LanD-like flavoproteins catalyze oxidative decarboxylation of the C-terminal Cys residue of a peptide to produce a reactive enethiol, which could be introduced into the final S-[(Z)-2-aminovinyl]-cysteine (AviCys) analogs through two pathways, a Michael addition with dehydroamino acids or a radical-initiating coupling with an Asn residue. This concept represents the details in enzymatic formation of AviCys analogs.

Abstract

The carboxyl-terminal (C-terminal) S-[(Z)-2-aminovinyl]-cysteine (AviCys) analogs have been identified in four families of ribosomally synthesized and post-translationally modified peptides (RiPPs): lanthipeptides, linaridins, thioamitides, and lipolanthines. Within identified biosynthetic pathways, a highly reactive enethiol intermediate, formed through an oxidative decarboxylation catalyzed by a LanD-like flavoprotein, can undergo two types of cyclization: a Michael addition with a dehydroamino acid or a coupling reaction initiated by a radical species. The collaborative actions of LanD-like proteins with diverse enzymes involved in dehydration, dethiolation or cyclization lead to the construction of structurally distinct peptide natural products with analogous C-terminal macrocyclic moieties. This concept summarizes existing knowledge regarding biosynthetic pathways of AviCys analogs to emphasize the diversity of biosynthetic mechanisms that paves the way for future genome mining explorations into diverse peptide natural products.