Organometallic and radical intermediates reveal mechanism of diphthamide biosynthesis

Diphthamide biosynthesis involves a carbon-carbon bond-forming reaction catalyzed by a radical S-adenosylmethionine (SAM) enzyme that cleaves a carbon-sulfur (C-S) bond in SAM to generate a 3-amino-3-carboxypropyl (ACP) radical. Using rapid freezing, we have captured an organometallic intermediate w...

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Vydáno v:	Science (American Association for the Advancement of Science) Ročník 359; číslo 6381; s. 1247
Hlavní autoři:	Dong, Min, Kathiresan, Venkatesan, Fenwick, Michael K, Torelli, Andrew T, Zhang, Yang, Caranto, Jonathan D, Dzikovski, Boris, Sharma, Ajay, Lancaster, Kyle M, Freed, Jack H, Ealick, Steven E, Hoffman, Brian M, Lin, Hening
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 16.03.2018
Témata:	Archaeal Proteins - chemistry Carbon - chemistry Crystallography, X-Ray Histidine - analogs & derivatives Histidine - biosynthesis Iron - chemistry Iron-Sulfur Proteins - chemistry Organometallic Compounds - chemistry Pyrococcus horikoshii - enzymology S-Adenosylmethionine - chemistry
ISSN:	1095-9203, 1095-9203
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Popis
Shrnutí:	Diphthamide biosynthesis involves a carbon-carbon bond-forming reaction catalyzed by a radical S-adenosylmethionine (SAM) enzyme that cleaves a carbon-sulfur (C-S) bond in SAM to generate a 3-amino-3-carboxypropyl (ACP) radical. Using rapid freezing, we have captured an organometallic intermediate with an iron-carbon (Fe-C) bond between ACP and the enzyme's [4Fe-4S] cluster. In the presence of the substrate protein, elongation factor 2, this intermediate converts to an organic radical, formed by addition of the ACP radical to a histidine side chain. Crystal structures of archaeal diphthamide biosynthetic radical SAM enzymes reveal that the carbon of the SAM C-S bond being cleaved is positioned near the unique cluster Fe, able to react with the cluster. Our results explain how selective C-S bond cleavage is achieved in this radical SAM enzyme.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1095-9203 1095-9203
DOI:	10.1126/science.aao6595