S-adenosylmethionine (SAM) seems like an innocuous combination of an amino acid and a nucleoside, yet it supports a wide variety of biochemical transformations whose scope remains underappreciated. Zhang et al. explore its intriguing role in the biosynthesis pathway of the antibiotic nosiheptide—a macrocyclic thiopeptide with an embedded indole. The first step is reductive cleavage of SAM to yield the 5′-deoxyadenosyl radical (5′-dA*) along with methionine. Surprisingly, 5′-dA* goes on in this case to abstract a hydrogen atom, not from the usual suspect (a carbon atom of the substrate), but from the indole nitrogen of tryptophan. This leads to a rather complicated sequence of events, with the final outcome being the release of the nitrogen atom and α-carbon (from the backbone portion of tryptophan) as ammonia and formaldehyde and the attachment of the carboxylate to the indole ring at C2; the indolic acid is then used to make nosiheptide. Having established this mechanism, the authors go on to introduce a fluorinated tryptophan derivative into the medium and show that the fluorinated indole functionality is incorporated (albeit somewhat less efficiently) into the corresponding final product, thereby broadening the structural diversity of this antibiotic class.
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