	lchAB lichenysin synthetase B	Lichenysin synthetase B [ Bacillus licheniformis DSM 13]	UniRef100_Q65NK4	Bacillus licheniformis DSM 13
491	comS ComS
492	lchAC lichenysin synthetase C	Lichenysin synthetase C [ Bacillus licheniformis DSM 13]	UniRef100_Q65NK3	Bacillus licheniformis DSM 13
493	lchAD thioesterase LchAD	Lichenysin synthetase D [ Bacillus licheniformis DSM 13]	UniRef100_Q65NK2	Bacillus licheniformis DSM 13
494	ycxC conserved membrane protein YcxC	Hypothetical protein ycxC [ Bacillus licheniformis DSM 13]	UniRef100_Q65NK1	Bacillus licheniformis DSM 13
495	ycxD probable transcriptional regulator YcxD	YcxD [ Bacillus licheniformis DSM 13]	UniRef100_Q65NK0	Bacillus licheniformis DSM 13
496	sfp phosphopantetheinyl transferase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NJ9	Bacillus licheniformis DSM 13
497	ybbA Putative carbohydrate esterase, Family 1, YbbA	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NJ8	Bacillus licheniformis DSM 13
498	BLP00462 hypothetical protein	Transcriptional activator, AraC family [ Bacillus cereus ]	UniRef100_Q73CS4	Bacillus cereus
499	yczE YczE	Hypothetical protein yczE [ Bacillus licheniformis DSM 13]	UniRef100_Q65NJ6	Bacillus licheniformis DSM 13
500	BLP04844 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NJ5	Bacillus licheniformis DSM 13
501	BLP00465 ABC transporter	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NJ4	Bacillus licheniformis DSM 13
502	BLP00466 putative transcriptional regulator	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NJ3	Bacillus licheniformis DSM 13
503	BLP00467 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62YZ2	Bacillus licheniformis DSM 13
504	BLP00469 Putative L-2,4-diaminobutyrate	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NJ2	Bacillus licheniformis DSM 13
	decarboxylase
505	BLP00470 methyl-accepting chemotaxis protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NJ1	Bacillus licheniformis DSM 13
506	yckI ABC transporter YckI	YckI [ Bacillus licheniformis DSM 13]	UniRef100_Q65NJ0	Bacillus licheniformis DSM 13
507	yckJ ABC transporter permease protein YckJ	Amino acid ABC transporter, permease protein, 3-TM region,	UniRef100_Q62YY8	Bacillus licheniformis DSM 13
		His/Glu/Gln/Arg/opine, Binding-protein-dependent transport
		systems inner membrane component [ Bacillus licheniformis
		DSM 13]
508	yckK putative extracellular solute-binding protein,	YckK [ Bacillus licheniformis DSM 13]	UniRef100_Q65NI8	Bacillus licheniformis DSM 13
	family 3 YckK
509	rocR transcriptional activator of arginine utilization	RocR [ Bacillus licheniformis DSM 13]	UniRef100_Q65NI7	Bacillus licheniformis DSM 13
	operons
510	rocD ornithine aminotransferase	RocD [ Bacillus licheniformis DSM 13]	UniRef100_Q65NI6	Bacillus licheniformis DSM 13
511	rocE amino acid permease	RocE [ Bacillus licheniformis DSM 13]	UniRef100_Q65NI5	Bacillus licheniformis DSM 13
512	rocF arginase	RocF [ Bacillus licheniformis DSM 13]	UniRef100_Q65NI4	Bacillus licheniformis DSM 13
513	yclA transcriptional regulator YclA	YclA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NI3	Bacillus licheniformis DSM 13
514	yclB 3-octaprenyl-4-hydroxybenzoate carboxy-lyase	YclB [ Bacillus licheniformis DSM 13]	UniRef100_Q65NI2	Bacillus licheniformis DSM 13
	YclB
515	yclC Carboxylyase-related protein YclC	YclC [ Bacillus licheniformis DSM 13]	UniRef100_Q65NI1	Bacillus licheniformis DSM 13
516	BLP00481 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NI0	Bacillus licheniformis DSM 13
517	BLP00482 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NH9	Bacillus licheniformis DSM 13
518	BLP00483 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NH8	Bacillus licheniformis DSM 13
519	BLP00484 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NH7	Bacillus licheniformis DSM 13
520	BLP00485 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NH6	Bacillus licheniformis DSM 13
521	BLP00486 hypothetical protein
522	BLP00487 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NH5	Bacillus licheniformis DSM 13
523	BLP00488 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NH4	Bacillus licheniformis DSM 13
524	BLP00489 hypothetical protein
525	BLP00490 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NH3	Bacillus licheniformis DSM 13
526	yxiD putative transposase protein YxiD	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NH2	Bacillus licheniformis DSM 13
527	yxiC YxiC	Hypothetical protein yxiC [ Bacillus licheniformis DSM 13]	UniRef100_Q62YX1	Bacillus licheniformis DSM 13
528	yxiB putative prefoldin	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NH0	Bacillus licheniformis DSM 13
529	BLP00494 ribose ABC transporter (ribose-binding	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NG9	Bacillus licheniformis DSM 13
	protein)
530	BLP00495 putative Histidine kinase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NG8	Bacillus licheniformis DSM 13
531	BLP00496 transcriptional regulator	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NG7	Bacillus licheniformis DSM 13
532	BLP00497 ribose ABC transporter (ribose-binding	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NG6	Bacillus licheniformis DSM 13
	protein)
533	BLP00498 sugar ABC transporter (ATP-binding	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NG5	Bacillus licheniformis DSM 13
	protein)
534	BLP00499 sugar ABC transporter (permease)	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NG4	Bacillus licheniformis DSM 13
535	ybfB Major facilitator superfamily protein YbfB	YbfB [ Bacillus licheniformis DSM 13]	UniRef100_Q65NG3	Bacillus licheniformis DSM 13
536	ybfA putative DNA binding protein YbfA	YbfA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NG2	Bacillus licheniformis DSM 13
537	BLP00502 hypothetical protein
538	lacA2 Glycoside Hydrolase Family 42	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NG1	Bacillus licheniformis DSM 13
539	phy phytase	PhyL [ Bacillus licheniformis ]	UniRef100_Q6DNH6	Bacillus licheniformis
540	yclF putative oligo-peptide transporter YclF	YclF [ Bacillus licheniformis DSM 13]	UniRef100_Q65NF9	Bacillus licheniformis DSM 13
541	BLP00506 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NF8	Bacillus licheniformis DSM 13
542	yclG Pectin lyase-like protein	YclG [ Bacillus licheniformis DSM 13]	UniRef100_Q65NF7	Bacillus licheniformis DSM 13
543	BLP00508 hypothetical protein	YczF [ Bacillus licheniformis DSM 13]	UniRef100_Q65NF6	Bacillus licheniformis DSM 13
544	BLP00509 hypothetical protein	GerKA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NF5	Bacillus licheniformis DSM 13
545	gerKC GerKC	Hypothetical protein gerKC [ Bacillus licheniformis DSM 13]	UniRef100_Q65NF4	Bacillus licheniformis DSM 13
546	gerKB GerKC	Hypothetical protein gerKB [ Bacillus licheniformis DSM 13]	UniRef100_Q65NF3	Bacillus licheniformis DSM 13
547	mtaD transcriptional regulator (MerR family)	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NF2	Bacillus licheniformis DSM 13
548	yclH ABC transporter YclH	YclH [ Bacillus licheniformis DSM 13]	UniRef100_Q65NF1	Bacillus licheniformis DSM 13
549	yclI hypothetical membrane protein YclI	YclI [ Bacillus licheniformis DSM 13]	UniRef100_Q65NF0	Bacillus licheniformis DSM 13
550	yclJ hypothetical sensory transduction protein YclJ	YclJ [ Bacillus licheniformis DSM 13]	UniRef100_Q65NE9	Bacillus licheniformis DSM 13
551	yclK Histidine kinase, homodimeric YclK	YclK [ Bacillus licheniformis DSM 13]	UniRef100_Q65NE8	Bacillus licheniformis DSM 13
552	tlpA methyl-accepting chemotaxis protein	TlpA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NE7	Bacillus licheniformis DSM 13
553	BLP00518 hypothetical protein
554	yclM Aspartate kinase YclM	YclM [ Bacillus licheniformis DSM 13]	UniRef100_Q65NE6	Bacillus licheniformis DSM 13
555	yclN putative transport system permease protein	YclN [ Bacillus licheniformis DSM 13]	UniRef100_Q65NE5	Bacillus licheniformis DSM 13
556	yclO putative transport system permease protein	YclO [ Bacillus licheniformis DSM 13]	UniRef100_Q65NE4	Bacillus licheniformis DSM 13
557	yclP ABC transporter	YclP [ Bacillus licheniformis DSM 13]	UniRef100_Q65NE3	Bacillus licheniformis DSM 13
