1887

15 Secondary Metabolism in Myxobacteria

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in
Zoomout

15 Secondary Metabolism in Myxobacteria, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555815677/9781555814205_Chap15-1.gif /docserver/preview/fulltext/10.1128/9781555815677/9781555814205_Chap15-2.gif

Abstract:

In the past 30 years myxobacteria have been established as proficient producers of various secondary metabolites and are regarded today as one of the few important sources for microbial natural products besides actinomycetes and fungi. Epothilone from recently successfully finished phase III clinical trials as an anticancer agent, as it represents a paclitaxel mimetic. Interestingly, secondary metabolites from myxobacteria often include structural elements which are rarely found in other sources. From the biosynthetic point of view, most of the isolated compounds represent hybrids of polyketides (PKs) and structural elements derived from nonribosomally made peptides (NRPs), whereas pure PKs are rarely found. Several members of this mixed polyketide/peptide structure have been identified that show differences in length of the polyene chain, methylation pattern, and/or hydroxylation of the terminal asparagine moiety. A genetic system is the limiting factor for identification and manipulation of secondary metabolite gene clusters in many organisms, including myxobacteria. The powerful combination of advanced cloning techniques and an advantageous expression host (which is currently far from being optimized) will allow the production of several interesting myxobacterial secondary metabolites in the future. It might even allow the production of new compounds directly from environmental DNA samples, eliminating the time-consuming or sometimes impossible isolation of pure cultures of any kind of putative producer of natural products.

Citation: Bode H, Müller R. 2008. 15 Secondary Metabolism in Myxobacteria, p 259-282. In Whitworth D (ed), Myxobacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815677.ch15
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of Figure 1
Figure 1

Myxobacterial secondary metabolites that act on the eukaryotic cytoskeleton (a) and examples of novel secondary metabolites from myxobacteria (b).

Citation: Bode H, Müller R. 2008. 15 Secondary Metabolism in Myxobacteria, p 259-282. In Whitworth D (ed), Myxobacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815677.ch15
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2
Figure 2

(a) Selected volatiles from and . (b) Biosynthesis of the main volatile compounds 9-methyldecane-3-one and ()-9-methyldecane-3-ol from DK1622 and of 9-methyl-1-phenyldecan-1-one from Sg a15.

Citation: Bode H, Müller R. 2008. 15 Secondary Metabolism in Myxobacteria, p 259-282. In Whitworth D (ed), Myxobacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815677.ch15
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3
Figure 3

Secondary metabolites isolated from DK1622. DKxanthene numbers indicate their molecular weight.

Citation: Bode H, Müller R. 2008. 15 Secondary Metabolism in Myxobacteria, p 259-282. In Whitworth D (ed), Myxobacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815677.ch15
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 4
Figure 4

Mechanisms of bacterial PKSs and NRPSs and examples of resulting natural products. Post-PKS and/or NRPS modifications are highlighted in gray. (a) Generalized example of a type I PKS consisting of noniteratively acting domains. Abbreviations: AT, acyltransferase; ACP, acyl carrier protein; KS, ketosynthase; KR, ketoreductase; DH, dehydratase; ER, enoylreductase; an a or a p inside the circles indicates the specificity of AT domains for malonyl-CoA or methylmalonyl-CoA, respectively (Staunton and Weissman, 2001). (b) Biosynthesis of erythromycin A is a well-studied example of the action of a type I PKS, 6-deoxyerythronolide B synthase (DEBS) (Staunton and ). (c) Type II PKS consisting of iteratively acting subunits as exemplified for the biosynthesis of tetracenomycin C: KS, ketosynthase KS, chain length factor (Shen, 2000). (d) Generalized example of NRPS biosynthesis: A, adenylation (the specificity of A domains is indicated according to standard amino acid abbreviations); T, peptidyl carrier protein; C, condensation; E, epimerization; HC, heterocyclization; Ox, oxidation (Sieber and Marahiel, 2005). (e) Formation of glycopeptide antibiotics like vancomycin provides well-documented examples of NRPS-directed biosynthesis, which are then further modified to give the active compounds ( ).

Citation: Bode H, Müller R. 2008. 15 Secondary Metabolism in Myxobacteria, p 259-282. In Whitworth D (ed), Myxobacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815677.ch15
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 5
Figure 5

Identification of myxobacterial biosynthesis gene clusters which allows the correlation between compounds and genes. Loss of production is easily detected by analytical methods (Silakowski et al., 2001a) or in compound-specific bioassays (Sandmann et al., 2004). Genomic DNA carrying different gene clusters responsible for the production of known and unknown compounds is simplified by a line. Extracts are made from mutants obtained via the targeted or the random approach and are either screened directly via HPLC/MS or used in a bioassay. In the example shown the destruction of the tubulin network is assayed after incubation of eukaryotic cells with the extracts followed by fixation and immunofluorescene microscopy of the cells.

Citation: Bode H, Müller R. 2008. 15 Secondary Metabolism in Myxobacteria, p 259-282. In Whitworth D (ed), Myxobacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815677.ch15
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 6
Figure 6

Biosynthesis of epothilone intermediates with alternate starter units. (a) Natural start of epothilone biosynthesis (Molnar et al., 2000). (b) Generation of alternative starting units using EpoC and different -acetylcysteamine thioesters (SNAC) (which serve as substrate mimics of the intermediary enzyme-bound thioesters) of heterocyclic carboxylic acids. Products were detected bound to EpoC ( ). (c) Similar work using EpoA, EpoB, and EpoC. In this case the products were detected after hydrolysis from the biosynthetic enzyme ( ). Abbreviations: MMCoA, methylmalonyl-CoA; Boc, Butyloxycarbonyl; ER, domains for enoylreductase; HC, heterocyclization; Ox, oxidation; for other abbreviations, see the legend to Fig. 4 . Reprinted from the (Bode and Müller, 2006) with kind permission of the publisher (© Springer-Verlag, Berlin, Germany).

