期刊
CHEMBIOCHEM
卷 17, 期 9, 页码 792-798出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201500567
关键词
acyl-CoA dehydrogenase; biosynthesis; epoxomicin; epoxyketone warhead; proteasome inhibitor
资金
- German Research Foundation (DFG) [KA 3071/4-1, SFB 766]
The alpha', beta'-epoxyketone moiety of proteasome inhibitors confers high binding specificity to the N-terminal threonine in catalytic proteasome beta-subunits. We recently identified the epoxomicin and eponemycin biosynthetic gene clusters and have now conducted isotope-enriched precursor feeding studies and comprehensive gene deletion experiments to shed further light on their biosynthetic pathways. Leucine and two methyl groups from S-adenosylmethionine were readily incorporated into the epoxyketone warhead, suggesting decarboxylation of the thioester intermediate. Formation of the alpha', beta'-epoxyketone is likely mediated by conserved acyl-CoA dehydrogenase-like enzymes, as indicated by complete loss of epoxomicin and eponemycin production in the respective knockout mutants. Our results clarify crucial questions in the formation of epoxyketone compounds and lay the foundation for in vitro biochemical studies on the biosynthesis of this pharmaceutically important class of proteasome inhibitors.
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