Radical-mediated cross-linking enzymes in RiPP biosynthesis

Area of Science:

• Biochemistry
• Molecular Biology
• Natural Product Chemistry

Background:

• Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a key source of diverse bioactive natural products.
• Recent advances have identified radical-mediated cross-linking enzymes crucial for RiPP biosynthesis.
• These enzymes facilitate complex modifications, including monoaryl and biaryl cyclophanes.

Purpose of the Study:

• To summarize recent developments in radical enzymes involved in RiPP biosynthesis.
• To highlight enzymes catalyzing cross-links involving two to five amino acids.
• To focus on the structural outcomes and radical mechanisms of these cross-linking enzymes.

Main Methods:

• Literature review of recent publications (January 2020 - February 2026).
• Analysis of enzyme classes including radical SAM, P450, DUF3328, BURP-domain, and α-ketoglutarate-dependent enzymes.
• Focus on studies detailing cross-linked structures and enzymatic mechanisms.

Main Results:

• Identification of various radical enzymes catalyzing peptide cross-linking.
• Characterization of monoaryl and biaryl cyclophane formation.
• Examples of cross-linking enzymes from bacteria, fungi, and plants are discussed.

Conclusions:

• Radical enzymes play a significant role in generating chemical diversity in RiPPs.
• Understanding these enzymes advances knowledge of natural product biosynthesis.
• Further research into radical enzymatic mechanisms promises new bioactive compounds.