Citation: Bode H, Müller R. 2008. 15 Secondary Metabolism in Myxobacteria, p 259-282. In Whitworth D (ed), Myxobacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815677.ch15
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 7
Figure 7

Unusual chain termination mechanisms found in myxobacteria. Active domains are shown in gray. (a) The biosynthesis of myxochelin as confirmed by in vitro studies ( ). (b) A similar mechanism was postulated for the biosynthesis of the myxalamids (Silakowski et al., 2001b). The reduction of the thioester to the aldehyde might also take place in a two-step mechanism with an enzyme-bound , -hemiacetal as intermediate. (c) Postulated final steps in the biosynthesis of myxothiazol (Silakowski et al., 1999) and melithiazol (Weinig et al., 2003) are in agreement with results from recent in vitro studies (Müller et al., 2006). (d) Postulated chromone ring formation in stigmatellin biosynthesis. Acetate and propionate units as determined from labeling experiments are shown in bold (Gaitatzis et al., 2002). Abbreviations: IC, isochorismate synthase; ArCP, aryl carrier protein; Red, reduction; Mox, monooxygenase; TE, thioesterase; for other abbreviations, see the legend to Fig. 4 . Reprinted from the (Bode and Müller, 2006) with kind permission of the publisher (© Springer-Verlag, Berlin, Germany).

Citation: Bode H, Müller R. 2008. 15 Secondary Metabolism in Myxobacteria, p 259-282. In Whitworth D (ed), Myxobacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815677.ch15
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 8
Figure 8

Alternative pathway to IV-CoA branching from the mevalonate-dependent isoprenoid biosynthesis.

Citation: Bode H, Müller R. 2008. 15 Secondary Metabolism in Myxobacteria, p 259-282. In Whitworth D (ed), Myxobacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815677.ch15
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 9
Figure 9

Heterologous expression of myxobacterial biosynthesis gene clusters exemplified for myxochromides from DW4/3-1 (Wenzel et al., 2005a). (1) Construction of cosmid library; (2) identification and analysis of the desired gene cluster; (3) “stitching” of the cluster and construction of the expression construct CMch37, using Red/ET technology; (4) transformation of the final cluster into ; and (5) production of myxochromide after induction.

Citation: Bode H, Müller R. 2008. 15 Secondary Metabolism in Myxobacteria, p 259-282. In Whitworth D (ed), Myxobacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815677.ch15
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 10
Figure 10

Effect of disruption ( ) and overexpression ( ) on chivosazol production (a) and fruiting body formation in So ce56 (b).

