@article{abd7fc3e9b544e06b5f474af7276836a,
title = "Organometallic and radical intermediates reveal mechanism of diphthamide biosynthesis",
abstract = "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{\textquoteright}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.",
author = "Min Dong and Venkatesan Kathiresan and Fenwick, {Michael K.} and Torelli, {Andrew T.} and Yang Zhang and Caranto, {Jonathan D.} and Boris Dzikovski and Ajay Sharma and Lancaster, {Kyle M.} and Freed, {Jack H.} and Ealick, {Steven E.} and Hoffman, {Brian M.} and Hening Lin",
note = "Funding Information: This work was supported by grants from the National Institutes of Health National Institute of General Medical Sciences (GM088276 to H.L., P41GM103521 to J.H.F., P41GM103403 to S.E.E, GM 111097 to B.M.H., and GM124908 to K.M.L.). This work is based on research conducted at the Northeastern Collaborative Access Team beamlines. The Pilatus 6M detector on 24- ID-C beamline is funded by a NIH- ORIP HEI grant (S10 RR029205). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE- AC02-06CH11357. Publisher Copyright: 2017 {\textcopyright} The Authors, some rights reserved.",
year = "2018",
month = mar,
day = "16",
doi = "10.1126/science.aao6595",
language = "English (US)",
volume = "359",
pages = "1247--1250",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6381",
}