The functionalization of unactivated C�H bonds is one of the more demanding reactions with which enzymes are tasked. The pKas of protons attached to unactivated carbon centers can approach values of 40 and beyond, rendering these C�H bonds inert to functionalization by polar processes. Indeed, functionalization of these inert bonds, almost by definition, involves radical intermediates, and is initiated by strategic abstraction of substrate hydrogen atoms (H�). Nature has evolved a number of metal-containing cofactors that act in concert with dioxygen to catalyze the hydroxylation of unactivated alkanes or epoxidation of alkenes. Under anaerobic conditions, the functional equivalent appears to be sulfhydrylation, initiated by abstraction of unactivated H� by a 5'-deoxyadenosyl 5'-radical formed via a reductive cleavage of the common metabolite S-adenosylmethionine. This lecture will detail mechanistic studies of three sulfhydrylation reactions involved in post-translational and post-transcriptional modifications. The first, lipoyl synthase, catalyzes the final step in the biosynthesis of the lipoyl cofactor, which is the sulfhydrylation of carbons 6 and 8 of n-octanoyl fatty amide chains attached to lysyl residues of lipoyl carrier proteins. The second and third reactions, catalyzed by RimO and MiaB, respectively, involve methylthiolation (insertion of �SCH3 groups) of a target aspartyl residue in protein S12 of the 30S subunit of the bacterial ribosome and methylthiolation of C2 of adenosine 37 in several tRNAs. Each of these proteins contains two [4Fe�4S] clusters, one of which is sacrificed during turnover as the activated source of the inserted sulfur atom.

Anaerobic functionalization of unactivated carbon centers

245th National Meeting (2013)

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