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J Am Chem Soc. 2016 Aug 10;138(31):9755-8. doi: 10.1021/jacs.6b04155. Epub 2016 Aug 2.

Organometallic Complex Formed by an Unconventional Radical S-Adenosylmethionine Enzyme.

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Department of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853, United States.
Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States.
Department of Biochemistry, Brandeis University , Waltham, Massachusetts 02453, United States.
Department of Chemistry and Department of Biochemistry and Molecular Biology, The Pennsylvania State University , University Park, Pennsylvania 16802, United States.
Howard Hughes Medical Institute, Cornell University , Ithaca, New York 14853, United States.


Pyrococcus horikoshii Dph2 (PhDph2) is an unusual radical S-adenosylmethionine (SAM) enzyme involved in the first step of diphthamide biosynthesis. It catalyzes the reaction by cleaving SAM to generate a 3-amino-3-carboxypropyl (ACP) radical. To probe the reaction mechanism, we synthesized a SAM analogue (SAMCA), in which the ACP group of SAM is replaced with a 3-carboxyallyl group. SAMCA is cleaved by PhDph2, yielding a paramagnetic (S = 1/2) species, which is assigned to a complex formed between the reaction product, α-sulfinyl-3-butenoic acid, and the [4Fe-4S] cluster. Electron-nuclear double resonance (ENDOR) measurements with (13)C and (2)H isotopically labeled SAMCA support a π-complex between the C═C double bond of α-sulfinyl-3-butenoic acid and the unique iron of the [4Fe-4S] cluster. This is the first example of a radical SAM-related [4Fe-4S](+) cluster forming an organometallic complex with an alkene, shedding additional light on the mechanism of PhDph2 and expanding our current notions for the reactivity of [4Fe-4S] clusters in radical SAM enzymes.

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