S-Adenosylmethionine

Abstract

S-Adenosylmethionine (SAM), with the unique thermodynamically activated but kinetically stable trivalent sulfonium cation in its side chain, is the second most widely used coenzyme after ATP. SAM can engage in a multitude of two-electron paths, where transfer of the methyl group as a nascent cation equivalent to O, N, S, and even carbon nucleophiles dominates natural product tailoring flux. The aminobutyryl group of SAM is also activated at C4 as an electrophilic carbon. Equally important, if not more so, in natural product biosynthetic pathways are one-electron redox routes where SAM, coordinated to an [4Fe–4S] cube, undergoes fragmentation to leave methionine coordinated to the iron–sulfur cluster, while generating the 5′-deoxyadenosyl radical (5′-dA<o>˙) in situ. This homolytic fragmentation leads to 5′-dA˙ as initiator of a variety of radical-based scaffold transformations in cosubstrates. More than 500 000 so-called radical SAM enzymes have been catalogued in protein databases, although only a few dozen have yet been characterized for the scope of their radical chemistry practised on specific cosubstrates.