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Aromatic side-chain crosslinking in RiPP biosynthesis
Sanath K Kandy1, Michael A Pasquale1, Jonathan R Chekan2
1Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, USA.
Nature Chemical Biology
|January 15, 2025
Summary
Nature uses diverse enzymes to crosslink aromatic amino acids in ribosomally synthesized and post-translationally modified peptides (RiPPs). This review highlights newly discovered cyclases, including P450s, rSAMs, burpitide cyclases, and DUF3328 proteins, responsible for these complex reactions.
Area of Science:
- Biochemistry
- Natural Product Biosynthesis
- Enzymology
Background:
- Peptide cyclization is crucial for bioactive molecules, especially in RiPPs.
- N- to C-terminal macrocyclization and lanthipeptide formation enzymes are well-studied.
- A diverse range of cyclases performing aromatic side-chain crosslinking in RiPPs are emerging.
Purpose of the Study:
- To review the emerging theme of aromatic amino acid side-chain crosslinking in RiPP biosynthesis.
- To focus on newly discovered enzymes catalyzing these challenging crosslinking reactions.
- To consolidate knowledge on diverse cyclization strategies in natural product chemistry.
Main Methods:
- Literature review of recent discoveries in RiPP biosynthesis.
- Focus on enzymatic mechanisms of aromatic crosslinking.
- Categorization of cyclases based on their catalytic activity and protein families.
Main Results:
- Multiple enzymatic routes exist for aromatic amino acid crosslinking in RiPPs.
- Cytochrome P450s and radical S-adenosylmethionine (rSAM) enzymes play a role in RiPP crosslinking.
- Novel enzyme classes like burpitide cyclases and DUF3328 (UstY) family proteins are involved.
Conclusions:
- Aromatic side-chain crosslinking is a significant and diverse modification in RiPPs.
- Understanding these cyclases expands knowledge of natural product diversity and enzyme function.
- Further characterization of these enzymes will reveal new biosynthetic pathways and catalytic mechanisms.
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