Citation: Bode H, Müller R. 2008. 15 Secondary Metabolism in Myxobacteria, p 259-282. In Whitworth D (ed), Myxobacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815677.ch15
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555815677.ch15
1. Austin, M. B., and, J. P. Noel. 2003. The chalcone synthase superfamily of type III polyketide synthases. Nat. Prod. Rep. 20:79110.
2. Bedorf, N.,, D. Schomburg,, K. Gerth, H. Reichenbach, and, G. Höfle. 1993. Isolation and structure elucidation of soraphen A1, a novel antifungal macrolide from Sorangium cellulosum. Liebigs Ann. Chem. 1993:10171021.
3. Bentley,, S. D.,, K. F. Chater,, A. M. Cerdeno-Tarraga,, G. L. Challis,, N. R. Thomson,, K. D. James,, D. E. Harris,, M. A. Quail,, H. Kieser,, D. Harper,, A. Bateman,, S. Brown,, G. Chandra,, C. W. Chen,, M. Collins,, A. Cronin,, A. Fraser,, A. Goble,, J. Hidalgo,, T. Hornsby,, S. Howarth,, C. H. Huang,, T. Kieser,, L. Larke,, L. Murphy,, K. Oliver,, S. O’Neil,, E. Rabbinowitsch,, M. A. Rajandream,, K. Rutherford,, S. Rutter,, K. Seeger,, D. Saunders,, S. Sharp,, R. Squares,, S. Squares,, K. Taylor,, T. Warren,, A. Wietzorrek,, J. Woodward,, B. G. Barrell,, J. Parkhill, and, D. A. Hopwood. 2002. Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417:141147.
4. Beyer, S.,, B. Kunze,, B. Silakowski, and, R. Müller. 1999. Metabolic diversity in myxobacteria: identification of the myxalamid and the stigmatellin biosynthetic gene cluster of Stigmatella aurantiaca Sg a15 and a combined polyketide-(poly)peptide gene cluster from the epothilone producing strain Sorangium cellulosum So ce90. Biochim. Biophys. Acta 1445:185195.
5. Bird, C.,, J. Lynch,, F. Pirt,, W. Reid, and, C. Brooks. 1971. Steroids and squalene in Methylococcus capsulatus grown on methane. Nature 230:473474.
6. Bode, H. B.,, B. Bethe,, R. Höfs, and, A. Zeeck. 2002. Big effects from small changes: possible ways to explore nature’s chemical diversity. Chembiochem 3:619627.
7. Bode,, H. B.,, H. Irschik,, S. C. Wenzel,, H. Reichenbach,, R. Müller, and, G. Höfle. 2003a. The leupyrrins: a structurally unique family of secondary metabolites from the myxobacterium Sorangium cellulosum. J. Nat. Prod. 66:12031206.
8. Bode, H. B., and, R. Müller. 2003. Possibility of bacterial recruitment of plant genes associated with the biosynthesis of secondary metabolites. Plant Physiol. 132:11531161.
9. Bode, H. B., and, R. Müller. 2005. The impact of bacterial genomics on natural product research. Angew. Chem. Int. Ed. Engl. 44:68286846.
10. Bode, H. B., and, R. Müller. 2006. Analysis of myxobacterial secondary metabolism goes molecular. J. Ind. Microbiol. Biotechnol. 33:577588.
11. Bode,, H. B.,, M. W. Ring,, G. Schwär,, R. M. Kroppenstedt,, D. Kaiser, and, R. Müller. 2006. 3-Hydroxy-3-methylglutarylcoenzyme A (CoA) synthase is involved in the biosynthesis of isovaleryl-CoA in the myxobacterium Myxococcus xanthus during fruiting body formation. J. Bacteriol. 188:65246528.
12. Bode,, H. B.,, S. C. Wenzel,, H. Irschik, G. Höfle, and, R. Müller. 2004. Unusual biosynthesis of leupyrrins in the myxobacterium Sorangium cellulosum. Angew. Chem. Int. Ed. Engl. 43:41634167.
13. Bode,, H. B.,, B. Zeggel,, B. Silakowski,, S., C. Wenzel,, H. Reichenbach, and, R. Müller. 2003b. Steroid biosynthesis in prokaryotes: identification of myxobacterial steroids and cloning of the first bacterial 2,3(S)-oxidosqualene cyclase from the myxobacterium Stigmatella aurantiaca. Mol. Microbiol. 47:471481.
14. Bretscher, A. P., and, D. Kaiser. 1978. Nutrition of Myxococcus xanthus, a fruiting myxobacterium. J. Bacteriol. 133:763768.
15. Burchard, R. P.,, A. C. Burchard, and, J. H. Parish. 1977. Pigmentation phenotype instability in Myxococcus xanthus. Can. J. Microbiol. 23:16571662.
16. Carvalho, R.,, R. Reid,, N. Viswanathan,, H. Gramajo, and, B. Julien. 2005. The biosynthetic genes for disorazoles, potent cytotoxic compounds that disrupt microtubule formation. Gene 359:9198.
17. Chater, K. F., and, M. J. Bibb. 1997. Regulation of bacterial antibiotic production p. 149–182. In H.-J. Rehm, and D. W. Reed (ed.), Biotechnology. VCH, Mannheim, Germany.
18. Dewick, P.M. 2002. The biosynthesis of C5-C25 terpenoid compounds. Nat. Prod. Rep. 19:181222.
19. Dickschat,, J. S.,, H. B. Bode,, T. Mahmud,, R. Müller, and, S. Schulz. 2005. A novel type of geosmin biosynthesis in myxobacteria. J. Org. Chem. 70:51745182.
20. Dickschat,, J. S.,, S. C. Wenzel,, H. B. Bode,, R. Müller, and, S. Schulz. 2004. Biosynthesis of volatiles by the myxobacterium Myxococcus xanthus. Chembiochem 5:778787.
21. Downard, J., and, D. Toal. 1995. Branched-chain fatty acids: the case for a novel form of cell-cell signalling during Myxococcus xanthus development. Mol. Microbiol. 16:171175.
22. Downard, J.,, S. V. Ramaswamy, and, K. S. Kil. 1993. Identification of esg, a genetic locus involved in cell-cell signaling during Myxococcus xanthus development. J. Bacteriol. 175:77627770.
23. Dworkin, M., and, S. M. Gibson. 1964. A system for studying microbial morphogenesis: rapid formation of microcysts in Myxococcus xanthus. Science 146:243244.
