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A Flavin-Dependent Decarboxylase-Dehydrogenase- Monooxygenase Assembles the Warhead of α,β-Epoxyketone Proteasome Inhibitors.
- Source :
-
Journal of the American Chemical Society . 4/6/2016, Vol. 138 Issue 13, p4342-4345. 4p. - Publication Year :
- 2016
-
Abstract
- The α,β-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 [13C-methyl]L-methionine implicated an α-dimethyl-β-keto acid intermediate in the biosynthesis of TMC-86A. Incubation of the chemically synthesized α-dimethyl-β-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 α-methyl-α,β-epoxyketone. This transformation appears to proceed via an unprecedented decarboxylation-dehydrogenation-monooxygenation cascade. The biosynthesis of the TMC-86A warhead is completed by cytochrome P450-mediated hydroxylation of the α-methyl-α,β-epoxyketone. [ABSTRACT FROM AUTHOR]
- Subjects :
- *FLAVINS
*DEHYDROGENASES
*MONOOXYGENASES
*STREPTOMYCES
*PROTEASOME inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 00027863
- Volume :
- 138
- Issue :
- 13
- Database :
- Academic Search Index
- Journal :
- Journal of the American Chemical Society
- Publication Type :
- Academic Journal
- Accession number :
- 114714922
- Full Text :
- https://doi.org/10.1021/jacs.6b01619