A Flavin-Dependent Decarboxylase–Dehydrogenase–Monooxygenase Assembles the Warhead of α,β-Epoxyketone Proteasome Inhibitors
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...
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| Veröffentlicht in: | Journal of the American Chemical Society 2016-04, Vol.138 (13), p.4342-4345 |
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| container_title | Journal of the American Chemical Society |
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| creator | Zabala, Daniel Cartwright, Joshua W Roberts, Douglas M Law, Brian J. C Song, Lijiang Samborskyy, Markiyan Leadlay, Peter F Micklefield, Jason Challis, Gregory L |
| description | 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. |
| doi_str_mv | 10.1021/jacs.6b01619 |
| format | Article |
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This transformation appears to proceed via an unprecedented decarboxylation–dehydrogenation–monooxygenation cascade. 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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.</description><subject>Carboxy-Lyases - metabolism</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Dinitrocresols</subject><subject>Dipeptides - pharmacology</subject><subject>Flavins - metabolism</subject><subject>Methionine - chemistry</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Proteasome Inhibitors - pharmacology</subject><subject>Stereoisomerism</subject><subject>Streptomyces - enzymology</subject><issn>0002-7863</issn><issn>1520-5126</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkE1OwzAQhS0EglLYsUZesiBgu4kdLytafiQQLEAsI8ee0JTELnaK6A7OwEngID0EJyFVC2zYePw037zRPIT2KDmihNHjsdLhiOeEcirXUIcmjEQJZXwddQghLBIp722h7RDGrYxZSjfRFuNSShLHHfTWx6eVei5tNIAJWAO2wQPQyufuZVapAF-v7wMYzYx3D2CX-spZ13aXGvdDgDqvIOBmBPhe-REog12B5x-H889oOGnRR2icBXzjXQMquBrwhR2Vedk4H3bQRqGqALur2kV3p8Pbk_Po8vrs4qR_Gakei5uIU66SXHOWCpMQowvBWY8lwhTApCZx-wolJFWMsFRyquPUmLggRGqp21-viw6WvhPvnqYQmqwug4aqUhbcNGRUCJkKyWXSoodLVHsXgocim_iyVn6WUZItQs8WoWer0Ft8f-U8zWswv_BPyn-rF1NjN_W2PfR_r2-BI5Az</recordid><startdate>20160406</startdate><enddate>20160406</enddate><creator>Zabala, Daniel</creator><creator>Cartwright, Joshua W</creator><creator>Roberts, Douglas M</creator><creator>Law, Brian J. 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| ispartof | Journal of the American Chemical Society, 2016-04, Vol.138 (13), p.4342-4345 |
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| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Carboxy-Lyases - metabolism Cytochrome P-450 Enzyme System - metabolism Dinitrocresols Dipeptides - pharmacology Flavins - metabolism Methionine - chemistry Proteasome Endopeptidase Complex - metabolism Proteasome Inhibitors - pharmacology Stereoisomerism Streptomyces - enzymology |
| title | A Flavin-Dependent Decarboxylase–Dehydrogenase–Monooxygenase Assembles the Warhead of α,β-Epoxyketone Proteasome Inhibitors |
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