Radical-mediated cross-linking enzymes in RiPP biosynthesis

Area of Science:

• Biochemistry
• Natural Product Chemistry
• Enzymology

Background:

• Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a key source of bioactive compounds.
• Radical-mediated cross-linking is crucial for RiPP structural diversity and bioactivity.
• Recent discoveries have expanded the known repertoire of enzymes involved in RiPP biosynthesis.

Purpose of the Study:

• To summarize recent developments in radical-mediated cross-linking enzymes in RiPP biosynthesis.
• To focus on enzymes catalyzing cross-links involving 2-5 amino acids.
• To highlight the cross-linked structures and radical enzymatic mechanisms.

Main Methods:

• Literature review of recent advancements (January 2020 - February 2026).
• Focus on radical SAM, P450, DUF3328, BURP-domain, and α-ketoglutarate-dependent enzymes.
• Analysis of cross-linking types: monoaryl cyclophanes and biaryl cyclophanes.

Main Results:

• Identification of various enzymes catalyzing complex cross-links in RiPPs.
• Characterization of cross-links involving one aromatic and one aliphatic amino acid, or two aromatic side chains.
• Elucidation of radical enzymatic mechanisms driving these transformations.

Conclusions:

• Radical enzymes play a significant role in generating structural complexity in RiPPs.
• Continued research into these enzymes promises new bioactive natural products.
• Understanding radical mechanisms is key to harnessing RiPP biosynthetic pathways.