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Abstract
Streptomyces nodosus produces the antifungal polyene amphotericin B. Numerous modifications of the amphotericin polyketide synthase have yielded new analogues. However, previous inactivation of the ketoreductase in module 10 resulted in biosynthesis of truncated polyketides. Here we show that modules downstream of this domain remain intact. Therefore, loss of ketoreductase-10 activity is sufficient to cause early chain termination. This modification creates a labile point in cycle 11 of the polyketide biosynthetic pathway. Non-extendable intermediates are released to accumulate as polyenyl-pyrones.
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Caffrey P, Lynch S, Flood E, Finnan S, Oliynyk M (2001) Amphotericin biosynthesis inStreptomyces nodosus: deductions from analysis of polyketide synthase and late genes. Chem Biol 8:713–723
Caffrey P, Aparicio JF, Malpartida F, Zotchev SB (2008) Biosynthetic engineering of polyene macrolides for generation of improved antifungal and antiparasitic agents. Curr Topics Med Chem 8:639–653
Carmody M, Byrne B, Murphy B, Breen C, Lynch S, Flood E, Finnan S, Caffrey P (2004) Analysis and manipulation of amphotericin biosynthetic genes by means of modified phage KC515 transduction techniques. Gene 343:107–115
Castonguay R, He W, Chen AY, Khosla C, Cane DE (2007) Stereospecificity of ketoreductase domains of the 6-deoxyerythronolide B synthase. J Am Chem Soc 129:13758–13769
Clark BR, Murphy C (2009) Biosynthesis of pyrrolylpolyenes inAuxarthron umbrinum. Org Biomol Chem 7:111–116
Coleman RS, Waleza MC (2006) Total synthesis of gymnoconjugatins A and B. J Org Chem 71:9841–9844
Heathcote ML, Staunton J, Leadlay PF (2001) Role of type II thioesterases: evidence for removal of short acyl chains produced by aberrant decarboxylation of chain extender units. Chem Biol 8:207–220
Kennedy RM, Abiko A, Masamune S (1988) Degradation of amphotericin B: cleavage of the glycosidic linkage with aluminum amalgam [Al(Hg)] of dichlorodicyanoquinone (DDQ). Tetrahedron Lett 29:447–450
Ma SM, Li JW-H, Choi JW, Zhou H, Lee KKM, Moorthie VA, Xie X, Kealey JT, Da Silva NA, Vederas JC, Tang Y (2009) Complete reconstitution of a highly reducing iterative polyketide synthase. Science 326:589–592
McGlacken GP, Fairlamb IJS (2005) 2-Pyrone natural products and mimetics: isolation, characterisation and biological activity. Nat Prod Rep 22:369–385
Murphy B, Andersen K, Borrissow C, Caffrey P, Griffith G, Hearn J, Ibrahim O, Khan N, Lamburn N, Lee M, Pugh K, Rawlings B (2010) Isolation and characterisation of amphotericin B analogues and truncated polyketide intermediates produced by genetic engineering ofStreptomyces nodosus. Org Biomol Chem 8:3758–3770
Power P, Dunne T, Murphy B, Nic Lochlainn L, Rai D, Borissow C, Rawlings B, Caffrey P (2008) Engineered synthesis of 7-oxo- and 15-deoxy-15-oxo-amphotericins: insights into structure-activity relationships in polyene antibiotics. Chem Biol 15:78–86
Starcevic A, Jaspars M, Cullum J, Hanrueli D, Long PF (2007) Predicting the nature and timing of epimerisation on a modular polyketide synthase. ChemBioChem 8:28–31
Valenzano CR, Lawson RJ, Chen AY, Khosla C, Cane DE (2009) The biochemical basis for sterochemical control in polyketide biosynthesis. J Am Chem Soc 131:18501–18511
Weissmann KJ, Timoney M, Bycroft M, Grice P, Hanefeld U, Staunton J, Leadlay PF (1997) The molecular basis of Celmer’s rules: the stereochemistry of the condensation step in chain extension on the erythromycin polyketide synthase. Biochemistry 36:13849–13855
Acknowledgments
NK received a PhD studentship from the Irish Higher Education Authority Programme for Research in Third Level Institutions. PC received the financial support of Science Foundation Ireland under Grant number 09/RFP/GEN2132.
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Authors and Affiliations
School of Biomolecular and Biomedical Science and Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
Naseem Khan & Patrick Caffrey
Department of Chemistry, University of Leicester, Leicester, LE1 7RH, UK
Bernard Rawlings
- Naseem Khan
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- Bernard Rawlings
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- Patrick Caffrey
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Correspondence toPatrick Caffrey.
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Khan, N., Rawlings, B. & Caffrey, P. A labile point in mutant amphotericin polyketide synthases.Biotechnol Lett33, 1121–1126 (2011). https://doi.org/10.1007/s10529-011-0538-3
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