558	yclQ Periplasmic binding protein	YclQ [ Bacillus licheniformis DSM 13]	UniRef100_Q65NE2	Bacillus licheniformis DSM 13
559	ycnB Drug resistance transporter YcnB	YcnB [ Bacillus licheniformis DSM 13]	UniRef100_Q65NE1	Bacillus licheniformis DSM 13
560	ycnC probable transcriptional regulator YcnC	YcnC [ Bacillus licheniformis DSM 13]	UniRef100_Q65NE0	Bacillus licheniformis DSM 13
561	BLP00526 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65ND9	Bacillus licheniformis DSM 13
562	nfrA2 NADPH-linked nitro_flavin reductase	YcnD [ Bacillus licheniformis DSM 13]	UniRef100_Q65ND8	Bacillus licheniformis DSM 13
563	ycnE Dimeric alpha-beta barrel	YcnE [ Bacillus licheniformis DSM 13]	UniRef100_Q65ND7	Bacillus licheniformis DSM 13
564	yczG putative transcriptional regulator YczG	YczG [ Bacillus licheniformis DSM 13]	UniRef100_Q65ND6	Bacillus licheniformis DSM 13
565	gabR transcriptional regulator GabR	GabR [ Bacillus licheniformis DSM 13]	UniRef100_Q65ND5	Bacillus licheniformis DSM 13
566	gabT 4-aminobutyrate aminotransferase	GabT [ Bacillus licheniformis DSM 13]	UniRef100_Q65ND4	Bacillus licheniformis DSM 13
567	BLP00532 Amino acid_polyamine transporter I	YhdG [ Bacillus licheniformis DSM 13]	UniRef100_Q65ND3	Bacillus licheniformis DSM 13
568	gabD succinate-semialdehyde dehydrogenase	GabD [ Bacillus licheniformis DSM 13]	UniRef100_Q65ND2	Bacillus licheniformis DSM 13
569	ywfM conserved hypothetical protein YwfM	YwfM [ Bacillus licheniformis DSM 13]	UniRef100_Q65ND1	Bacillus licheniformis DSM 13
570	BLP04699 hypothetical protein
571	BLP00534 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65ND0	Bacillus licheniformis DSM 13
572	ycnI conserved membrane protein	YcnI [ Bacillus licheniformis DSM 13]	UniRef100_Q65NC9	Bacillus licheniformis DSM 13
573	ycnJ putative copper export protein YcnJ	YcnJ [ Bacillus licheniformis DSM 13]	UniRef100_Q65NC8	Bacillus licheniformis DSM 13
574	ycnK probable transcriptional regulator YcnK	YcnK [ Bacillus licheniformis DSM 13]	UniRef100_Q65NC7	Bacillus licheniformis DSM 13
575	BLP00538 hypothetical protein
576	nasB assimilatory nitrate reductase (electron transfer	NasB [ Bacillus licheniformis DSM 13]	UniRef100_Q65NC6	Bacillus licheniformis DSM 13
	subunit)
577	nasC assimilatory nitrate reductase (catalytic subunit)	NasC [ Bacillus licheniformis DSM 13]	UniRef100_Q65NC5	Bacillus licheniformis DSM 13
578	nasD assimilatory nitrite reductase (subunit)	NasD [ Bacillus licheniformis DSM 13]	UniRef100_Q65NC4	Bacillus licheniformis DSM 13
579	nasE assimilatory nitrite reductase (subunit)	NasE [ Bacillus licheniformis DSM 13]	UniRef100_Q65NC3	Bacillus licheniformis DSM 13
580	nasF uroporphyrin-III C-methyltransferase	NasF [ Bacillus licheniformis DSM 13]	UniRef100_Q65NC2	Bacillus licheniformis DSM 13
581	BLP04700 hypothetical protein
582	BLP00544 putative regulatory protein	YdhC [ Bacillus licheniformis DSM 13]	UniRef100_Q65NC1	Bacillus licheniformis DSM 13
583	BLP00545 Sodium_sulphate symporter	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NC0	Bacillus licheniformis DSM 13
584	BLP00546 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NB9	Bacillus licheniformis DSM 13
585	BLP00547 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NB7	Bacillus licheniformis DSM 13
586	BLP00548 transcriptional regulator	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NB6	Bacillus licheniformis DSM 13
587	BLP00549 putative sugar phosphotransferase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NB5	Bacillus licheniformis DSM 13
588	BLP00550 putative sugar phosphotransferase system	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NB4	Bacillus licheniformis DSM 13
	protein
589	tktA transketolase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NB3	Bacillus licheniformis DSM 13
590	BLP00552 1-deoxyxylulose-5-phosphate synthase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65NB2	Bacillus licheniformis DSM 13
591	ycsE putative hydrolase YcsE	YcsE [ Bacillus licheniformis DSM 13]	UniRef100_Q65NB1	Bacillus licheniformis DSM 13
592	BLP00554 hypothetical protein
593	ycsF putative lactam utilization protein YcsF	YcsF [ Bacillus licheniformis DSM 13]	UniRef100_Q65NB0	Bacillus licheniformis DSM 13
594	ycsG putative branched chain amino acids transporter	Hypothetical protein ycsG [ Bacillus licheniformis DSM 13]	UniRef100_Q65NA9	Bacillus licheniformis DSM 13
	YcsG
595	ycsI conserved protein YcsI	Hypothetical protein ycsI [ Bacillus licheniformis DSM 13]	UniRef100_Q65NA8	Bacillus licheniformis DSM 13
596	kipI kinase inhibitor KipI	Hypothetical protein kipI [ Bacillus licheniformis DSM 13]	UniRef100_Q65NA7	Bacillus licheniformis DSM 13
597	kipA KipA	Hypothetical protein kipA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NA6	Bacillus licheniformis DSM 13
598	kipR transcriptional regulator KipR	KipR [ Bacillus licheniformis DSM 13]	UniRef100_Q65NA5	Bacillus licheniformis DSM 13
599	ycsK Lipolytic enzyme, G-D-S-L	YcsK [ Bacillus licheniformis DSM 13]	UniRef100_Q65NA4	Bacillus licheniformis DSM 13
600	BLP00562 hypothetical protein	MtlA [ Bacillus licheniformis DSM 13]	UniRef100_Q65NA3	Bacillus licheniformis DSM 13
601	mtlD mannitol-1-phosphate dehydrogenase	MtlD [ Bacillus licheniformis DSM 13]	UniRef100_Q65NA1	Bacillus licheniformis DSM 13
602	mtlR transcriptional regulator MtlR	MtlR [ Bacillus licheniformis DSM 13]	UniRef100_Q65NA0	Bacillus licheniformis DSM 13
603	ydaD putative Short-chain dehydrogenase_reductase	YdaD [ Bacillus licheniformis DSM 13]	UniRef100_Q65N99	Bacillus licheniformis DSM 13
	YdaD
604	ydaE YdaE	YdaE [ Bacillus licheniformis DSM 13]	UniRef100_Q65N98	Bacillus licheniformis DSM 13
605	BLP00567 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N97	Bacillus licheniformis DSM 13
606	ydaG FMN-binding split barrel domain protein YdaG	YdaG [ Bacillus licheniformis DSM 13]	UniRef100_Q65N96	Bacillus licheniformis DSM 13
607	BLP00569 hypothetical protein
608	ydaH conserved membrane protein YdaH	Hypothetical protein ydaH [ Bacillus licheniformis DSM 13]	UniRef100_Q65N95	Bacillus licheniformis DSM 13
609	BLP00571 Cell envelope-related transcriptional	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N94	Bacillus licheniformis DSM 13
	attenuator
610	ydzA conserved membrane protein YdzA	Hypothetical protein ydzA [ Bacillus licheniformis DSM 13]	UniRef100_Q65N93	Bacillus licheniformis DSM 13
611	BLP00573 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N92	Bacillus licheniformis DSM 13
612	lrpC transcriptional regulator (Lrp_AsnC family)	LrpC [ Bacillus licheniformis DSM 13]	UniRef100_Q65N91	Bacillus licheniformis DSM 13
613	topB DNA topoisomerase III	TopB [ Bacillus licheniformis DSM 13]	UniRef100_Q65N90	Bacillus licheniformis DSM 13
614	BLP00576 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62YP3	Bacillus licheniformis DSM 13
615	BLP00577 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62YP2	Bacillus licheniformis DSM 13
616	BLP04921 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62YP1	Bacillus licheniformis DSM 13
617	ydaO putative amino acid permease	YdaO [ Bacillus licheniformis DSM 13]	UniRef100_Q65N89	Bacillus licheniformis DSM 13
618	BLP00579 hypothetical protein
619	ydaP Pyruvate decarboxylase	YdaP [ Bacillus licheniformis DSM 13]	UniRef100_Q65N88	Bacillus licheniformis DSM 13
620	BLP00581 putative chitin binding protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N87	Bacillus licheniformis DSM 13
621	BLP00582 hypothetical protein
622	BLP00583 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62YN4	Bacillus licheniformis DSM 13
623	ydaF GCN5-related N-acetyltransferase	YdaF [ Bacillus licheniformis DSM 13]	UniRef100_Q65N83	Bacillus licheniformis DSM 13
624	mntH manganese transporter	MntH [ Bacillus licheniformis DSM 13]	UniRef100_Q65N82	Bacillus licheniformis DSM 13
625	ydaS Transglycosylase-associated protein	YdaS [ Bacillus licheniformis DSM 13]	UniRef100_Q65N81	Bacillus licheniformis DSM 13
626	ansB L-aspartase AnsB	AnsB [ Bacillus licheniformis DSM 13]	UniRef100_Q65N80	Bacillus licheniformis DSM 13
