Radical-mediated cross-linking enzymes in RiPP biosynthesis

Covering: January 2020 to February 2026Ribosomally synthesized and post-translationally modified peptides (RiPPs) continue to be a rich source of chemically diverse and bioactive peptide natural products. In recent years, rapid progress has been made in the discovery of radical-mediated cross-linking enzymes involved in RiPP biosynthesis. These enzymes, such as radical SAM, P450, DUF3328, BURP-domain, and α-ketoglutarate-dependent enzymes have been found to catalyze various cross-linkings between one aromatic side chain and one aliphatic amino acid (monoaryl cyclophane) or between two aromatic side chains (biaryl cyclophane) on the precursor peptides. This highlight aims to summarize the latest development of these enzymes that catalyze the formation of cross-links involving two to five amino acids from bacteria, fungi and plants, with a particular focus on the cross-linked structure and radical enzymatic mechanism.