Biosynthesis of ebelactone A: Isotopic tracer, advanced precursor and genetic studies reveal a thioesterase-independent cyclization to give a polyketide β-lactone

Journal of Antibiotics

Volumn 66, Issue 7, 2013, Pages 421-430

  Wyatt, Morgan A ^a,b   Ahilan, Yasodha ^a   Argyropoulos, Panos ^c   Boddy, Christopher N ^c   Magarvey, Nathan A ^a,b   Harrison, Paul H M ^a  

^a MCMASTER UNIVERSITY   (Canada)

^b MCMASTER UNIVERSITY   (Canada)

^c UNIVERSITY OF OTTAWA   (Canada)

Author keywords

biosynthesis; ebelactone; gene cluster; isotope shift; polyketide; Streptomyces

Indexed keywords

CARBON 13; CARBONYL DERIVATIVE; EBELACTONE A; HYDROXYL GROUP; OXYGEN 18; POLYKETIDE SYNTHASE;

ARTICLE; BIOSYNTHESIS; CHEMICAL BOND; CONTROLLED STUDY; CYCLIZATION; GENE CLUSTER; NONHUMAN; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; STREPTOMYCES; STREPTOMYCES ABURAVIENSIS;

BIOSYNTHETIC PATHWAYS; CARBON ISOTOPES; CYCLIZATION; GENES, BACTERIAL; ISOTOPE LABELING; LACTONES; MULTIGENE FAMILY; OXYGEN ISOTOPES; POLYKETIDES; STREPTOMYCES;

EID: 84881014724     PISSN: 00218820     EISSN: 18811469     Source Type: Journal    
DOI: 10.1038/ja.2013.48     Document Type: Article

References (41)

