Biosynthetic origins of the natural product, thiolactomycin: a unique and selective inhibitor of type II dissociated fatty acid synthases.
Thiolactomycin (TLM), a natural product produced by both Nocardia and Streptomyces spp., is a potent and highly selective inhibitor of the type II dissociated fatty acid synthases of plants and bacteria. The unique mode of action of TLM and its low toxicity make it an attractive compound for development of new antimicrobial agents. In this study, incorporation studies with 13C-labeled precursors demonstrate that TLM is derived from one acetate-derived starter unit and three methylmalonate-derived extender units. The unusual thiolactone represented by TLM represents a novel class of polyketide-derived antibiotics in which an unusual cyclization process, which terminates the biosynthetic pathway, involves incorporation of a sulfur atom from l-cysteine. Manipulation of this pathway through techniques such a combinatorial biosynthesis and mutasynthesis may provide a new route for economically viable production of useful TLM analogues.
Brown
Maria S
MS
Bioprocess R&D, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, USA.
Akopiants
Konstantin
K
Resceck
Diane M
DM
McArthur
Hamish A I
HA
McCormick
Ellen
E
Reynolds
Kevin A
KA
D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000138:chemical synthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D054889:Fatty Acid Synthase, Type II; D005285:Fermentation; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009615:Nocardia / Q000378:metabolism; D013876:Thiophenes / Q000138:chemical synthesis* / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D013876:Thiophenes; C035068:thiolactomycin; D000123:Acetyltransferases; D054889:Fatty Acid Synthase, Type II