A labile point in mutant amphotericin polyketide synthases.
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.
School of Biomolecular and Biomedical Science and Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.
Naseem
N
Khan
Bernard
B
Rawlings
Patrick
P
Caffrey
D000666:Amphotericin B / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000737:chemistry; D000935:Antifungal Agents / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001709:Biotechnology; D005798:Genes, Bacterial; D015394:Molecular Structure; D009154:Mutation; D048630:Polyketide Synthases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015202:Protein Engineering; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics
D000935:Antifungal Agents; D001426:Bacterial Proteins; D048630:Polyketide Synthases; D000666:Amphotericin B