627	BLP04701 hypothetical protein
628	BLP00588 hypothetical protein
629	yojK Glycosyl Transferase Family 1	YojK [ Bacillus licheniformis DSM 13]	UniRef100_Q65N79	Bacillus licheniformis DSM 13
630	ydaT conserved protein YdaT	Hypothetical protein ydaT [ Bacillus licheniformis DSM 13]	UniRef100_Q65N78	Bacillus licheniformis DSM 13
631	BLP00591 hypothetical protein
632	ydbA YdbA	YdbA [ Bacillus licheniformis DSM 13]	UniRef100_Q65N77	Bacillus licheniformis DSM 13
633	BLP00593 Na_H antiporter	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N76	Bacillus licheniformis DSM 13
634	ydbB conserved protein YdbB	YdbB [ Bacillus licheniformis DSM 13]	UniRef100_Q65N75	Bacillus licheniformis DSM 13
635	gsiB general stress protein	GsiB [ Bacillus licheniformis DSM 13]	UniRef100_Q65N74	Bacillus licheniformis DSM 13
636	ydbI conserved membrane protein YdbI	Hypothetical protein ydbI [ Bacillus licheniformis DSM 13]	UniRef100_Q65N73	Bacillus licheniformis DSM 13
637	BLP00597 proton_sodium-glutamate symport protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N72	Bacillus licheniformis DSM 13
638	ydbJ ABC transporter	YdbJ [ Bacillus licheniformis DSM 13]	UniRef100_Q65N71	Bacillus licheniformis DSM 13
639	ydbK probable ABC transport system permease	Hypothetical protein ydbK [ Bacillus licheniformis DSM 13]	UniRef100_Q62YM0	Bacillus licheniformis DSM 13
	protein YdbK
640	ydbL YdbL	Hypothetical protein ydbL [ Bacillus licheniformis DSM 13]	UniRef100_Q65N69	Bacillus licheniformis DSM 13
641	ydbM putative Acyl-CoA dehydrogenase YdbM	YdbM [ Bacillus licheniformis DSM 13]	UniRef100_Q65N68	Bacillus licheniformis DSM 13
642	ydbN small antisense RNA YdbN	Hypothetical protein ydbN [ Bacillus licheniformis DSM 13]	UniRef100_Q65N67	Bacillus licheniformis DSM 13
643	BLP00603 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62YL6	Bacillus licheniformis DSM 13
644	ydbP putative thiredoxin protein YdpP	YdbP [ Bacillus licheniformis DSM 13]	UniRef100_Q65N66	Bacillus licheniformis DSM 13
645	ddl D-alanyl-D-alanine ligase A	Ddl [ Bacillus licheniformis DSM 13]	UniRef100_Q65N65	Bacillus licheniformis DSM 13
646	murF UDP-N-acetylmuramoylalanyl-D-glutamyl-2,6-	MurF [ Bacillus licheniformis DSM 13]	UniRef100_Q65N64	Bacillus licheniformis DSM 13
	diaminopimelate-D-alanyl-D-alanine ligase
647	BLP00607 Esterase_lipase_thioesterase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N63	Bacillus licheniformis DSM 13
648	ydbR probable ATP-dependent RNA helicase YdbR	YdbR [ Bacillus licheniformis DSM 13]	UniRef100_Q65N62	Bacillus licheniformis DSM 13
649	ydbS conserved membrane protein YdbS	YdbS [ Bacillus licheniformis DSM 13]	UniRef100_Q65N61	Bacillus licheniformis DSM 13
650	ydbT conserved membrane protein	YdbT [ Bacillus licheniformis DSM 13]	UniRef100_Q65N60	Bacillus licheniformis DSM 13
651	ydcA conserved membrane protein YdcA	YdcA [ Bacillus licheniformis DSM 13]	UniRef100_Q65N59	Bacillus licheniformis DSM 13
652	ydcC conserved membrane protein YdcC	YdcC [ Bacillus licheniformis DSM 13]	UniRef100_Q65N58	Bacillus licheniformis DSM 13
653	dal D-alanine racemase	Alr [ Bacillus licheniformis DSM 13]	UniRef100_Q65N57	Bacillus licheniformis DSM 13
654	endoAl transcriptional inhibitor endoAl	YdcD [ Bacillus licheniformis DSM 13]	UniRef100_Q65N56	Bacillus licheniformis DSM 13
655	endoA putative RNase	YdcE [ Bacillus licheniformis DSM 13]	UniRef100_Q65N55	Bacillus licheniformis DSM 13
656	rsbR RbsR	Hypothetical protein rsbR [ Bacillus licheniformis DSM 13]	UniRef100_Q65N54	Bacillus licheniformis DSM 13
657	rsbS antagonist of RsbT	RsbS [ Bacillus licheniformis DSM 13]	UniRef100_Q65N53	Bacillus licheniformis DSM 13
658	rsbT switch protein_serine-threonine kinase	RsbT [ Bacillus licheniformis DSM 13]	UniRef100_Q65N52	Bacillus licheniformis DSM 13
659	rsbU serine phosphatase	RsbU [ Bacillus licheniformis DSM 13]	UniRef100_Q65N51	Bacillus licheniformis DSM 13
660	rsbV anti-anti-sigma factor (antagonist of RsbW)	RsbV [ Bacillus licheniformis DSM 13]	UniRef100_Q65N50	Bacillus licheniformis DSM 13
661	rsbW switch protein_serine kinase and anti-sigma	RsbW [ Bacillus licheniformis DSM 13]	UniRef100_Q65N49	Bacillus licheniformis DSM 13
	factor (inhibitory sigma-B binding protein)
662	sigB RNA polymerase sigma-37 factor (sigma-B)	SigB [ Bacillus licheniformis DSM 13]	UniRef100_Q65N48	Bacillus licheniformis DSM 13
663	rsbX serine phosphatase	RsbX [ Bacillus licheniformis DSM 13]	UniRef100_Q65N47	Bacillus licheniformis DSM 13
664	ydcI putative RNA binding protein containing S1 RNA	RuvA domain 2-like, Nucleic acid-binding OB-fold [ Bacillus	UniRef100_Q62YJ5	Bacillus licheniformis DSM 13
	binding domain, YdcI	licheniformis DSM 13]
665	BLP00625 hypothetical protein	TetR [ Bacillus licheniformis DSM 13]	UniRef100_Q65N45	Bacillus licheniformis DSM 13
666	BLP04703 hypothetical protein
667	ydgH conserved hypothetical protein YdgH	YdgH [ Bacillus licheniformis DSM 13]	UniRef100_Q65N44	Bacillus licheniformis DSM 13
668	ydcK conserved protein YdcK	Hypothetical protein ydcK [ Bacillus licheniformis DSM 13]	UniRef100_Q65N43	Bacillus licheniformis DSM 13
669	BLP00628 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N41	Bacillus licheniformis DSM 13
670	BLP00629 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N40	Bacillus licheniformis DSM 13
671	BLP00630 fatty acid desaturase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N39	Bacillus licheniformis DSM 13
672	BLP00631 hypothetical protein	CspC [ Bacillus licheniformis DSM 13]	UniRef100_Q65N38	Bacillus licheniformis DSM 13
673	cspC cold-shock protein	CspC [ Bacillus licheniformis DSM 13]	UniRef100_Q65N37	Bacillus licheniformis DSM 13
674	BLP00633 hypothetical protein	GroES-like [ Bacillus licheniformis DSM 13]	UniRef100_Q62YI5	Bacillus licheniformis DSM 13
675	yyaS conserved membrane protein YyaS	Hypothetical protein yyaS [ Bacillus licheniformis DSM 13]	UniRef100_Q65N35	Bacillus licheniformis DSM 13
676	yybA negative regulator of yyaTS —YybA	YybA [ Bacillus licheniformis DSM 13]	UniRef100_Q65N34	Bacillus licheniformis DSM 13
677	paiA transcriptional regulator PaiA	PaiA [ Bacillus licheniformis DSM 13]	UniRef100_Q65N33	Bacillus licheniformis DSM 13
678	paiB transcriptional regulator	PaiB [ Bacillus licheniformis DSM 13]	UniRef100_Q65N32	Bacillus licheniformis DSM 13
679	BLP00638 arginase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N31	Bacillus licheniformis DSM 13
680	BLP00639 putative carboxy-lyase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N30	Bacillus licheniformis DSM 13
681	ydeO conserved hypothetical protein YdeO	YdeO [ Bacillus licheniformis DSM 13]	UniRef100_Q65N29	Bacillus licheniformis DSM 13
682	BLP00641 Lysine exporter protein	LysE [ Bacillus licheniformis DSM 13]	UniRef100_Q65N28	Bacillus licheniformis DSM 13
683	BLP00642 putative regulatory protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N27	Bacillus licheniformis DSM 13
684	BLP00643 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N26	Bacillus licheniformis DSM 13
685	BLP00645 Major facilitator superfamily, transporter	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N25	Bacillus licheniformis DSM 13
686	BLP00646 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N24	Bacillus licheniformis DSM 13
687	ydgF Amino acid permease YdgF	YdgF [ Bacillus licheniformis DSM 13]	UniRef100_Q65N23	Bacillus licheniformis DSM 13
688	BLP04706 hypothetical protein
689	BLP00648 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N22	Bacillus licheniformis DSM 13
690	BLP00649 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N21	Bacillus licheniformis DSM 13
691	BLP00650 hypothetical protein
692	sigV RNA polymerase ECF(extracytoplasmic	SigV (RNA polymerase ECF(Extracytoplasmic function)-type	UniRef100_Q65N20	Bacillus licheniformis DSM 13
	function)-type sigma factor (sigma-V)	sigma factor) [ Bacillus licheniformis DSM 13]
693	yrhM YrhM	Hypothetical protein yrhM [ Bacillus licheniformis DSM 13]	UniRef100_Q65N19	Bacillus licheniformis DSM 13
694	yrhL ABC transporter	YrhL [ Bacillus licheniformis DSM 13]	UniRef100_Q65N18	Bacillus licheniformis DSM 13
