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Reversible Formation of Alkyl Radicals at [Fe4S4] Clusters and Its Implications for Selectivity in Radical SAM Enzymes

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posted on 2020-08-06, 22:18 authored by Alexandra C. Brown, Daniel L. M. Suess
All kingdoms of life use the transient 5′-deoxyadenosyl radical (5′-dAdo•) to initiate a wide range of difficult chemical reactions. Because of its high reactivity, the 5′-dAdo• must be generated in a controlled manner to abstract a specific H atom and avoid unproductive reactions. In radical S-adenosylmethionine (SAM) enzymes, the 5′-dAdo• is formed upon reduction of SAM by an [Fe4S4] cluster. An organometallic precursor featuring an Fe–C bond between the [Fe4S4] cluster and the 5′-dAdo group was recently characterized and shown to be competent for substrate radical generation, presumably via Fe–C bond homolysis. Such reactivity is without precedent for Fe–S clusters. Here, we show that synthetic [Fe4S4]–alkyl clusters undergo Fe–C bond homolysis when the alkylated Fe site has a suitable coordination number, thereby providing support for the intermediacy of organometallic species in radical SAM enzymes. Addition of pyridine donors to [(IMes)3Fe4S4–R]+ clusters (R = alkyl or benzyl; IMes = 1,3-dimesitylimidazol-2-ylidene) generates R•, ultimately forming R–R coupled hydrocarbons. This process is facile at room temperature and allows for the generation of highly reactive radicals including primary carbon radicals. Mechanistic studies, including use of the 5-hexenyl radical clock, demonstrate that Fe–C bond homolysis occurs reversibly. Using these experimental insights and kinetic simulations, we evaluate the circumstances in which an organometallic intermediate can direct the 5′-dAdo• toward productive H-atom abstraction. Our findings demonstrate that reversible homolysis of even weak M–C bonds is a feasible protective mechanism for the 5′-dAdo• that can allow selective X–H bond activation in both radical SAM and adenosylcobalamin enzymes.

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