24. Elnakady, Y.,, F. Sasse,, H. Lünsdorf, and, H. Reichenbach. 2004. Disorazol A1, a highly effective antimitotic agent acting on tubulin polymerization and inducing apoptosis in mammalian cells. Biochem. Pharmacol. 67:927935.
25. Feng,, Z., J. Qi,, T. Tsuge,, Y. Oba,, T. Kobayashi,, Y. Suzuki,, Y. Sakagami, and, M. Ojika. 2005. Construction of a bacterial artificial chromosome library for a myxobacterium of the genus Cystobacter and characterization of an antibiotic biosynthetic gene cluster. Biosci. Biotechnol. Biochem. 69:13721380.
26. Ferrer, M.,, F. Martinez-Abarca, and, P. N. Golyshin. 2005. Mining genomes and ‘metagenomes’ for novel catalysts. Curr. Opin. Biotechnol. 16:588593.
27. Fudou,, R.,, T. Iizuka,, S. Sato,, T. Ando,, N. Shimba, and, S. Yamanaka. 2001. Haliangicin, a novel antifungal metabolite produced by a marine myxobacterium. 2. Isolation and structure elucidation. J. Antibiot. 54:153156.
28. Funa,, N.,, Y. Ohnishi,, I. Fujii,, M. Shibuya,, Y. Ebizuka, and, S. Horinouchi. 1999. A new pathway for polyketide synthesis in microorganisms. Nature 400:897899.
29. Gaitatzis, N.,, B. Kunze, and, R. Müller. 2001. In vitro reconstitution of the myxochelin biosynthetic machinery of Stigmatella aurantiaca Sg a15: biochemical characterization of a reductive release mechanism from nonribosomal peptide synthetases. Proc. Natl. Acad. Sci. USA 98:1113611141.
30. Gaitatzis,, N.,, B. Silakowski,, B. Kunze,, G. Nordsiek,, H. Blöcker,, G. Höfle, and, R. Müller. 2002. The biosynthesis of the aromatic myxobacterial electron transport inhibitor stigmatellin is directed by a novel type of modular polyketide synthase. J. Biol. Chem. 277:1308213090.
31. Garcia-Bernardo, J.,, L. Xiang,, H. Hong,, B. S. Moore, and, P. F. Leadlay. 2004. Engineered biosynthesis of phenyl-substituted polyketides. Chembiochem 5:11291131.
32. Gerth, K., and, R. Müller. 2005. Moderately thermophilic myxobacteria: novel potential for production of natural products. Environ. Microbiol. 7:874880.
33. Gerth, K.,, S. Pradella,, O. Perlova,, S. Beyer, and, R. Müller. 2003. Myxobacteria: proficient producers of novel natural products with various biological activities—past and future biotechnological aspects with the focus on the genus Sorangium. J. Biotechnol. 106:233253.
34. Goldman,, B. S.,, W. C. Nierman,, D. Kaiser,, S. C. Slater,, A. S. Durkin,, J. Eisen,, C. M. Ronning,, W. B. Barbazuk,, M. Blanchard,, C. Field,, C. Halling,, G. Hinkle,, O. Iartchuk,, H. S. Kim,, C. Mackenzie,, R. Madupu,, N. Miller,, A. Shvartsbeyn,, S. A. Sullivan,, M. Vaudin,, R. Wiegand, and, H. B. Kaplan. 2006. Evolution of sensory complexity recorded in a myxobacterial genome. Proc. Natl. Acad. Sci. USA 103:1520015205.
35. Gronewold, T. M.,, F. Sasse,, H. Lunsdorf, and, H. Reichenbach. 1999. Effects of rhizopodin and latrunculin B on the morphology and on the actin cytoskeleton of mammalian cells. Cell Tissue Res. 295:121129.
36. Gross, F.,, D. Gottschalk, and, R. Müller. 2005. Posttranslational modification of myxobacterial carrier protein domains in Pseudomonas sp. by an intrinsic phosphopantetheinyl transferase. Appl. Microbiol. Biotechnol. 68:6674.
37. Gross,, F.,, N. Luniak,, O. Perlova,, N. Gaitatzis,, H. JenkeKodama,, K. Gerth,, D. Gottschalk,, E. Dittmann, and, R. Müller. 2006a. Bacterial type III polyketide synthases: phylogenetic analysis and potential for the production of novel secondary metabolites by heterologous expression in pseudomonads. Arch. Microbiol. 185:2838.
38. Gross,, F.,, M. W. Ring,, O. Perlova,, J. Fu,, S. Schneider,, K. Gerth,, S. Kuhlmann,, F. Stewart,, Y. Zhang, and, R. Müller. 2006b. Metabolic engineering of Pseudomonas putida for methylmalonyl-CoA biosynthesis to enable complex heterologous secondary metabolite formation. Chem. Biol. 13:12531264.
39. Hafner,, E. W.,, B. W. Holley,, K. S. Holdom,, S. E. Lee,, R. G. Wax,, D. Beck,, H. A. McArthur, and, W. C. Wernau. 1991. Branched-chain fatty acid requirement for avermectin production by a mutant of Streptomyces avermitilis lacking branched-chain 2-oxo acid dehydrogenase activity. J. Antibiot. 44:349356.
40. Heath, R. J., and, C. O. Rock. 2002. The Claisen condensation in biology. Nat. Prod. Rep. 19:581596.
41. Hicks,, L. M.,, S. E. O’Connor,, M. T. Mazur,, C. T. Walsh, and, N. L. Kelleher. 2004. Mass spectrometric interrogation of thioester-bound intermediates in the initial stages of epothi-lone biosynthesis. Chem. Biol. 11:327335.
42. Hill, A.,, B. Thompson,, J. Harris, and, R. Segret. 2003. Investigation of the early stages in soraphen A biosynthesis. Chem. Commun. (Cambridge) 2003:13581359.
43. Hill, A. M., and, B. L. Thompson. 2003. Novel soraphens from precursor directed biosynthesis. Chem. Commun. (Cambridge) 2003:13601361.
44. Höfle, G., and, H. Reichenbach. 2005. Epothilone, a myxobacterial metabolite with promising antitumor activity, p. 413450. In G. M. Cragg,, D. G. Kingston,, and D. J. Newman (ed.), Anticancer Agents from Natural Products. Taylor & Francis, Boca Raton, FL.