695	ydgK putative Drug resistance transporter	YdgK [ Bacillus licheniformis DSM 13]	UniRef100_Q65N17	Bacillus licheniformis DSM 13
696	ywpD two-component sensor histidine kinase	YwpD [ Bacillus licheniformis DSM 13]	UniRef100_Q65N16	Bacillus licheniformis DSM 13
697	BLP00656 two-component response regulator	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N15	Bacillus licheniformis DSM 13
698	BLP00657 LPXTG-motif containing, cell wall anchor	Hypothetical Surface protein from Gram-positive cocci,	UniRef100_Q65N14	Bacillus licheniformis DSM 13
	domain protein	anchor region [ Bacillus licheniformis DSM 13]
699	BLP00658 hypothetical protein
700	ywpE conserved protein YwpE	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65N13	Bacillus licheniformis DSM 13
701	BLP00660 hypothetical protein
702	BLP00661 hypothetical protein
703	iolT major inositol transport protein IolT	YdjK [ Bacillus licheniformis DSM 13]	UniRef100_Q65N12	Bacillus licheniformis DSM 13
704	thiL thiamine-monophosphate kinase	ThiL [ Bacillus licheniformis DSM 13]	UniRef100_Q65N11	Bacillus licheniformis DSM 13
705	ydiB hypothetical conserved protein YdiB	YdiB [ Bacillus licheniformis DSM 13]	UniRef100_Q65N10	Bacillus licheniformis DSM 13
706	ydiC Peptidase M22, glycoprotease YdiC	YdiC [ Bacillus licheniformis DSM 13]	UniRef100_Q65N09	Bacillus licheniformis DSM 13
707	ydiD Ribosomal-protein-alanine acetyltransferase	YdiD [ Bacillus licheniformis DSM 13]	UniRef100_Q65N08	Bacillus licheniformis DSM 13
	YdiD
708	gcp O-sialoglycoprotein endopeptidase	Gcp [ Bacillus licheniformis DSM 13]	UniRef100_Q65N07	Bacillus licheniformis DSM 13
709	ydiF ABC transporter YdiF	YdiF [ Bacillus licheniformis DSM 13]	UniRef100_Q65N06	Bacillus licheniformis DSM 13
710	BLP00669 hypothetical protein
711	moaC Molybdopterin cofactor biosynthesis protein	YdiG [ Bacillus licheniformis DSM 13]	UniRef100_Q65N05	Bacillus licheniformis DSM 13
	MoaC
712	rex redox regulator Rex	YdiH [ Bacillus licheniformis DSM 13]	UniRef100_Q65N04	Bacillus licheniformis DSM 13
713	tatAY component of the twin-arginine pre-protein	TatAY [ Bacillus licheniformis DSM 13]	UniRef100_Q65N03	Bacillus licheniformis DSM 13
	translocation pathway
714	tatCY component of the twin-arginine pre-protein	TatCY [ Bacillus licheniformis DSM 13]	UniRef100_Q65N02	Bacillus licheniformis DSM 13
	translocation pathway
715	ydiK YdiK	YdiK [ Bacillus licheniformis DSM 13]	UniRef100_Q65N01	Bacillus licheniformis DSM 13
716	ydiL Aldo_keto reductase	YdiL [ Bacillus licheniformis DSM 13]	UniRef100_Q65N00	Bacillus licheniformis DSM 13
717	groES class I heat-shock protein (chaperonin)	GroES [ Bacillus licheniformis DSM 13]	UniRef100_Q65MZ9	Bacillus licheniformis DSM 13
718	groEL class I heat-shock protein (chaperonin)	GroEL [ Bacillus licheniformis DSM 13]	UniRef100_Q65MZ8	Bacillus licheniformis DSM 13
719	BLP04707 hypothetical protein
720	BLP04846 conserved hypothetical protein	Hypothetical Sugar transporter superfamily [ Bacillus	UniRef100_Q62YE4	Bacillus licheniformis DSM 13
		licheniformis DSM 13]
721	BLP00678 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62YE3	Bacillus licheniformis DSM 13
722	BLP00679 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62YE2	Bacillus licheniformis DSM 13
723	BLP00680 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62YE0	Bacillus licheniformis DSM 13
724	yoaR conserved protein YoaR	YoaR [ Bacillus licheniformis DSM 13]	UniRef100_Q65MZ6	Bacillus licheniformis DSM 13
725	yfmQ conserved hypothetical protein YfmQ	YfmQ [ Bacillus licheniformis DSM 13]	UniRef100_Q65MZ5	Bacillus licheniformis DSM 13
726	BLP00683 hypothetical protein
727	BLP00684 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MZ4	Bacillus licheniformis DSM 13
728	yoqW YoqW	YoqW [ Bacillus licheniformis DSM 13]	UniRef100_Q65MZ3	Bacillus licheniformis DSM 13
729	BLP00686 conserved hypothetical	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65G40	Bacillus licheniformis DSM 13
730	BLP00687 putative regulatory protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MZ2	Bacillus licheniformis DSM 13
731	BLP00688 phosphoenolpyruvate synthase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MZ1	Bacillus licheniformis DSM 13
732	yoaF YoaF	Hypothetical protein yoaF [ Bacillus licheniformis DSM 13]	UniRef100_Q65MZ0	Bacillus licheniformis DSM 13
733	BLP00690 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MY9	Bacillus licheniformis DSM 13
734	BLP00691 hypothetical protein
735	dltE DltE	Hypothetical protein dltE [ Bacillus licheniformis DSM 13]	UniRef100_Q65MY8	Bacillus licheniformis DSM 13
736	pnbA para-nitrobenzyl esterase (intracellular esterase	PnbA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MY7	Bacillus licheniformis DSM 13
	B)
737	BLP00694 inositol transport protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MY6	Bacillus licheniformis DSM 13
738	pspA phage shock protein A homolog	PspA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MY5	Bacillus licheniformis DSM 13
739	ydjG conserved protein YdjG	Hypothetical protein ydjG [ Bacillus licheniformis DSM 13]	UniRef100_Q65MY4	Bacillus licheniformis DSM 13
740	ydjH conserved membrane protein YdjH	Hypothetical protein ydjH [ Bacillus licheniformis DSM 13]	UniRef100_Q65MY3	Bacillus licheniformis DSM 13
741	ydjI conserved protein YdjI	Hypothetical protein ydjI [ Bacillus licheniformis DSM 13]	UniRef100_Q65MY2	Bacillus licheniformis DSM 13
742	BLP00699 putative oxidoreductase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MY1	Bacillus licheniformis DSM 13
743	yrhO putative cyclodextrin metabolism protein YrhO	YrhO [ Bacillus licheniformis DSM 13]	UniRef100_Q65MY0	Bacillus licheniformis DSM 13
744	yrhP Lysine exporter protein YrhP	YrhP [ Bacillus licheniformis DSM 13]	UniRef100_Q65MX9	Bacillus licheniformis DSM 13
745	ykvA2 conserved membrane protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MX8	Bacillus licheniformis DSM 13
746	BLP00703 sporulation related protein Stage V protein E	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MX7	Bacillus licheniformis DSM 13
747	BLP00704 cell-division protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MX6	Bacillus licheniformis DSM 13
748	BLP00705 hypothetical protein
749	BLP00706 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MX5	Bacillus licheniformis DSM 13
750	BLP00707 hypothetical protein	Winged helix DNA-binding [ Bacillus licheniformis DSM 13]	UniRef100_Q62YB6	Bacillus licheniformis DSM 13
751	BLP00708 hypothetical protein
752	yjeAA conserved hypothetical protein	Hypothetical protein yjeAA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MX2	Bacillus licheniformis DSM 13
753	yjeA Putative Carbohydrate Esterase Family 4 protein	YjeA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MX1	Bacillus licheniformis DSM 13
754	amyL alpha amylase, Glycoside Hydrolase Family 13	Alpha-amylase precursor [ Bacillus licheniformis ]	UniRef100_P06278	Bacillus licheniformis
755	yvdE probable transcriptional regulator YvdE	YvdE [ Bacillus licheniformis DSM 13]	UniRef100_Q65MW9	Bacillus licheniformis DSM 13
756	yvdF Glycoside Hydrolase Family 13 YvdF	Maltogenic alpha-amylase [ Bacillus licheniformis DSM 13]	UniRef100_Q65MW8	Bacillus licheniformis DSM 13
757	mdxE maltodextrin transport system substrate-binding	YvdG [ Bacillus licheniformis DSM 13]	UniRef100_Q65MW7	Bacillus licheniformis DSM 13
	protein MdxE
758	mdxF maltodextrin transport system permease protein	YvdH [ Bacillus licheniformis DSM 13]	UniRef100_Q65MW6	Bacillus licheniformis DSM 13
	MdxF
759	mdxG maltodextrin transport system permease	YvdI [ Bacillus licheniformis DSM 13]	UniRef100_Q65MW5	Bacillus licheniformis DSM 13
	protein MdxG
760	yvdJ conserved membrane protein YvdJ	Hypothetical protein yvdJ [ Bacillus licheniformis DSM 13]	UniRef100_Q65MW4	Bacillus licheniformis DSM 13
761	yvdK Glycoside Hydrolase Family 65, YvdK	YvdK [ Bacillus licheniformis DSM 13]	UniRef100_Q65MW3	Bacillus licheniformis DSM 13
762	malL Glycoside Hydrolase Family 13, MalL	MalL [ Bacillus licheniformis DSM 13]	UniRef100_Q65MW2	Bacillus licheniformis DSM 13
