Radical enzymatic peptide cyclization in natural product biosynthesis

Area of Science:

• Biochemistry and Natural Product Chemistry
• Enzymology and Synthetic Biology

Background:

• Cyclic peptides are crucial in drug discovery due to their stability and bioactivity.
• Radical-mediated enzymatic cyclization is a key strategy for creating complex peptide natural products.

Purpose of the Study:

• To review radical enzymes involved in peptide macrocyclization.
• To highlight their biosynthetic roles and potential applications.

Main Methods:

• Survey of radical enzyme families (rSAM, P450s, BURP-domain oxidases).
• Analysis of radical-driven cyclization in RiPPs and NRPS pathways.
• Examination of natural product examples and emerging themes.

Main Results:

• Identification of diverse radical enzymes catalyzing C-C, C-S, C-N, and C-O bond formation.
• Illustration of mechanistic diversity in peptide cyclization.
• Highlighting novel crosslinking, macrocycle sizes, and chirality.

Conclusions:

• Radical enzymology expands the structural diversity of peptide natural products.
• Advances in genome mining and enzymology reveal new radical transformations.
• Significant potential for synthetic biology, drug discovery, and peptide engineering.