45. Iizuka, T.,, Y. Jojima,, R. Fudou,, A. Hiraishi,, J. W. Ahn, and, S. Yamanaka. 2003a. Plesiocystis pacifica gen. nov., sp. nov., a marine myxobacterium that contains dihydrogenated menaquinone, isolated from the Pacific coasts of Japan. Int. J. Syst. Evol. Microbiol. 53:189195.
46. Iizuka, T.,, Y. Jojima,, R. Fudou,, M. Tokura,, A. Hiraishi, and, S. Yamanaka. 2003b. Enhygromyxa salina gen. nov., sp. nov., a slightly halophilic myxobacterium isolated from the coastal areas of Japan. Syst. Appl. Microbiol. 26:189196.
47. Iizuka, T.,, Y. Jojima,, R. Fudou, and, S. Yamanaka. 1998. Isolation of myxobacteria from the marine environment. FEMS Microbiol. Lett. 169:317322.
48. Ikeda, H.,, J. Ishikawa,, A. Hanamoto,, M. Shinose,, H. Kikuchi,, T. Shiba,, Y. Sakaki,, M. Hattori, and, S. Omura. 2003. Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat. Biotechnol. 21:526531.
49. Irschik, H.,, R. Jansen,, K. Gerth,, G. Höfle, and, H. Reichen-bach. 1995. Chivosazol A, a new inhibitor of eukaryotic organisms isolated from myxobacteria. J. Antibiot. (Tokyo) 48:962966.
50. Irschik, H.,, W. Trowitzsch-Kienast,, K. Gerth,, G. Höfle, and, H. Reichenbach. 1988. Saframycin Mx1, a new natural saframycin isolated from a myxobacterium. J. Antibiot. (Tokyo) 41:993998.
51. Jansen, R.,, H. Irschik,, H. Reichenbach, and, G. Höfle. 1997. Antibiotics from gliding bacteria, LXXX. Chivosazoles A-F: novel antifungal and cytotoxic macrolides from Sorangium cellulosum (Myxobacteria). Liebigs Ann. Chem. 1997:17251732.
52. Jansen, R.,, B. Kunze,, H. Reichenbach, and, G. Höfle. 1996. Chondramides A-D, new cytostatic and antifungal cyclodepsipeptides from Chondromyces crocatus (myxobacteria): isolation and structure elucidation. Liebigs Ann. Chem. 1996:285290.
53. Jansen, R.,, B. Kunze,, H. Reichenbach, and, G. Höfle. 2000. Antibiotics from gliding bacteria LXXXVI, Apicularen A and B, cytotoxic 10-membered lactones with a novel mechanism of action from Chondromyces species (myxobacteria): isolation, structure elucidation, and biosynthesis. Eur. J. Org. Chem. 6:913919.
54. Jansen, R.,, G. Reifenstahl,, K. Gerth,, H. Reichenbach, and, G. Höfle. 1983. Antibiotika aus Gleitenden Bakterien, XV: Myxalamide A, B, C und D, eine Gruppe homologer Anti-biotika aus Myxococcus xanthus Mx x12 (Myxobacterales). Liebigs Ann. Chem. 7:10811095.
55. Julien, B., and, S. Shah. 2002. Heterologous expression of epothilone biosynthetic genes in Myxococcus xanthus. Anti-microb. Agents Chemother. 46:27722778.
56. Julien,, B.,, S. Shah,, R. Ziermann,, R. Goldman,, L. Katz, and, C. Khosla. 2000. Isolation and characterization of the epothilone biosynthetic gene cluster from Sorangium cellulosum. Gene 249:153160.
57. Knaggs, A. R. 2003. The biosynthesis of shikimate metabolites. Nat. Prod. Rep. 20:119136.
58. Kohl, W.,, A. Gloe, and, H. Reichenbach. 1983. Steroids from the myxobacterium Nannocystis exedens. J. Gen. Microbiol. 129:16291635.
59. Kopp, M.,, H. Irschik,, F. Gross,, O. Perlova,, A. Sandmann,, K. Gerth, and, R. Müller. 2004. Critical variations of conjugational DNA transfer into secondary metabolite multiproducing Sorangium cellulosum strains So ce12 and So ce56: development of a mariner-based transposon mutagenesis system. J. Biotechnol. 107:2940.
60. Kopp, M.,, H. Irschik,, S. Pradella, and, R. Müller. 2005. Production of the tubulin destabilizer disorazol in Sorangium cellulosum: biosynthetic machinery and regulatory genes. Chembiochem 6:12771286.
61. Kunze, B.,, N. Bedorf,, W. Kohl,, G. Höfle, and, H. Reichenbach. 1989. Myxochelin A, a new iron-chelating compound from Angiococcus disciformis (Myxobacterales). Production, isolation, physico-chemical and biological properties. J. Antibiot. (Tokyo) 42:1417.
62. Kunze, B.,, H. Reichenbach,, R. Müller, and, G. Höfle. 2005. Aurafuron A and B, new bioactive polyketides from Stigma-tella aurantiaca and Archangium gephyra (myxobacteria). J. Antibiot. (Tokyo) 58:244251.
63. Lau, J.,, S. Frykman,, R. Regentin,, S. Ou,, H. Tsuruta, and, P. Licari. 2002. Optimizing the heterologous production of epothilone D in Myxococcus xanthus. Biotechnol. Bioeng. 78:280288.
64. Laue, B. E., and, R. E. Gill. 1995. Using a phase-locked mutant of Myxococcus xanthus to study the role of phase variation in development. J. Bacteriol. 177:40894096.
65. Leibold, T.,, F. Sasse,, H. Reichenbach, and, G. Höfle. 2004. Cyrmenins, novel antifungal peptides containing a nitrogen-linked beta-methoxyacrylate pharmacophore: isolation and structural elucidation. Eur. J. Org. Chem. 2004:431435.
66. Ligon, J.,, S. Hill,, J. Beck,, R. Zirkle,, I. Monar,, J. Zawodny,, S. Money, and, T. Schupp. 2002. Characterization of the bio-synthetic gene cluster for the antifungal polyketide soraphen A from Sorangium cellulosum So ce26. Gene 285:257267.
67. Lorenz, P., and, J. Eck. 2005. Metagenomics and industrial applications. Nat. Rev. Microbiol. 3:510516.
68. Mahmud,, T.,, H. B. Bode,, B. Silakowski,, R. M. Kroppenstedt,, M. Xu,, S. Nordhoff,, G. Höfle, and, R. Müller. 2002. A novel biosynthetic pathway providing precursors for fatty acid biosynthesis and secondary metabolite formation in myxobacteria. J. Biol. Chem. 277:3276832774.