763	pgcM beta-phosphoglucomutase and glucose-1-	PgcM [ Bacillus licheniformis DSM 13]	UniRef100_Q65MW1	Bacillus licheniformis DSM 13
	phosphate phosphodismutase
764	BLP00721 hypothetical protein
765	tyrZ tyrosyl-tRNA synthetase	TyrZ [ Bacillus licheniformis DSM 13]	UniRef100_Q65MW0	Bacillus licheniformis DSM 13
766	ywaE probable transcriptional regulator YwaE	YwaE [ Bacillus licheniformis DSM 13]	UniRef100_Q65MV9	Bacillus licheniformis DSM 13
767	BLP00724 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MV8	Bacillus licheniformis DSM 13
768	BLP00725 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MV7	Bacillus licheniformis DSM 13
769	ydjM YdjM	Rare lipoprotein A [ Bacillus licheniformis DSM 13]	UniRef100_Q62Y99	Bacillus licheniformis DSM 13
770	ydjN YdjN	YdjN [ Bacillus licheniformis DSM 13]	UniRef100_Q65MV5	Bacillus licheniformis DSM 13
771	yeaA conserved protein YeaA	Hypothetical protein yeaA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MV4	Bacillus licheniformis DSM 13
772	BLP00730 Small nuclear-like ribonucleoprotein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MV3	Bacillus licheniformis DSM 13
773	BLP00731 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MV2	Bacillus licheniformis DSM 13
774	BLP00732 hypothetical protein
775	sipS type I signal peptidase	SipS [ Bacillus licheniformis DSM 13]	UniRef100_Q65MV1	Bacillus licheniformis DSM 13
776	BLP00734 putative methyltransferase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MV0	Bacillus licheniformis DSM 13
777	BLP00735 hypothetical protein
778	yhfK conserved protein YhfK	Hypothetical protein yhfK [ Bacillus licheniformis DSM 13]	UniRef100_Q65MU9	Bacillus licheniformis DSM 13
779	ydeE probable transcriptional regulator YdeE	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MU8	Bacillus licheniformis DSM 13
780	cotA spore coat protein (outer)	CotA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MU7	Bacillus licheniformis DSM 13
781	BLP00739 Acyltransferase 3	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MU6	Bacillus licheniformis DSM 13
782	BLP00740 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MU5	Bacillus licheniformis DSM 13
783	yeaB Cation efflux protein	YeaB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MU4	Bacillus licheniformis DSM 13
784	yeaC YeaC	YeaC [ Bacillus licheniformis DSM 13]	UniRef100_Q65MU3	Bacillus licheniformis DSM 13
785	yeaD conserved protein YeaD	Hypothetical protein yeaD [ Bacillus licheniformis DSM 13]	UniRef100_Q65MU2	Bacillus licheniformis DSM 13
786	yebA transglutaminase-like enzymes, putative	YebA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MU1	Bacillus licheniformis DSM 13
	cysteine protease YebA
787	guaA GMP synthetase	GuaA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MU0	Bacillus licheniformis DSM 13
788	pbuG hypoxanthine_guanine permease	PbuG [ Bacillus licheniformis DSM 13]	UniRef100_Q65MT9	Bacillus licheniformis DSM 13
789	BLP00747 hypothetical protein
790	yebC YbeC	YebC [ Bacillus licheniformis DSM 13]	UniRef100_Q65MT8	Bacillus licheniformis DSM 13
791	BLP00749 hypothetical protein
792	yebE conserved membrane protein YebE	Hypothetical protein yebE [ Bacillus licheniformis DSM 13]	UniRef100_Q65MT6	Bacillus licheniformis DSM 13
793	yebG conserved protein YebG	Hypothetical protein yebG [ Bacillus licheniformis DSM 13]	UniRef100_Q65MT5	Bacillus licheniformis DSM 13
794	purE phosphoribosylaminoimidazole carboxylase I	PurE [ Bacillus licheniformis DSM 13]	UniRef100_Q65MT4	Bacillus licheniformis DSM 13
795	purK phosphoribosylaminoimidazole carboxylase II	PurK [ Bacillus licheniformis DSM 13]	UniRef100_Q65MT3	Bacillus licheniformis DSM 13
796	purB adenylosuccinate lyase	PurB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MT2	Bacillus licheniformis DSM 13
797	purC phosphoribosylaminoimidazole	PurC [ Bacillus licheniformis DSM 13]	UniRef100_Q65MT1	Bacillus licheniformis DSM 13
	succinocarboxamide synthetase
798	purS PurS	Hypothetical protein purS [ Bacillus licheniformis DSM 13]	UniRef100_Q65MT0	Bacillus licheniformis DSM 13
799	purQ phosphoribosylformylglycinamidine synthetase I	PurQ [ Bacillus licheniformis DSM 13]	UniRef100_Q65MS9	Bacillus licheniformis DSM 13
800	purL phosphoribosylformylglycinamidine synthetase II	PurL [ Bacillus licheniformis DSM 13]	UniRef100_Q65MS8	Bacillus licheniformis DSM 13
801	purF glutamine phosphoribosylpyrophosphate	PurF [ Bacillus licheniformis DSM 13]	UniRef100_Q65MS7	Bacillus licheniformis DSM 13
	amidotransferase
802	purM phosphoribosylaminoimidazole synthetase	PurM [ Bacillus licheniformis DSM 13]	UniRef100_Q65MS6	Bacillus licheniformis DSM 13
803	purN phosphoribosylglycinamide formyltransferase	PurN [ Bacillus licheniformis DSM 13]	UniRef100_Q65MS5	Bacillus licheniformis DSM 13
804	purH phosphoribosylaminoimidazole carboxy formyl	PurH [ Bacillus licheniformis DSM 13]	UniRef100_Q65MS4	Bacillus licheniformis DSM 13
	formyltransferase and inosine-monophosphate
	cyclohydrolase
805	purD phosphoribosylglycinamide synthetase	PurD [ Bacillus licheniformis DSM 13]	UniRef100_Q65MS3	Bacillus licheniformis DSM 13
806	BLP00764 hypothetical protein	Homeodomain-like [ Bacillus licheniformis DSM 13]	UniRef100_Q62Y67	Bacillus licheniformis DSM 13
807	yjiB Cytochrome P450	YjiB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MS1	Bacillus licheniformis DSM 13
808	BLP04847 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62Y65	Bacillus licheniformis DSM 13
809	yybP YybP	YybP [ Bacillus licheniformis DSM 13]	UniRef100_Q65MS0	Bacillus licheniformis DSM 13
810	BLP00767 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MR9	Bacillus licheniformis DSM 13
811	BLP00768 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MR8	Bacillus licheniformis DSM 13
812	yerA putative Metallo-dependent hydrolase	YerA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MR7	Bacillus licheniformis DSM 13
813	yerB conserved protein YerB	Hypothetical protein yerB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MR6	Bacillus licheniformis DSM 13
814	yerC conserved protein YerC	YerC [ Bacillus licheniformis DSM 13]	UniRef100_Q65MR5	Bacillus licheniformis DSM 13
815	pcrB PcrB	PcrB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MR4	Bacillus licheniformis DSM 13
816	pcrA ATP-dependent DNA helicase	PcrA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MR3	Bacillus licheniformis DSM 13
817	ligA DNA ligase	LigA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MR2	Bacillus licheniformis DSM 13
818	yerH YerH	Hypothetical protein yerH [ Bacillus licheniformis DSM 13]	UniRef100_Q65MR1	Bacillus licheniformis DSM 13
819	BLP00776 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MR0	Bacillus licheniformis DSM 13
820	BLP00777 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MQ9	Bacillus licheniformis DSM 13
821	BLP00778 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MQ8	Bacillus licheniformis DSM 13
822	BLP00779 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MQ7	Bacillus licheniformis DSM 13
823	BLP00780 zin-ion binding putative hydrolase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MQ6	Bacillus licheniformis DSM 13
824	BLP00781 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MQ5	Bacillus licheniformis DSM 13
825	BLP00782 putative phosphopentomutase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MQ4	Bacillus licheniformis DSM 13
826	BLP00783 putative alanine racemase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MQ3	Bacillus licheniformis DSM 13
827	BLP04708 hypothetical protein
828	nagB N-acetylglucosamine-6-phosphate isomerase	NagB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MQ2	Bacillus licheniformis DSM 13
829	BLP00785 hypothetical protein
830	sapB SapB	Hypothetical protein sapB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MQ1	Bacillus licheniformis DSM 13
831	BLP00787 hypothetical protein
832	opuE proline transporter	OpuE [ Bacillus licheniformis DSM 13]	UniRef100_Q65MQ0	Bacillus licheniformis DSM 13
833	BLP00789 hypothetical protein
834	gatC glutamyl-tRNA(Gln) amidotransferase (subunit	GatC (Glutamyl-tRNA(Gln) amidotransferase) [ Bacillus	UniRef100_Q65MP9	Bacillus licheniformis DSM 13