1. Lowe, C. & Vederas, J. C. Naturally-occurring beta-lactones- occurrence, syntheses and properties-a review. Org. Prep. Proced. Int. 27, 305-346 (1995).
2. Uotani, K., Naganawa, H., Kondo, S., Aoyagi, T. & Umezawa, H. Structural studies on ebelactone A and B, esterase inhibitors produced by actinomycetes. J. Antibiot. (Tokyo) 35, 1495-1499 (1982).
3. Aldridge, D. C., Giles, D. & Turner, W. B. Antibiotic 1233A: a fungal b-lactone. J. Am. Chem. Soc. Perkin Trans. 1 23, 3888-3891 (1971).
4. Weibel, E. K., Hadvary, P., Hochuli, E., Kupfer, E. & Lengsfeld, H. Lipstatin, an inhibitor of pancreatic lipase, produced by Streptomyces toxytricini. I. Producing organism, fermentation, isolation and biological activity. J. Antibiot. (Tokyo) 40, 1081-1085 (1987).
5. Feling, R. H. et al. Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew. Chem. Int. Ed. 42, 355-357 (2003).
6. Gulder, T. A. & Moore, B. S. Salinosporamide natural products: potent 20 S proteasome inhibitors as promising cancer chemotherapeutics. Angew. Chem. Int. Ed. 49, 9346-9367 (2010).
7. Anderson, J. W. Orlistat for the management of overweight individuals and obesity: a review of potential for the 60-mg, over-the-counter dosage. Exp. Opin. Pharmacother. 8, 1733-1742 (2007).
8. Romo, D. et al. Synthesis and inhibitory action on HMG-CoA synthase of racemic and optically active oxetan-2-ones (beta-lactones). Bioorg. Med. Chem. 6, 1255-1272 (1998).
9. Umezawa, H. et al. Ebelactone, an inhibitor of esterase, produced by actinomycetes. J. Antibiot. (Tokyo) 33, 1594-1596 (1980).
10. Nonaka, Y. et al. Effects of ebelactone B, a lipase inhibitor, on intestinal fat absorption in the rat. J. Enz. Inhib. 10, 57-63 (1996).
11. Koller, W., Trail, F. & Parker, D. M. Ebelactones inhibit cutinases produced by fungal plant pathogens. J. Antibiot. (Tokyo) 43, 734-735 (1990).
12. Livingstone, M., Larsson, O., Sukarieh, R., Pelletier, J. & Sonenberg, N. A chemical genetic screen for mTOR pathway inhibitors based on 4E-BP-dependent nuclear accumulation of eIF4E. Chem. Biol. 16, 1240-1249 (2009).
13. Ostrowska, H. et al. Ebelactone B, an inhibitor of extracellular cathepsin A-type enzyme, suppresses platelet aggregation ex vivo in renovascular hypertensive rats. J. Cardio. Pharm. 45, 348-353 (2005).
14. De Pascale, G., Nazi, I., Harrison, P. H. & Wright, G. D. Beta-Lactone natural products and derivatives inactivate homoserine transacetylase, a target for antimicrobial agents. J. Antibiot. (Tokyo) 64, 483-487 (2011).
15. Cooksey, J. P., Ford, R., Kocienski, P. J., Pelotier, B. & Pons, J. M. A synthesis of (-)-ebelactones A and B. Te t r a h e d r o n 66, 6462-6467 (2010).
16. Uotani, K., Naganawa, H., Aoyagi, T. & Umezawa, H. Biosynthetic studies of ebelactone A and B by 13C NMR spectrometry. J. Antibiot. (Tokyo) 35, 1670-1674 (1982).
17. O'Hagan, D. The polyether and macrolide antibiotics: biogenetic analysis and structural correlations. Nat. Prod. Rep. 6, 205-219 (1989).
18. Rachid, S. et al. Mining the cinnabaramide biosynthetic pathway to generate novel proteasome inhibitors. Chembiochem. 12, 922-931 (2011).
19. Udwary, D. W. et al. Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica. Proc. Natl Acad. Sci. USA 104, 10376-10381 (2007).
20. Yang, H. W. & Romo, D. Methods for the synthesis of optically active beta-lactones (2-oxetanones). Tetrahedron 55, 6403-6434 (1999).
21. Cho, S. W. & Romo, D. Total synthesis of (-)-belactosin C and derivatives via double diastereoselective tandem mukaiyama aldol lactonizations. Org. Lett. 9, 1537-1540 (2007).
22. Jew, S., Terashima, S. & Koga, K. Asymmetric halolactonization reaction.2. Elucidation of general applicability and mechanism of the asymmetric bromolactonization reaction. Tetrahedron. 35, 2345-2352 (1979).
23. Goese, M., Eisenreich, W., Kupfer, E., Weber, W. & Bacher, A. Biosynthetic origin of hydrogen atoms in the lipase inhibitor lipstatin. J. Biol. Chem. 275, 21192-21196 (2000).
24. Parenty, A., Moreau, X. & Campagne, J.M. Macrolactonizations in the total synthesis of natural products. Chem. Rev. 106, 911-939 (2006).
25. Bergmann, S. et al. Genomics-driven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans. Nat. Chem. Biol. 3, 213-217 (2007).
26. Saepudin, E. & Harrison, P. The biosynthesis of antibiotic F-244 in Fusarium Sp ATCC-20788-origin of the carbon, hydrogen, and oxygen-atoms. Can. J. Chem. 73, 1-5 (1995).
27. Cane, D. E. & Yang, C. C. Biosynthetic origin of the carbon skeleton and oxygen-atoms of nargenicin-A1. J. Am. Chem. Soc. 106, 784-787 (1984).
28. Vederas, J. C. The use of stable isotopes in biosynthetic-studies. Nat. Prod. Rep. 4, 277-337 (1987).
29. Vederas, J. C. & Nakashima, T. T. Biosynthesis of averufin by aspergillus-parasiticus-detection of O-18-label by C-13-NMR isotope shifts. J. Chem. Soc. Chem. Comm. 4, 183-185 (1980).
30. Jokisaari, J. C-13-C-13 spin-spin coupling-constants and C-13 isotope effects on C-13 chemical-shifts in some 4-membered rings. Org. Magn. Resonance 11, 157-159 (1978).
31. Yue, S., Duncan, J. S., Yamamoto, Y. & Hutchinson, C. R. Macrolide biosynthesis-Tylactone formation involves the processive addition of 3 carbon units. J. Am. Chem. Soc. 109, 1253-1255 (1987).
32. Cane, D. E. & Yang, C. C. Macrolide biosynthesis.4. intact incorporation of a chain-elongation intermediate into erythromycin. J. Am. Chem. Soc. 109, 1255-1257 (1987).
33. Masamune, S., Hayase, Y., Chan, W. K. & Sobczak, R. L. Tylonolide hemiacetal, aglycone of tylosin, and its partial synthesis. J. Am. Chem. Soc. 98, 7874-7875 (1976).
34. Dick, L. R. et al. Mechanistic studies on the inactivation of the proteasome by lactacystin A central role for clasto-lactacystin beta-lactone. J. Biol. Chem. 271, 7273-7276 (1996).
35. Gokhale, R. S., Hunziker, D., Cane, D. E. & Khosla, C. Mechanism and specificity of the terminal thioesterase domain from the erythromycin polyketide synthase. Chem. Biol. 6, 117-125 (1999).
36. Wang, M. & Boddy, C. N. Examining the role of hydrogen bonding interactions in the substrate specificity for the loading step of polyketide synthase thioesterase domains. Biochem. 47, 11793-11803 (2008).
37. Pinto, A., Wang, M., Horsman, M. & Boddy, C. N. 6-deoxyerythronolide B synthase thioesterase-catalyzed macrocyclization is highly stereoselective. Org. Lett. 14, 2278-2281 (2012).
38. Wang, M., Zhou, H., Wirz, M., Tang, Y. & Boddy, C. N. A thioesterase from an iterative fungal polyketide synthase shows macrocyclization and cross coupling activity and may play a role in controlling iterative cycling through product offloading. Biochem. 48, 6288-6290 (2009).
39. Zhao, C. H. et al. Oxazolomycin biosynthesis in streptomyces albus JA3453 featuring an "Acyltransferase-less" type I polyketide synthase that incorporates two distinct extender units. J. Biol. Chem. 285, 20097-20108 (2010).
40. Bisang, C. et al. A chain initiation factor common to both modular and aromatic polyketide synthases. Nature 401, 502-505 (1999).
41. Medema, M. H. et al. AntiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nuc. Acid. Res. 39, W339-W346 (2011).