Organometallic and radical intermediates reveal mechanism of diphthamide biosynthesis

Min Dong, Venkatesan Kathiresan, Michael K. Fenwick, Andrew T. Torelli, Yang Zhang, Jonathan D. Caranto, Boris Dzikovski, Ajay Sharma, Kyle M. Lancaster, Jack H. Freed, Steven E. Ealick*, Brian M. Hoffman, Hening Lin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1247-1250
Number of pages4
Issue number6381
StatePublished - Mar 16 2018

ASJC Scopus subject areas

  • General


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