	C)	licheniformis DSM 13]
835	gatA glutamyl-tRNA(Gln) amidotransferase (subunit	GatA (Glutamyl-tRNA(Gln) amidotransferase) [ Bacillus	UniRef100_Q65MP8	Bacillus licheniformis DSM 13
	A)	licheniformis DSM 13]
836	gatB glutamyl-tRNA(Gln) amidotransferase (subunit	GatB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MP7	Bacillus licheniformis DSM 13
	B)
837	BLP00793 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MP6	Bacillus licheniformis DSM 13
838	BLP00794 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MP5	Bacillus licheniformis DSM 13
839	ydhT Glutamine amidotransferase, class-II	YdhT [ Bacillus licheniformis DSM 13]	UniRef100_Q65MP4	Bacillus licheniformis DSM 13
840	yerO putative transcriptional regulator YerO	YerO [ Bacillus licheniformis DSM 13]	UniRef100_Q65MP3	Bacillus licheniformis DSM 13
841	swrC swarming and motility protein SwrC	YerP [ Bacillus licheniformis DSM 13]	UniRef100_Q65MP2	Bacillus licheniformis DSM 13
842	BLP00798 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MP1	Bacillus licheniformis DSM 13
843	yjcK putative ribosomal-protein-alanine N-	YjcK [ Bacillus licheniformis DSM 13]	UniRef100_Q65MP0	Bacillus licheniformis DSM 13
	acetyltransferase YjcK
844	BLP00800 putative inosine-uridine preferring	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MN9	Bacillus licheniformis DSM 13
	nucleoside hydrolase
845	yerQ putative kinase related to diacylglycerol kinase	Hypothetical protein yerQ [ Bacillus licheniformis DSM 13]	UniRef100_Q65MN8	Bacillus licheniformis DSM 13
	YerQ
846	yefA putative RNA methyltransferase YefA	YefA (TRNA (Uracil-5-)-methyltransferase/TrmA) [ Bacillus	UniRef100_Q65MN7	Bacillus licheniformis DSM 13
		licheniformis DSM 13]
847	BLP00803 hypothetical protein	Hypothetical protein [ Bacillus cereus ]	UniRef100_Q73EH0	Bacillus cereus
848	BLP00805 HNH endonuclease domain protein	HNH endonuclease domain protein [ Bacillus cereus ]	UniRef100_Q73EG9	Bacillus cereus
849	CDS_00859 hypothetical protein	S-adenosylmethionine synthetase [ Bacillus cereus ]	UniRef100_Q73EG7	Bacillus cereus
850	BLP00806 putative S-adenosylmethinone synthetase	S-adenosylmethionine synthetase [ Bacillus cereus ]	UniRef100_Q73EG7	Bacillus cereus
851	BLP00807 DNA methylase	DNA methylase, family protein [ Bacillus cereus ]	UniRef100_Q73EG6	Bacillus cereus
852	BLP00808 cytosine methyltransferase	DNA-cytosine methyltransferase [ Bacillus cereus ]	UniRef100_Q73EG5	Bacillus cereus
853	rapK response regulator aspartate phosphatase	RapK [ Bacillus licheniformis DSM 13]	UniRef100_Q65MM8	Bacillus licheniformis DSM 13
854	phrK regulator of the activity of RapK phosphatase	Regulator of the activity of phosphatase RapK [ Bacillus	UniRef100_Q62Y21	Bacillus licheniformis DSM 13
		licheniformis DSM 13]
855	BLP04709 hypothetical protein
856	BLP00811 putative SAM methytransferase	Hypothetical protein (Hypothetical SAM (And some other	UniRef100_Q65MM6	Bacillus licheniformis DSM 13
		nucleotide) binding motif) [ Bacillus licheniformis DSM 13]
857	BLP00812 hypothetical protein
858	yeel hypothetical protein Yeel	Yeel [ Bacillus licheniformis DSM 13]	UniRef100_Q65MM5	Bacillus licheniformis DSM 13
859	BLP00814 Putative HTH-type transcriptional regulator	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MM4	Bacillus licheniformis DSM 13
860	BLP00815 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MM3	Bacillus licheniformis DSM 13
861	yfmT Aldehyde dehydrogenase YfmT	YfmT [ Bacillus licheniformis DSM 13]	UniRef100_Q65MM2	Bacillus licheniformis DSM 13
862	yfmS putative chemotaxis sensory transducer YfmS	YfmS [ Bacillus licheniformis DSM 13]	UniRef100_Q65MM1	Bacillus licheniformis DSM 13
863	BLP00818 Sodium_sulphate symporter	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MM0	Bacillus licheniformis DSM 13
864	yfmR ABC transporter YfmR	YfmR [ Bacillus licheniformis DSM 13]	UniRef100_Q65ML9	Bacillus licheniformis DSM 13
865	BLP00820 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65ML8	Bacillus licheniformis DSM 13
866	yciA conserved hypothetical protein YciA	YciA [ Bacillus licheniformis DSM 13]	UniRef100_Q65ML7	Bacillus licheniformis DSM 13
867	BLP00822 NAD-binding site protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65ML6	Bacillus licheniformis DSM 13
868	BLP00823 GTP binding protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65ML5	Bacillus licheniformis DSM 13
869	yciC Cobalamin synthesis protein_P47K	YciC [ Bacillus licheniformis DSM 13]	UniRef100_Q65ML4	Bacillus licheniformis DSM 13
870	bioW 6-carboxyhexanoate-CoA ligase	BioW [ Bacillus licheniformis DSM 13]	UniRef100_Q65ML3	Bacillus licheniformis DSM 13
871	bioA adenosylmethionine-8-amino-7-oxononanoate	BioA [ Bacillus licheniformis DSM 13]	UniRef100_Q65ML2	Bacillus licheniformis DSM 13
	aminotransferase
872	bioF 8-amino-7-oxononanoate synthase	BioF [ Bacillus licheniformis DSM 13]	UniRef100_Q65ML1	Bacillus licheniformis DSM 13
873	bioD dethiobiotin synthetase	BioD [ Bacillus licheniformis DSM 13]	UniRef100_Q65ML0	Bacillus licheniformis DSM 13
874	bioB biotin synthetase	BioB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MK9	Bacillus licheniformis DSM 13
875	bioI cytochrome P450 enzyme	BioI [ Bacillus licheniformis DSM 13]	UniRef100_Q65MK8	Bacillus licheniformis DSM 13
876	BLP00831 cation transporter	Hypothetical protein (Hypothetical Cation (Not K+) channel,	UniRef100_Q65MK7	Bacillus licheniformis DSM 13
		TM region, Cation channel, non-ligand gated) [ Bacillus
		licheniformis DSM 13]
877	ymfP Putative DNA binding protein YmfP	YfmP [ Bacillus licheniformis DSM 13]	UniRef100_Q65MK6	Bacillus licheniformis DSM 13
878	yfmO putative multidrug efflux protein	YfmO [ Bacillus licheniformis DSM 13]	UniRef100_Q65MK5	Bacillus licheniformis DSM 13
879	yfmM ABC transporter	YfmM [ Bacillus licheniformis DSM 13]	UniRef100_Q65MK4	Bacillus licheniformis DSM 13
880	yfmL putative ATP binding helicase	YfmL [ Bacillus licheniformis DSM 13]	UniRef100_Q65MK3	Bacillus licheniformis DSM 13
881	yfmJ putative oxidoreductase	YfmJ [ Bacillus licheniformis DSM 13]	UniRef100_Q65MK2	Bacillus licheniformis DSM 13
882	BLP00837 hypothetical protein	YfmB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MK1	Bacillus licheniformis DSM 13
883	yflT conserved hypothetical protein YflT	YflT [ Bacillus licheniformis DSM 13]	UniRef100_Q65MK0	Bacillus licheniformis DSM 13
884	yflS putative 2-oxoglutarate_malate translocator	YflS [ Bacillus licheniformis DSM 13]	UniRef100_Q65MJ9	Bacillus licheniformis DSM 13
885	BLP00840 Putative Type IIc bacteriocin lichenein
886	BLP00841 ABC transporter, ATPase subunit	ABC transporter ATP-binding protein [ Clostridium tetani ]	UniRef100_Q893J7	Clostridium tetani
887	BLP00842 ABC transporter, permease subunit	ABC transporter-associated permease [ Clostridium tetani ]	UniRef100_Q899Z8	Clostridium tetani
888	BLP00843 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MJ8	Bacillus licheniformis DSM 13
889	BLP00844 Beta-lactamase-like protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MJ7	Bacillus licheniformis DSM 13
890	yflN Beta-lactamase-like protein YflN	YflN [ Bacillus licheniformis DSM 13]	UniRef100_Q65MJ6	Bacillus licheniformis DSM 13
891	BLP00846 putative carboxypeptidase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MJ5	Bacillus licheniformis DSM 13
892	nos Nitric oxide synthase Nos	YflM [ Bacillus licheniformis DSM 13]	UniRef100_Q65MJ4	Bacillus licheniformis DSM 13
893	sdpl conserved membrane protein Sdpl	Hypothetical protein yvaZ [ Bacillus licheniformis DSM 13]	UniRef100_Q65MJ3	Bacillus licheniformis DSM 13
894	sdpR Transcriptional regulator SdpR	Winged helix DNA-binding [ Bacillus licheniformis DSM 13]	UniRef100_Q62XY4	Bacillus licheniformis DSM 13
895	yflL Acylphosphatase YflL	YflL [ Bacillus licheniformis DSM 13]	UniRef100_Q65MJ1	Bacillus licheniformis DSM 13
896	yflK conserved hypothetical protein with MOSC	YflK [ Bacillus licheniformis DSM 13]	UniRef100_Q65MJ0	Bacillus licheniformis DSM 13
	domain YflK
897	yflJ hypothetical protein	YflJ [ Bacillus licheniformis DSM 13]	UniRef100_Q65MI9	Bacillus licheniformis DSM 13
