Abstract
In recent years, members of the marine actinomycete genus Salinispora have proven to be a precious source of structurally diverse secondary metabolites, including the potent anticancer agent salinosporamide A and the enediyne-derived sporolides. The tremendous potential of these marine-dwelling microbes for natural products biosynthesis, however, was not fully realized until sequencing of the Salinispora tropica genome revealed the presence of numerous orphan biosynthetic loci besides a plethora of rare metabolic pathways. This contribution summarizes the biochemical exploration of this prolific organism, highlighting studies in which genome-based information was exploited for the discovery of new enzymatic processes and the engineering of unnatural natural products. Inactivation of key genes within the salinosporamide pathway has expanded its inherent metabolic plasticity and enabled access to various salinosporamide derivatives by mutasynthesis. New insights into the biosynthesis of the sporolides allowed us to increase production titers of these structurally complex molecules, thereby providing the means to search for the DNA cleaving presporolide enediyne.
Conference
International Conference on Biodiversity and Natural Products (ICOB-6 & ISCNP-26), International Conference on Biodiversity, International Symposium on the Chemistry of Natural Products, ICOB, ISCNP, Biodiversity, Natural Products, Charlottetown, Prince Edward Island, Canada, 2008-07-13–2008-07-18
References
1. P. R. Jensen, R. Dwight, W. Fenical. Appl. Environ. Microbiol. 57, 1102 (1991).10.1128/aem.57.4.1102-1108.1991Search in Google Scholar
2. doi:10.1128/AEM.68.10.5005-5011.2002, T. J. Mincer, P. R. Jensen, C. A. Kauffman, W. Fenical. Appl. Environ. Microbiol. 68, 5005 (2002).Search in Google Scholar
3. doi:10.1099/ijs.0.63625-0, L. A. Maldonado, W. Fenical, P. R. Jensen, C. A. Kauffman, T. J. Mincer, A. C. Ward, A. T. Bull, M. Goodfellow. Int. J. System. Evol. Microbiol. 55, 1759 (2005).Search in Google Scholar
4. doi:10.1111/j.1462-2920.2006.01093.x, P. R. Jensen, C. Mafnas. Environ. Microbiol. 8, 1881 (2006).Search in Google Scholar
5. doi:10.1038/nchembio841, W. Fenical, P. R. Jensen. Nat. Chem. Biol. 2, 666 (2006).Search in Google Scholar
6. doi:10.1016/j.ccr.2005.10.013, D. Chauhan, L. Catley, G. L. Li, K. Podar, T. Hideshima, M. Velankar, C. Mitsiades, N. Mitsiades, H. Yasui, A. Letai, H. Ovaa, C. Berkers, B. Nicholson, T. H. Chao, S. T. C. Neuteboom, P. Richardson, M. A. Palladino, K. C. Anderson. Cancer Cell 8, 407 (2005).Search in Google Scholar
7. doi:10.1128/AEM.01891-06, P. R. Jensen, P. G. Williams, D.-C. Oh, L. Zeigler, W. Fenical. Appl. Environ. Microbiol. 73, 1146 (2007).Search in Google Scholar
8. doi:10.1073/pnas.0700962104, D. W. Udwary, L. Zeigler, R. N. Asolkar, V. Singan, A. Lapidus, W. Fenical, P. R. Jensen, B. S. Moore. Proc. Natl. Acad. Sci. USA 104, 10376 (2007).Search in Google Scholar
9. doi:10.1002/ange.200390083, R. H. Feling, G. O. Buchanan, T. J. Mincer, C. A. Kauffman, P. R. Jensen, W. Fenical. Angew. Chem., Int. Ed. 115, 369 (2003).Search in Google Scholar
10. doi:10.1351/pac199971091673, S. Omura, M. Hayashi, H. Tomoda. Pure Appl. Chem. 71, 1673 (1999).Search in Google Scholar
11. doi:10.1016/j.cbpa.2008.06.033, B. S. Moore, A. E. Eustaquio, R. P. McGlinchey. Curr. Opin. Chem. Biol. 12, 434 (2008).Search in Google Scholar
12. doi:10.1021/ja993588m, M. Groll, K. B. Kim, N. Kairies, R. Huber, C. M. Crews. J. Am. Chem. Soc. 122, 1237 (2000).Search in Google Scholar
