Radical enzymatic peptide cyclization in natural product biosynthesis

Cyclic peptides are privileged scaffolds in natural product biosynthesis and drug discovery, valued for their structural diversity, metabolic stability, and potent biological activities. Radical-mediated enzymatic cyclization has emerged as a powerful biosynthetic strategy for constructing structurally complex and bioactive peptide natural products. This review surveys the growing repertoire of radical enzymes, including radical S-adenosylmethionine (rSAM) enzymes, cytochrome P450s, BURP-domain oxidases, and additional enzyme families that catalyze site-selective C-C, C-S, C-N, and C-O bond formation during peptide macrocyclization. Emphasis is placed on radical-driven cyclization reactions involved in natural product biosynthesis, covering both RiPPs and NRPS pathways. Examples of cyclic peptide natural products include vancomycin, arylomicin, telocidin, streptide, and nosiheptide illustrate the mechanistic and structural diversity of radical peptide cyclases. Key emerging themes include a diverse array of side-chain crosslinking, 3-4 residue macrocycles, and unique forms of chirality. This review also discusses advances in genome mining and mechanistic enzymology that continue to reveal new radical transformations and unusual enzyme mechanisms. Collectively, these insights highlight the role of radical enzymology in expanding the structural space of peptide-based natural products and its potential for applications in synthetic biology, drug discovery, and peptide engineering.