69. Mahmud, T.,, S. C. Wenzel,, E. Wan,, K. W. Wen,, H. B. Bode,, N. Gaitatzis, and, R. Müller. 2005. A novel biosynthetic pathway to isovaleryl-CoA in myxobacteria: the involvement of the mevalonate pathway. Chembiochem 6:322330.
70. Meiser, P.,, H. B. Bode, and, R. Müller. 2006. The unique DK-xanthene secondary metabolite family from the myxobacterium Myxococcus xanthus is required for developmental sporulation. Proc. Natl. Acad. Sci. USA 103:1912819133.
71. Michal, G. 1999. Biochemical Pathways. Spektrum Akad. Verlag, Heidelberg, Germany.
72. Molnar, I.,, T. Schupp,, M. Ono,, R. Zirkle,, M. Milnamow,, B. Nowak-Thompson,, N. Engel,, C. Toupet,, A. Stratmann,, D. D. Cyr,, J. Gorlach,, J. M. Mayo,, A. Hu,, S. Goff,, J. Schmid, and, J. M. Ligon. 2000. The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90. Chem. Biol. 7:97109.
73. Moss, S. J.,, C. J. Martin, and, B. Wilkinson. 2004. Loss of co-linearity by modular polyketide synthases: a mechanism for the evolution of chemical diversity. Nat. Prod. Rep. 21:575593.
74. Müller, I., and, R. Müller. 2006. Biochemical characterization of MelJ and MelK. FEBS J. 273:37683778.
75. Müller, I.,, S. Weinig,, H. Steinmetz,, B. Kunze,, S. Veluthoor,, T. Mahmud, and, R. Müller. 2006. A unique mechanism for methyl ester formation via an amide intermediate found in myxobacteria. Chembiochem 7:11971205.
76. Müller, R. 2004. Don’t classify polyketide synthases. Chem. Biol. 11:46.
77. Niggemann, J.,, M. Herrmann,, K. Gerth,, H. Irschik,, H. Reichenbach, and, G. Höfle. 2004. Tuscolid and tuscoron A and B: isolation, structural elucidation and studies on the biosynthesis of novel Furan-3(2H)-one-containing metabolites from the myxobacterium Sorangium cellulosum. Eur. J. Org. Chem. 2004:487492.
78. O’Connor, S. E.,, C. T. Walsh, and, F. Liu. 2003. Biosynthesis of epothilone intermediates with alternate starter units: engineering polyketide-nonribosomal interfaces. Angew. Chem. Int. Ed. Engl. 42:39173921.
79. Omura, S.,, H. Ikeda,, J. Ishikawa,, A. Hanamoto,, C. Takahashi,, M. Shinose,, Y. Takahashi,, H. Horikawa,, H. Nakazawa,, T. Osonoe,, H. Kikuchi,, T. Shiba,, Y. Sakaki, and, M. Hattori. 2001. Genome sequence of an industrial microorganism Streptomyces avermitilis: deducing the ability of producing secondary metabolites. Proc. Natl. Acad. Sci. USA 98:1221512220.
80. Paitan, Y.,, G. Alon,, E. Orr,, E. Z. Ron, and, E. Rosenberg. 1999. The first gene in the biosynthesis of the polyketide antibiotic TA of Myxococcus xanthus codes for a unique PKS module coupled to a peptide synthetase. J. Mol. Biol. 286:465474.
81. Pearson, A.,, M. Budin, and, J. J. Brocks. 2003. Phylogenetic and biochemical evidence for sterol synthesis in the bacterium Gemmata obscuriglobus. Proc. Natl. Acad. Sci. USA 100:1535215357.
82. Perlova, O.,, J. Fu,, S. Kuhlmann,, D. Krug,, F. Stewart,, Y. Zhang, and, R. Müller. 2006a. Reconstitution of myxothiazol bio-synthetic gene cluster by Red/ET recombination and heterologous expression in Myxococcus xanthus. Appl. Environ. Microbiol. 72:74857494.
83. Perlova, O.,, K. Gerth,, A. Hans,, O. Kaiser, and, R. Müller. 2006b. Identification and analysis of the chivosazol biosynthetic gene cluster from the myxobacterial model strain Sorangium cellulosum So ce56. J. Biotechnol. 121:174191.
84. Petit, F., and, J. F. Guespin-Michel. 1992. Production of an extracellular milk-clotting activity during development in Myxococcus xanthus. J. Bacteriol. 174:51365140.
85. Piel, J. 2004. Metabolites from symbiotic bacteria. Nat. Prod. Rep. 21:519538.
86. Plaga, W.,, I. Stamm, and, H. U. Schairer. 1998. Intercellular signaling in Stigmatella aurantiaca: purification and characterization of stigmolone, a myxobacterial pheromone. Proc. Natl. Acad. Sci. USA 95:1126311267.
87. Pospiech, A.,, J. Bietenhader, and, T. Schupp. 1996. Two multifunctional peptide synthetases and an O-methyltransferase are involved in the biosynthesis of the DNA-binding antibiotic and antitumour agent saframycin Mx1 from Myxococcus xanthus. Microbiology 142(Pt.4):741746.
88. Pospiech, A.,, B. Cluzel,, H. Bietenhader, and, T. Schupp. 1995. A new Myxococcus xanthus gene cluster for the biosynthesis of the antibiotic saframycin Mx1 encoding a peptide synthetase. Microbiology 141:17931803.
89. Rachid, S.,, D. Krug,, I. Kochems,, B. Kunze,, M. Scharfe,, H. Blöcker,, M. Zabriski, and, R. Müller. 2006a. Molecular and biochemical studies of chondramide formation—highly cytotoxic natural products from Chondromyces crocatus Cm c5. Chem. Biol. 13:667681.
90. Rachid, S.,, F. Sasse,, S. Beyer, and, R. Müller. 2006b. Identification of StiR, the first regulator of secondary metabolite formation in the myxobacterium Cystobacter fuscus Cb f17.1. J. Biotechnol. 121:429441.
91. Rachid, S.,, K. Gerth,, I. Kochems, and, R. Müller. 2007. Deciphering regulatory mechanisms for secondary metabolite production in the myxobacterium Sorangium cellulosum So ce56. Mol. Microbiol. 63:17831796.