13. doi:10.1021/ja058320b, M. Groll, R. Huber, B. C. M. Potts. J. Am. Chem. Soc. 128, 5136 (2006).Search in Google Scholar
14. doi:10.1021/jo050511+, P. G. Williams, G. O. Buchanan, R. H. Feling, C. A. Kauffman, P. R. Jensen, W. Fenical. J. Org. Chem. 70, 6196 (2005).Search in Google Scholar
15. doi:10.1021/np0603471, K. A. Reed, R. R. Manam, S. S. Mitchell, J. Xu, S. Teisan, T.-H. Chao, G. Deyanat-Yadzi, S. T. C. Neuteboom, K. S. Lam, B. C. M. Potts. J. Nat. Prod. 70, 269 (2007).Search in Google Scholar
16. doi:10.1021/ol063102o, L. L. Beer, B. S. Moore. Org. Lett. 9, 845 (2007).Search in Google Scholar
17. doi:10.1021/cr050313i, F. H. Vaillancourt, E. Yeh, D. A. Vosburg, S. Garneau-Tsodikova, C. T. Walsh. Chem. Rev. 106, 3364 (2006).Search in Google Scholar
18. doi:10.1038/nature02280, C. Dong, F. Huang, H. Deng, C. Schaffrath, J. B. Spencer, D. O'Hagan, J. H. Naismith. Nature 427, 561 (2004).Search in Google Scholar
19. doi:10.1038/nchembio.2007.56, A. S. Eustaquio, F. Pojer, J. P. Noel, B. S. Moore. Nat. Chem. Biol. 4, 69 (2008).Search in Google Scholar
20. doi:10.1038/ja.2007.2, K. S. Lam, G. Tsueng, K. A. McArthur, S. S. Mitchell, B. C. M. Potts, J. Xu. J. Antibiot. 60, 13 (2007).Search in Google Scholar
21. The substrate discrimination of subsequent pathway enzymes prevents an in vivo production of iodosalinosporamide.Search in Google Scholar
22. doi:10.1021/jm048995+, V. R. Macherla, S. S. Mitchell, R. R. Manam, K. A. Reed, T.-H. Chao, B. Nicholson, G. Deyanat-Yazdi, B. Mai, P. R. Jensen, W. F. Fenical, S. T. C. Neuteboom, K. S. Lam, M. A. Palladino, B. C. M. Potts. J. Med. Chem. 48, 3684 (2005).Search in Google Scholar
23. doi:10.1002/anie.200800177, A. S. Eustaquio, B. S. Moore. Angew. Chem., Int. Ed. 47, 3936 (2008).Search in Google Scholar
24. E. J. Corey, W. Z. Li. Chem. Pharm. Bull. 47, 1 (1999).10.1248/cpb.47.1Search in Google Scholar
25. doi:10.1021/ja052376o, L. R. Reddy, J.-F. Fournier, B. V. S. Reddy, E. J. Corey. J. Am. Chem. Soc. 127, 8974 (2005).Search in Google Scholar
26. doi:10.1021/ja8029398, R. P. McGlinchey, M. Nett, A. S. Eustaquio, R. N. Asolkar, W. Fenical, B. S. Moore. J. Am. Chem. Soc. 130, 7822 (2008).Search in Google Scholar
27. doi:10.1021/ol050901i, G. O. Buchanan, P. G. Williams, R. H. Feling, C. A. Kauffman, P. R. Jensen, W. Fenical. Org. Lett. 7, 2731 (2005).Search in Google Scholar
28. doi:10.1021/ol052686b, D.-C. Oh, P. G. Williams, C. A. Kauffman, P. R. Jensen, W. Fenical. Org. Lett. 8, 1021 (2006).Search in Google Scholar
29. doi:10.1021/ja070023e, C. L. Perrin, B. L. Rodgers, J. M. O'Connor. J. Am. Chem. Soc. 129, 4795 (2007).Search in Google Scholar
30. doi:10.1021/bi701438r, J. Brownlee, P. He, G. R. Moran, D. H. T. Harrison. Biochemistry 47, 2002 (2008).Search in Google Scholar
31. doi:10.1021/ja710488m, R. P. McGlinchey, M. Nett, B. S. Moore. J. Am. Chem. Soc. 130, 2406 (2008).Search in Google Scholar
32. doi:10.1016/S1074-5521(00)00043-0, B. K. Hubbard, M. G. Thomas, C. T. Walsh. Chem. Biol. 7, 931 (2000).Search in Google Scholar
33. doi:10.1007/s00253-007-0900-5, H. Gross. Appl. Microbiol. Biotechnol. 75, 267 (2007).Search in Google Scholar
34. doi:10.1021/jm700948z, G. L. Challis. J. Med. Chem. 51, 2618 (2008).Search in Google Scholar
35. doi:10.1021/ja711188x, A. W. Schultz, D.-C. Oh, J. R. Carney, R. T. Williamson, D. W. Udwary, P. R. Jensen, S. J. Gould, W. Fenical, B. S. Moore. J. Am. Chem. Soc. 130, 4507 (2008).Search in Google Scholar
© 2013 Walter de Gruyter GmbH, Berlin/Boston
