Chapter 13: S-Adenosylmethionine

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.