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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. SuessAll
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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alkylated Fe sitepyridine donorsH atomcarbon radicalschemical reactions5- hexenyladenosylcobalamin enzymesbondreactive radicalsorganometallic precursorMechanistic studiesRadical SAM Enzymescoordination numberdAdoorganometallic speciesReversible FormationAlkyl RadicalsH-atom abstractionlife useFe 4 S 4clusterSAM enzymesSuch reactivityroom temperaturehomolysi
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