Radical S‑Adenosylmethionine Protein NosN Forms the Side Ring System of Nosiheptide by Functionalizing the Polythiazolyl Peptide S‑Conjugated Indolic Moiety

NosN is a radical S-adenosylmethionine protein observed in the biosynthesis of the bicyclic thiopeptide nosiheptide. Insights are provided in terms of the timing of NosN action, its catalytic mechanism, and its role in side ring formation. Beyond being a methyltransferase, NosN transforms a polythiazolyl peptide intermediate by functionalizing the S-conjugated indolic moiety to selectively build a C1 unit, form an ester linkage to the thiopeptide framework, and establish the side ring system specific for nosiheptide.