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A flavin-dependent decarboxylase–dehydrogenase–monooxygenase assembles the warhead of α,β-Epoxyketone proteasome inhibitors
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Zabala, Daniel, Cartwright, Joshua W., Roberts, Douglas M., Law, Brian J. C., Song, Lijiang, Samborskyy, Markiyan, Leadlay, P. F., Micklefield, Jason and Challis, Gregory L. (2016) A flavin-dependent decarboxylase–dehydrogenase–monooxygenase assembles the warhead of α,β-Epoxyketone proteasome inhibitors. Journal of the American Chemical Society, 138 (13). pp. 4342-4345. doi:10.1021/jacs.6b01619 ISSN 0002-7863.
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Official URL: http://dx.doi.org/10.1021/jacs.6b01619
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.
| Item Type: | Journal Article | ||||||
|---|---|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) |
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| Journal or Publication Title: | Journal of the American Chemical Society | ||||||
| Publisher: | American Chemical Society | ||||||
| ISSN: | 0002-7863 | ||||||
| Official Date: | 21 March 2016 | ||||||
| Dates: |
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| Volume: | 138 | ||||||
| Number: | 13 | ||||||
| Page Range: | pp. 4342-4345 | ||||||
| DOI: | 10.1021/jacs.6b01619 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Restricted or Subscription Access |
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