898	yflI conserved hypothetical protein YflI	YflI [ Bacillus licheniformis DSM 13]	UniRef100_Q65MI8	Bacillus licheniformis DSM 13
899	yflG Peptidase M24A, methionine aminopeptidase,	YflG [ Bacillus licheniformis DSM 13]	UniRef100_Q65MI7	Bacillus licheniformis DSM 13
	subfamily 1
900	yflE Sulfatase YflE	YflE [ Bacillus licheniformis DSM 13]	UniRef100_Q65MI6	Bacillus licheniformis DSM 13
901	BLP00856 hypothetical protein
902	yflB conserved hypothetical protein YflB	YflB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MI5	Bacillus licheniformis DSM 13
903	yflA Sodium:alanine symporter YflA	YflA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MI4	Bacillus licheniformis DSM 13
904	treP phosphotransferase system (PTS) trehalose-	TreP (Phosphotransferase system (PTS) trehalose-specific	UniRef100_Q65MI3	Bacillus licheniformis DSM 13
	specific enzyme IIBC component	enzyme IIBC component) [ Bacillus licheniformis DSM 13]
905	treA Glycoside Hydrolase Family 13	TreA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MI2	Bacillus licheniformis DSM 13
906	treR transcriptional regulator (GntR family)	TreR [ Bacillus licheniformis DSM 13]	UniRef100_Q65MI1	Bacillus licheniformis DSM 13
907	BLP00862 putative transferase hexapeptide repeat	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MI0	Bacillus licheniformis DSM 13
	containing protein
908	BLP00863 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MH9	Bacillus licheniformis DSM 13
909	BLP00864 hypothetical protein
910	BLP00865 Hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MH9	Bacillus licheniformis DSM 13
911	BLP00866 Hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MH8	Bacillus licheniformis DSM 13
912	spsC spore coat biosynthesis protein	Hypothetical protein spsCA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MH7	Bacillus licheniformis DSM 13
913	BLP00868 putative transferase hexapeptide repeat	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MH6	Bacillus licheniformis DSM 13
	containing protein
914	BLP00869 NAD-dependent epimerase_dehydratase	YtcB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MH5	Bacillus licheniformis DSM 13
915	BLP00870 putative transferase, conserved	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MH4	Bacillus licheniformis DSM 13
	hypothetical protein
916	BLP00871 putative glycosyl transferase family 2_4	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MH3	Bacillus licheniformis DSM 13
	protein
917	BLP00872 TPR-like, putative glycosyl transferase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MH2	Bacillus licheniformis DSM 13
	family 2 protein
918	spsC spore coat biosynthesis protein	SpsC [ Bacillus licheniformis DSM 13]	UniRef100_Q65MH1	Bacillus licheniformis DSM 13
919	BLP00874 putative Oxidoreductase	YrbE [ Bacillus licheniformis DSM 13]	UniRef100_Q65MH0	Bacillus licheniformis DSM 13
920	BLP00875 UDP-glucose 6-dehydrogenase	YtcA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MG9	Bacillus licheniformis DSM 13
921	BLP00876 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MG8	Bacillus licheniformis DSM 13
922	ydeP conserved hypothetical DNA binding protein	YdeP [ Bacillus licheniformis DSM 13]	UniRef100_Q65MG7	Bacillus licheniformis DSM 13
	YdeP
923	nfsB NADH-dependent nitro_flavin oxidoreductase	YfkO [ Bacillus licheniformis DSM 13]	UniRef100_Q65MG6	Bacillus licheniformis DSM 13
924	yfkN putative nucleotidase YfkN	YfkN [ Bacillus licheniformis DSM 13]	UniRef100_Q65MG5	Bacillus licheniformis DSM 13
925	yfkM general stress protein YfkM	YfkM [ Bacillus licheniformis DSM 13]	UniRef100_Q65MG4	Bacillus licheniformis DSM 13
926	yfkK conserved protein YfkK	Hypothetical protein ytkK [ Bacillus licheniformis DSM 13]	UniRef100_Q65MG3	Bacillus licheniformis DSM 13
927	BLP00882 putative Sodium:aminoacid symporter	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MG2	Bacillus licheniformis DSM 13
928	yfkJ protein-tyrosine phosphatase YfkJ	Low molecular weight phosphotyrosine protein phosphatase	UniRef100_Q62XV3	Bacillus licheniformis DSM 13
		[ Bacillus licheniformis DSM 13]
929	yfkI YfkI	Hypothetical protein yfkI [ Bacillus licheniformis DSM 13]	UniRef100_Q65MG0	Bacillus licheniformis DSM 13
930	yfkH Possible RNase YfkH	YfkH [ Bacillus licheniformis DSM 13]	UniRef100_Q65MF9	Bacillus licheniformis DSM 13
931	yfkF putative transcriptional regulator YfkF	YfkF [ Bacillus licheniformis DSM 13]	UniRef100_Q65MF8	Bacillus licheniformis DSM 13
932	BLP00887 putative stress response protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MF7	Bacillus licheniformis DSM 13
933	yfkE H_Ca2 exchanger YfkE	YfkE [ Bacillus licheniformis DSM 13]	UniRef100_Q65MF6	Bacillus licheniformis DSM 13
934	yfkD conserved protein YfkD	Hypothetical protein yfkD [ Bacillus licheniformis DSM 13]	UniRef100_Q65MF5	Bacillus licheniformis DSM 13
935	yfkA conserved protein YfkA	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MF4	Bacillus licheniformis DSM 13
936	yfjT conserved protein YfjT	Hypothetical protein yrjT [ Bacillus licheniformis DSM 13]	UniRef100_Q65MF3	Bacillus licheniformis DSM 13
937	yfjS putative Carbohydrate Esterase Family 4 YfjS	YfjS [ Bacillus licheniformis DSM 13]	UniRef100_Q65MF2	Bacillus licheniformis DSM 13
938	BLP00893 putative iron-binding oxidoreductase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MF1	Bacillus licheniformis DSM 13
939	BLP00894 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MF0	Bacillus licheniformis DSM 13
940	corA Magnesium and cobalt transport protein CorA	YfjQ [ Bacillus licheniformis DSM 13]	UniRef100_Q65ME9	Bacillus licheniformis DSM 13
941	yfjP putative DNA glycosylase	YfjP [ Bacillus licheniformis DSM 13]	UniRef100_Q65ME8	Bacillus licheniformis DSM 13
942	yfjO tRNA (uracil-5-)-methyltransferase	YfjO [ Bacillus licheniformis DSM 13]	UniRef100_Q65ME7	Bacillus licheniformis DSM 13
943	yfjM conserved protein YfjM	YfjM [ Bacillus licheniformis DSM 13]	UniRef100_Q65ME6	Bacillus licheniformis DSM 13
944	BLP00900 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65ME5	Bacillus licheniformis DSM 13
945	BLP00901 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65ME4	Bacillus licheniformis DSM 13
946	yfjL putative transporter YfjL	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65ME3	Bacillus licheniformis DSM 13
947	yvkB probable transcriptional regulator	YvkB [ Bacillus licheniformis DSM 13]	UniRef100_Q65ME2	Bacillus licheniformis DSM 13
948	ydhE UDP-glycosyltransferase, Glycosyl Transferase	YdhE [ Bacillus licheniformis DSM 13]	UniRef100_Q65ME1	Bacillus licheniformis DSM 13
	Family 1, YdhE
949	BLP00905 hypothetical protein	YckD [ Bacillus licheniformis DSM 13]	UniRef100_Q65ME0	Bacillus licheniformis DSM 13
950	yceI Sugar transporter superfamily YceI	YceI [ Bacillus licheniformis DSM 13]	UniRef100_Q65MD9	Bacillus licheniformis DSM 13
951	sacX negative regulatory protein of SacY	SacX [ Bacillus licheniformis DSM 13]	UniRef100_Q65MD8	Bacillus licheniformis DSM 13
952	sacY transcriptional antiterminator	SacY [ Bacillus licheniformis DSM 13]	UniRef100_Q65MD7	Bacillus licheniformis DSM 13
953	ybcF Carbonic anhydrase YbcF	YbcF [ Bacillus licheniformis DSM 13]	UniRef100_Q65MD6	Bacillus licheniformis DSM 13
954	ybcD conserved hypothetical protein YbcD	YbcD [ Bacillus licheniformis DSM 13]	UniRef100_Q65MD5	Bacillus licheniformis DSM 13
955	ndhF NADH dehydrogenase (subunit 5)	NdhF [ Bacillus licheniformis DSM 13]	UniRef100_Q65MD4	Bacillus licheniformis DSM 13
956	ybcI conserved protein YbcI	YbcI [ Bacillus licheniformis DSM 13]	UniRef100_Q65MD3	Bacillus licheniformis DSM 13
957	BLP00913 hypothetical protein
958	BLP00914 putative intracellular protease	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MD2	Bacillus licheniformis DSM 13
959	acoA acetoin dehydrogenase E1 component (TPP-	AcoA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MD1	Bacillus licheniformis DSM 13
	dependent alpha subunit)
960	acoB acetoin dehydrogenase E1 component (TPP-	AcoB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MD0	Bacillus licheniformis DSM 13
	dependent beta subunit)