92. Recktenwald, J.,, R. Shawky,, O. Puk,, F. Pfennig,, U. Keller,, W. Wohlleben, and, S. Pelzer. 2002. Nonribosomal biosynthesis of vancomycin-type antibiotics: a heptapeptide backbone and eight peptide synthetase modules. Microbiology 148:11051118.
93. Reichenbach, H. 2001. Myxobacteria, producers of novel bioactive substances. J. Ind. Microbiol. Biotechnol. 27:149156.
94. Ring,, M. W.,, G. Schwär,, V. Thiel,, J. S. Dickschat,, R. M. Kroppenstedt,, S. Schulz, and, H. B. Bode. 2006. Novel iso-branched etherlipids as specific markers of developmental sporulation in the myxobacterium Myxococcus xanthus. J. Biol. Chem. 268:3669136700.
95. Rosenbluh, A., and, E. Rosenberg. 1989. Sporulation of Myxococcus xanthus in liquid shake flask cultures. J. Bacteriol. 171:45214524.
96. Sandmann, A.,, J. S. Dickschat,, H. Jenke-Kodama,, B. Kunze,, E. Dittmann, and, R. Müller. 2007. Aurachin alkaloid biosynthesis in the Gram-negative myxobacterium Stigmatella aurantiaca: involvement of a type II polyketide synthase. Angew. Chem. Int. Ed. Engl. 46:27122716.
97. Sandmann, A.,, F. Sasse, and, R. Müller. 2004. Identification and analysis of the core biosynthetic machinery of tubulysin, a potent cytotoxin with potential anticancer activity. Chem. Biol. 11:10711079.
98. Sasse, F.,, B. Kunze,, T. M. Gronewold, and, H. Reichenbach. 1998. The chondramides: cytostatic agents from myxobacteria acting on the actin cytoskeleton. J. Natl. Cancer Inst. 90:15591563.
99. Sasse, F.,, T. Leibold,, B. Kunze,, G. Höfle, and, H. Reichenbach. 2003. Cyrmenins, new betamethoxyacrylate inhibitors of the electron transport. Production, isolation, physico-chemical and biological properties. J. Antibiot. (Tokyo) 56:827831.
100. Sasse, F.,, H. Steinmetz,, J. Heil,, G. Höfle, and, H. Reichenbach. 2000. Tubulysins, new cytostatic peptides from myxobacteria acting on microtubuli: production, isolation, physico-chemical and biological properties. J. Antibiot. (Tokyo) 53:879885.
101. Sasse, F.,, H. Steinmetz,, G. Höfle, and, H. Reichenbach. 1993. Rhizopodin, a new compound from Myxococcus stipitatus (myxobacteria) causes formation of rhizopodia-like structures in animal cell cultures. Production, isolation, physico-chemical and biological properties. J. Antibiot. (Tokyo) 46:741748.
102. Schley, C.,, M. O. Altmeyer,, R. Swart,, R. Müller, and, C. G. Huber. 2006. Proteome analysis of Myxococcus xanthus by off-line two-dimensional chromatographic separation using monolithic poly-(styrene-divinylbenzene) columns combined with ion-trap tandem mass spectrometry. J. Proteome Res. 5:27602768.
103. Schmidt, E. W.,, J. T. Nelson,, D. A. Rasko,, S. Sudek,, J. A. Eisen,, M. G. Haygood, and, J. Ravel. 2005. Patellamide A and C biosynthesis by a microcin-like pathway in Prochloron didemni, the cyanobacterial symbiont of Lissoclinum patella. Proc. Natl. Acad. Sci. USA 102:73157320.
104. Schneider, T. L.,, C. T. Walsh, and, S. E. O’Connor. 2002. Utilization of alternate substrates by the first three modules of the epothilone synthetase assembly line. J. Am. Chem. Soc. 124:1127211273.
105. Schulz, S.,, J. Fuhlendorff, and, H. Reichenbach. 2004. Identification and synthesis of volatiles released by the myxobacterium Chondromyces crocatus. Tetrahedron 60:38633872.
106. Schupp, T.,, C. Toupet,, B. Cluzel,, S. Neff,, S. Hill,, J. J. Beck, and, J. M. Ligon. 1995. A Sorangium cellulosum (myxobacterium) gene cluster for the biosynthesis of the macrolide antibiotic soraphen A: cloning, characterization, and homology to polyketide synthase genes from actinomycetes. J. Bacteriol. 177:36733679.
107. Shen, B. 2000. Biosynthesis of aromatic polyketides, p. 153. In A. Meijere,, K. Houk,, H. Kessler,, J. Lehn,, S. Ley,, S. Schreiber,, and J. Thiem (ed.), Topics in Current Chemistry. Springer Verlag, Berlin, Germany.
108. Sieber, S. A., and, M. A. Marahiel. 2005. Molecular mechanisms underlying nonribosomal peptide synthesis: approaches to new antibiotics. Chem. Rev. 105:715738.
109. Silakowski, B.,, B. Kunze, and, R. Müller. 2001a. Multiple hybrid polyketide synthase/nonribosomal peptide synthetase gene clusters in the myxobacterium Stigmatella aurantiaca. Gene 275:233240.
110. Silakowski, B.,, B. Kunze,, G. Nordsiek,, H. Blöcker,, G. Höfle, and, R. Müller. 2000. The myxochelin iron transport regulon of the myxobacterium Stigmatella aurantiaca Sg a15. Eur. J. Biochem. 267:64766485.
111. Silakowski, B.,, G. Nordsiek,, B. Kunze,, H. Blöcker, and, R. Müller. 2001b. Novel features in a combined polyketide synthase/non-ribosomal peptide synthetase: the myxalamid biosynthetic gene cluster of the myxobacterium Stigmatella aurantiaca Sga15. Chem. Biol. 8:5969.
112. Silakowski,, B.,, H. U. Schairer,, H. Ehret,, B. Kunze,, S. Weinig,, G. Nordsiek,, P. Brandt,, H. Blöcker,, G. Höfle,, S. Beyer, and, R. Müller. 1999. New lessons for combinatorial biosynthesis from myxobacteria: the myxothiazol biosynthetic gene cluster of Stigmatella aurantiaca DW4/3-1. J. Biol. Chem. 274:3739137399.
