Radical SAM-dependent enzymes: Jacks-of-all-trades in RiPP pathways

Covering: up to 2026The cofactor S-adenosyl-L-methionine (SAM) plays a key role in the biosynthesis of ribosomally synthesised and post-translationally modified peptide (RiPP) natural products. SAM-dependent enzymes have been shown to catalyse important steps in RiPP biosynthesis, including methylation, desaturation, epimerisation, splicing reactions, and oxidative decarboxylation. Furthermore, a range of SAM-dependent cross-linking reactions result in the formation of complex macrocyclic peptide products, which often exhibit enhanced stability and intriguing biological activities. These post-translational modifications occur in all parts of the peptide molecule, including side chains, peptide backbones, and N- and C-termini. Newly identified RiPP pathways continue to reveal interesting SAM-dependent enzymes that install remarkable chemical moieties. In view of the recent advances in this field, the objective of this review is to provide an overview of the significant chemical diversity of RiPP natural products generated by SAM-dependent enzymes, with a particular focus on post-translational modifications introduced by radical SAM enzymes.