Journal
NATURE
Volume 465, Issue 7300, Pages 891-U4Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature09138
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Funding
- Dreyfus Foundation
- NIH/NIGMS [R01GM088276]
- NIH/NCRR [P41-RR016292]
- US National Center for Research Resources at the US National Institutes of Health [RR-15301]
- US Department of Energy, Office of Basic Energy Sciences [DE-AC02-06CH11357]
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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 59-deoxyadenosyl radical. Instead, it breaks the Cc, 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.
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