Diphthamide biosynthesis requires an organic radical generated by an iron–sulphur enzyme

Yang Zhang, Xuling Zhu, Andrew T. Torelli, Michael Lee, Boris Dzikovski, Rachel M. Koralewski, Eileen Wang, Jack Freed, Carsten Krebs, Steven E. Ealick () and Hening Lin ()
Additional contact information
Yang Zhang: Cornell University, Ithaca, New York 14853, USA
Xuling Zhu: Cornell University, Ithaca, New York 14853, USA
Andrew T. Torelli: Cornell University, Ithaca, New York 14853, USA
Michael Lee: The Pennsylvania State University, University Park, Pennsylvania 16802, USA
Boris Dzikovski: Cornell University, Ithaca, New York 14853, USA
Rachel M. Koralewski: Cornell University, Ithaca, New York 14853, USA
Eileen Wang: Cornell University, Ithaca, New York 14853, USA
Jack Freed: Cornell University, Ithaca, New York 14853, USA
Carsten Krebs: The Pennsylvania State University, University Park, Pennsylvania 16802, USA
Steven E. Ealick: Cornell University, Ithaca, New York 14853, USA
Hening Lin: Cornell University, Ithaca, New York 14853, USA

Nature, 2010, vol. 465, issue 7300, 891-896

Abstract: Abstract Archaeal and eukaryotic translation elongation factor 2 contain a unique post-translationally modified histidine residue called diphthamide, which is the target of diphtheria toxin. The biosynthesis of diphthamide was proposed to involve three steps, with the first being the formation of a C–C bond between the histidine residue and the 3-amino-3-carboxypropyl group of S-adenosyl-l-methionine (SAM). However, further details of the biosynthesis remain unknown. Here we present structural and biochemical evidence showing that the first step of diphthamide biosynthesis in the archaeon Pyrococcus horikoshii uses a novel iron–sulphur-cluster enzyme, Dph2. Dph2 is a homodimer and each of its monomers can bind a [4Fe–4S] cluster. Biochemical data suggest that unlike the enzymes in the radical SAM superfamily, Dph2 does not form the canonical 5′-deoxyadenosyl radical. Instead, it breaks the Cγ,Met–S bond of SAM and generates a 3-amino-3-carboxypropyl radical. Our results suggest that P. horikoshii Dph2 represents a previously unknown, SAM-dependent, [4Fe–4S]-containing enzyme that catalyses unprecedented chemistry.

Date: 2010
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DOI: 10.1038/nature09138

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