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  • Review Article
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Aromatic side-chain crosslinking in RiPP biosynthesis

Nature Chemical Biology volume 21, pages 168–181 (2025)Cite this article

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Abstract

Peptide cyclization is a defining feature of many bioactive molecules, particularly in the ribosomally synthesized and post-translationally modified peptide (RiPP) family of natural products. Although enzymes responsible for N- to C-terminal macrocyclization, lanthipeptide formation or heterocycle installation have been well documented, a diverse array of cyclases have been discovered that perform crosslinking of aromatic side chains. These enzymes form either biaryl linkages between two aromatic amino acids or a crosslink between one aliphatic amino acid and one aromatic amino acid. Incredibly, nature has evolved multiple routes to install these crosslinks. While enzymes such as cytochromes P450 and radical S-adenosylmethionine (rSAM) enzymes are well known from other pathways, this role in RiPP biosynthesis has only recently been appreciated. Others, such as burpitide cyclases and DUF3328 (UstY) family proteins, come from eukaryotes and are relatively uncharacterized enzyme classes. This Review covers the emerging theme of aromatic amino acid side-chain crosslinking in RiPPs by focusing on the newly discovered enzymes responsible for catalyzing these challenging reactions.

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Fig. 1: Aromatic moiety crosslinks.
Fig. 2: rSAM enzyme-installed crosslinks.
Fig. 3: rSAM-catalyzed ether bond formation.
Fig. 4: P450-installed crosslinks.
Fig. 5: BpC-installed crosslinks.
Fig. 6: Example dikaritin RiPPs.
Fig. 7: Other crosslinking reactions.

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Change history

  • 23 January 2025

    In the version of this article initially published, the name of peer reviewer A. James Link was listed incompletely and is now amended in the HTML and PDF versions of the article.

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Acknowledgements

This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health (R35GM147439 to J.R.C.) and the National Center for Complementary and Integrative Health (T32AT008938 to M.A.P.).

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  1. These authors contributed equally: Sanath K. Kandy, Michael A. Pasquale.

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  1. Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, USA

    Sanath K. Kandy, Michael A. Pasquale & Jonathan R. Chekan

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  1. Sanath K. Kandy
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  2. Michael A. Pasquale
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S.K.K., M.A.P. and J.R.C. contributed to discussions and wrote the manuscript.

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Correspondence to Jonathan R. Chekan.

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Kandy, S.K., Pasquale, M.A. & Chekan, J.R. Aromatic side-chain crosslinking in RiPP biosynthesis. Nat Chem Biol 21, 168–181 (2025). https://doi.org/10.1038/s41589-024-01795-y

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