961	acoC acetoin dehydrogenase E2 component	AcoC [ Bacillus licheniformis DSM 13]	UniRef100_Q65MC9	Bacillus licheniformis DSM 13
	(dihydrolipoamide acetyltransferase)
962	acoL acetoin dehydrogenase E3 component	AcoL [ Bacillus licheniformis DSM 13]	UniRef100_Q65MC8	Bacillus licheniformis DSM 13
	(dihydrolipoamide dehydrogenase)
963	acoR transcriptional regulator	AcoR [ Bacillus licheniformis DSM 13]	UniRef100_Q65MC7	Bacillus licheniformis DSM 13
964	yfjF conserved membrane protein YfjF	Hypothetical protein yfjF [ Bacillus licheniformis DSM 13]	UniRef100_Q62XR9	Bacillus licheniformis DSM 13
965	glvA Glycoside Hydrolase, Family 4, GlvA	MalA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MC5	Bacillus licheniformis DSM 13
966	glvR ATP-dependent helicase, DEAD-box	YfiA [ Bacillus licheniformis DSM 13]	UniRef100_Q65MC4	Bacillus licheniformis DSM 13
967	malP phosphotransferase system (PTS) maltose-	Phosphotransferase system (PTS) maltose-specific enzyme	UniRef100_Q62XR6	Bacillus licheniformis DSM 13
	specific enzyme IICB component	IICB component [ Bacillus licheniformis DSM 13]
968	BLP00924 putative SAM methyltransferase	Hypothetical protein (Hypothetical SAM (And some other	UniRef100_Q65MC2	Bacillus licheniformis DSM 13
		nucleotide) binding motif) [ Bacillus licheniformis DSM 13]
969	BLP00925 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MC1	Bacillus licheniformis DSM 13
970	yvaP possible transcriptional regulator YvaP	YodB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MC0	Bacillus licheniformis DSM 13
971	yfiD conserved membrane protein YfiD	YfiD [ Bacillus licheniformis DSM 13]	UniRef100_Q65MB9	Bacillus licheniformis DSM 13
972	yfiE Glyoxalase I YfiE	YfiE [ Bacillus licheniformis DSM 13]	UniRef100_Q65MB8	Bacillus licheniformis DSM 13
973	xynBA Glycoside Hydrolase Family 43	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MB7	Bacillus licheniformis DSM 13
974	xynBB Glycoside Hydrolase Family 43	XynB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MB6	Bacillus licheniformis DSM 13
975	yfiF probable transcriptional regulator YfiF	YfiF [ Bacillus licheniformis DSM 13]	UniRef100_Q65MB5	Bacillus licheniformis DSM 13
976	BLP00932 putative extracellular solute-binding	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MB4	Bacillus licheniformis DSM 13
	protein, family 1
977	BLP00933 hypothetical protein
978	ydeQ NAD(P)H dehydrogenase (quinone)	YdeQ (NAD(P)H dehydrogenase) [ Bacillus licheniformis DSM	UniRef100_Q65MB3	Bacillus licheniformis DSM 13
		13]
979	yjhB hypothetical protein, putative hydrolase	YjhB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MB2	Bacillus licheniformis DSM 13
980	BLP00936 hypothetical protein	Hypothetical protein yfiT [ Bacillus licheniformis DSM 13]	UniRef100_Q65MB1	Bacillus licheniformis DSM 13
981	yfiX conserved membrane protein YfiX	Hypothetical protein yfiX [ Bacillus licheniformis DSM 13]	UniRef100_Q65MA9	Bacillus licheniformis DSM 13
982	BLP00938 hypothetical protein
983	yfhB Phenazine biosynthesis-like protein	YfhB [ Bacillus licheniformis DSM 13]	UniRef100_Q65MA8	Bacillus licheniformis DSM 13
984	yfhC Nitroreductase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MA7	Bacillus licheniformis DSM 13
985	yfhD conserved hypothetical YfhD	Hypothetical protein yfhD [ Bacillus licheniformis DSM 13]	UniRef100_Q65MA6	Bacillus licheniformis DSM 13
986	BLP00942 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62XP8	Bacillus licheniformis DSM 13
987	BLP00943 putative acetyl transferase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65MA5	Bacillus licheniformis DSM 13
988	yfhF Conserved hypothetical protein, YfcH	YfhF [ Bacillus licheniformis DSM 13]	UniRef100_Q65MA4	Bacillus licheniformis DSM 13
989	recX conserved protein RecX	YfhG [ Bacillus licheniformis DSM 13]	UniRef100_Q65MA3	Bacillus licheniformis DSM 13
990	yfhH conserved protein YfhH	Hypothetical protein yfhH [ Bacillus licheniformis DSM 13]	UniRef100_Q65MA2	Bacillus licheniformis DSM 13
991	BLP00947 hypothetical protein
992	sspK small acid-soluble spore protein	SspK [ Bacillus licheniformis DSM 13]	UniRef100_Q65MA1	Bacillus licheniformis DSM 13
993	yfhJ conserved protein YfhJ	Hypothetical protein yfhJ [ Bacillus licheniformis DSM 13]	UniRef100_Q65MA0	Bacillus licheniformis DSM 13
994	BLP00950 hypothetical protein
995	csbB stress response protein, Glycosyl Transferase	CsbB [ Bacillus licheniformis DSM 13]	UniRef100_Q65M99	Bacillus licheniformis DSM 13
	Family 2
996	BLP00952 putative transporter	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65M98	Bacillus licheniformis DSM 13
997	yfhO conserved membrane protein YfhO	Hypothetical protein yfhO [ Bacillus licheniformis DSM 13]	UniRef100_Q65M97	Bacillus licheniformis DSM 13
998	yfhP Predicted membrane-bound metal-dependent	YfhP [ Bacillus licheniformis DSM 13]	UniRef100_Q65M96	Bacillus licheniformis DSM 13
	hydrolase
999	yfhQ putative A_G-specific adenine glycosylase YfhQ	YfhQ [ Bacillus licheniformis DSM 13]	UniRef100_Q65M95	Bacillus licheniformis DSM 13
1000	yfhS conserved protein YhfS	Hypothetical protein yfhS [ Bacillus licheniformis DSM 13]	UniRef100_Q65M94	Bacillus licheniformis DSM 13
1001	fabL enoyl-acyl carrier protein reductase	FabL [ Bacillus licheniformis DSM 13]	UniRef100_Q65M93	Bacillus licheniformis DSM 13
1002	sspE small acid-soluble spore protein (gamma-type	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65M92	Bacillus licheniformis DSM 13
	SASP)
1003	ygaB conserved hypothetical protein YgaB	YgaB [ Bacillus licheniformis DSM 13]	UniRef100_Q65M91	Bacillus licheniformis DSM 13
1004	ygaC conserved hypothetical protein YgaC	YgaC [ Bacillus licheniformis DSM 13]	UniRef100_Q65M90	Bacillus licheniformis DSM 13
1005	ygaD ABC transporter YgaD	YgaD [ Bacillus licheniformis DSM 13]	UniRef100_Q65M89	Bacillus licheniformis DSM 13
1006	appDC oligopeptide ABC transporter (ATP-binding	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65M88	Bacillus licheniformis DSM 13
	protein)
1007	appFC oligopeptide ABC transporter (ATP-binding	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65M87	Bacillus licheniformis DSM 13
	protein)
1008	appAC oligopeptide ABC transporter (binding protein)	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65M86	Bacillus licheniformis DSM 13
1009	appBC oligopeptide ABC transporter (permease)	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65M85	Bacillus licheniformis DSM 13
1010	appCC oligopeptide ABC transporter (permease)	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65M84	Bacillus licheniformis DSM 13
1011	ygaE conserved hypothetical protein YgaE	YgaE [ Bacillus licheniformis DSM 13]	UniRef100_Q65M83	Bacillus licheniformis DSM 13
1012	gsaB glutamate-1-semialdehyde aminotransferase	GsaB [ Bacillus licheniformis DSM 13]	UniRef100_Q65M82	Bacillus licheniformis DSM 13
1013	ygaF YgaF	YgaF [ Bacillus licheniformis DSM 13]	UniRef100_Q65M81	Bacillus licheniformis DSM 13
1014	perR transcriptional regulator (Fur family)	PerR [ Bacillus licheniformis DSM 13]	UniRef100_Q65M80	Bacillus licheniformis DSM 13
1015	BLP00970 hypothetical protein
1016	ygzB conserved hypothetical protein ygzB	YgzB [ Bacillus licheniformis DSM 13]	UniRef100_Q65M79	Bacillus licheniformis DSM 13
1017	ygxA conserved protein YgxA	Hypothetical protein ygxA [ Bacillus licheniformis DSM 13]	UniRef100_Q65M78	Bacillus licheniformis DSM 13
1018	BLP00973 hypothetical protein
1019	BLP00974 response regulator aspartate phosphatase	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65M77	Bacillus licheniformis DSM 13
1020	BLP00975 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65M75	Bacillus licheniformis DSM 13
1021	BLP00976 hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62XL7	Bacillus licheniformis DSM 13
1022	BLP00977 conserved hypothetical protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q65M74	Bacillus licheniformis DSM 13
1023	BLP00978 conserved hyopothetical phagelike protein	Hypothetical protein [ Bacillus licheniformis DSM 13]	UniRef100_Q62XL6	Bacillus licheniformis DSM 13
1024	BLP00979 hypothetical phage-like protein	Hypothetical protein [ Bacillus licheniformis DSM 13]