Widely Distributed Biosynthetic Cassette Is Responsible for Diverse Plant Side-Chain-Cross-Linked Cyclopeptides

Cyclopeptide alkaloids are an abundant class of plant cyclopeptides with over 200 analogs described and bioactivities ranging from analgesic to antiviral. While these natural products have been known for decades, their biosynthetic basis remains unclear. Using a transcriptome-mining approach, we link the cyclopeptide alkaloids from Ceanothus americanus to dedicated RiPP precursor peptides and identify new, widely distributed split BURP-domain containing gene clusters. Precursor peptides from these biosynthetic cassettes directly map to both cyclopeptide alkaloids from Ziziphus jujuba and the structurally distinct hibispeptins from Hibiscus syriacus . Guided by our bioinformatic analysis, we identify and isolate new cyclopeptides from Coffea arabica , which we named arabipeptins. These results expand our understanding of the biosynthetic pathways responsible for diverse plant side chain cross-linked cyclopeptides and suggest the presence of previously unknown natural products or protein post-translational modifications that are widely distributed in eudicots. ### Competing Interest Statement The authors have declared no competing interest.