A Flavin-Dependent Decarboxylase-Dehydrogenase-Monooxygenase Assembles the Warhead of α,β-Epoxyketone Proteasome Inhibitors.

Research output: Research - peer-reviewArticle

  • External authors:
  • Daniel Zabala
  • Joshua W Cartwright
  • Douglas M Roberts
  • Brian Law
  • Lijiang Song
  • Markiyan Samborskyy
  • Peter F Leadlay
  • Gregory L Challis

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 [(13)C-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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)4342−4345
JournalJ. Am. Chem. Soc.
Volume138
DOIs
StatePublished - 25 Mar 2016