113. Simunovic, V.,, J. Zapp,, S. Rachid,, D. Krug,, P. Meiser, and, R. Müller. 2006. Myxovirescin biosynthesis is directed by an intriguing megasynthetase consisting of hybrid polyketide synthases/nonribosomal peptide synthetase, 3-hydroxy-3-methylglutaryl CoA synthases and trans-acting acyltransferases. Chembiochem 7:12061220.
114. Snyder, R. V.,, P. D. Gibbs,, A. Palacios,, L. Abiy,, R. Dickey,, J. V. Lopez, and, K. S. Rein. 2003. Polyketide synthase genes from marine dinoflagellates. Mar. Biotechnol. (NY) 5:112.
115. Söker, U.,, B. Kunze,, H. Reichenbach, and, G. Höfle. 2003. Dawenol, a new polyene metabolite from the myxobacterium Stigmatella aurantiaca. Z. Naturforsch. B 58:10241026.
116. Sola-Landa, A.,, R. S. Moura, and, J. F. Martin. 2003. The two-component PhoR-PhoP system controls both primary metabolism and secondary metabolite biosynthesis in Streptomyces lividans. Proc. Natl. Acad. Sci. USA 100:61336138.
117. Sprusansky, O.,, K. Stirrett,, D. Skinner,, C. Denoya, and, J. West-pheling. 2005. The bkdR gene of Streptomyces coelicolor is required for morphogenesis and antibiotic production and encodes a transcriptional regulator of a branched-chain amino acid dehydrogenase complex. J. Bacteriol. 187:664671.
118. Sprusansky, O.,, L. Zhou,, S. Jordan,, J. White, and, J. West-pheling. 2003. Identification of three new genes involved in morphogenesis and antibiotic production in Streptomyces coelicolor. J. Bacteriol. 185:61476157.
119. Staunton, J., and, K. J. Weissman. 2001. Polyketide biosynthesis: a millennium review. Nat. Prod. Rep. 18:380416.
120. Tang, L.,, S. Shah,, L. Chung,, J. Carney,, L. Katz,, C. Khosla, and, B. Julien. 2000. Cloning and heterologous expression of the epothilone gene cluster. Science 287:640642.
121. Thiericke, R., and, J. Rohr. 1993. Biological variation of microbial metabolites by precursor-directed biosynthesis. Nat. Prod. Rep. 10:265289.
122. Toal, D. R.,, S. W. Clifton,, B. A. Roe, and, J. Downard. 1995. The esg locus of Myxococcus xanthus encodes the E1 alpha and E1 beta subunits of a branched-chain keto acid dehydrogenase. Mol. Microbiol. 16:177189.
123. Trowitsch, W.,, L. Witte, and, H. Reichenbach. 1981. Geosmin from earthly smelling cultures of Nannocystis exedens (Myxobacterales). FEMS Microbiol. Lett. 12:257260.
124. Trowitzsch Kienast, W.,, K. Schober,, V. Wray,, K. Gerth,, H. Reichenbach, and, G. Höfle. 1989. Zur Konstitution der Myxovirescine B-T und Biogenese des Myxovirescins A. Liebigs Ann. Chem. 1989:345355.
125. Walsh, C. T. 2002. Combinatorial biosynthesis of antibiotics: challenges and opportunities. Chembiochem 3:125134.
126. Weinig, S.,, H. J. Hecht,, T. Mahmud, and, R. Müller. 2003. Melithiazol biosynthesis: further insights into myxobacterial PKS/NRPS systems and evidence for a new subclass of methyl transferases. Chem. Biol. 10:939952.
127. Weissman, K. J., and, P. F. Leadlay. 2005. Combinatorial biosynthesis of reduced polyketides. Nat. Rev. Microbiol. 3:925936.
128. Weist, S., and, R. D. Süssmuth. 2005. Mutational biosynthesis— a tool for the generation of structural diversity in the biosynthesis of antibiotics. Appl. Microbiol. Biotechnol. 68:141150.
129. Wenzel, S., and, R. Müller. 2005a. Recent developments towards the heterologous expression of complex bacterial natural product biosynthetic pathways. Curr. Opin. Biotechnol. 16:594606.
130. Wenzel, S. C.,, F. Gross,, Y. Zhang,, J. Fu,, F. A. Stewart, and, R. Müller. 2005a. Heterologous expression of a myxobacterial natural products assembly line in pseudomonads via red/ET recombineering. Chem. Biol. 12:349356.
131. Wenzel, S. C.,, B. Kunze,, G. Höfle,, B. Silakowski,, M. Scharfe,, H. Blöcker, and, R. Müller. 2005b. Structure and biosynthesis of myxochromides S1-3 in Stigmatella aurantiaca: evidence for an iterative bacterial type I polyketide synthase and for module skipping in nonribosomal peptide biosynthesis. Chembiochem 6:375385.
132. Wenzel, S. C.,, P. Meiser,, T. Binz,, T. Mahmud, and, R. Müller. 2006. Nonribosomal peptide biosynthesis: point mutations and module skipping lead to chemical diversity. Angew. Chem. Int. Ed. 45:22962301.
133. Wenzel, S. C., and, R. Müller. 2005b. Formation of novel secondary metabolites by bacterial multimodular assembly lines: deviations from text book biosynthetic logic. Curr. Opin. Chem. Biol. 9:447458.
134. Wilkinson, C. J.,, E. J. Frost,, J. Staunton, and, P. F. Leadlay. 2001. Chain initiation on the soraphen-producing modular polyketide synthase from Sorangium cellulosum. Chem. Biol. 8:11971208.
135. Zirkle, R.,, J. M. Ligon, and, I. Molnar. 2004. Heterologous production of the antifungal polyketide antibiotic soraphen A of Sorangium cellulosum So ce26 in Streptomyces lividans. Microbiology 150:27612774.

Tables

Generic image for table
Table 1

Completely sequenced biosynthesis gene clusters identified from myxobacteria

Citation: Bode H, Müller R. 2008. 15 Secondary Metabolism in Myxobacteria, p 259-282. In Whitworth D (ed), Myxobacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815677.ch15

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error