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.
Published Version
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