期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 138, 期 13, 页码 4342-4345出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.6b01619
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资金
- BBSRC
- Syngenta through an sLoLa [BB/K002341/1]
- BBSRC MIBTP Doctoral Training Partnership [BB/J014532/1]
- BBSRC [BB/K002341/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [1360172, BB/K002341/1] Funding Source: researchfish
The alpha,beta-epoxyketone proteasome inhibitor TMC-86A was discovered as a previously unreported metabolite of Streptomyces chromofuscus ATCC49982, and the gene cluster responsible for its biosynthesis was identified via genome sequencing. Incorporation experiments with [C-13-methyl]L-methionine implicated an alpha-dirriethyl-beta-keto acid intermediate in the biosynthesis of TMC-86A. Incubation of the chemically synthesized alpha-dimethyl-beta-keto acid with a purified recombinant flavin-dependent enzyme that is conserved in all known pathways for epoxyketone biosynthesis resulted in formation of the corresponding alpha-methyl-alpha,beta-epoxyketone. This transformation appears to proceed via an unprecedented decarboxylation dehydrogenation mono-oxygenation cascade. The biosynthesis of the TMC-86A warhead is completed by cytochrome P450-mediated hydroxylation of the alpha-methyl-alpha,beta-epoxyketone.
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