biostudies-literatureUnknownHungerford JHorace H. Rackham School of Graduate Studies, University of MichiganHermann Frasch FoundationPharmaceutical Research and Manufacturers of America FoundationNew Mexico Department of AgricultureNational Institute of General Medical SciencesNIGMS NIH HHSCyclopeptide alkaloids are an expanding class of plant peptide natural products defined by a macrocyclic ether cross-link via a tyrosine-derived phenol. Classical cyclopeptide alkaloids are characterized by strained 13- to 15-membered cyclophanes and terminal modifications such as <i>N</i>-methylation and C-terminal styrylamine moieties. While synthetic access to many classical cyclopeptide alkaloids has been established, no biosynthetic route has been reported. Here, we elucidate the biosynthetic pathway of a 14-membered cyclopeptide alkaloid, lotusine A, from the Chinese date tree (<i>Ziziphus jujuba</i>), which features peptide cyclization on a ribosomal precursor peptide by a split burpitide cyclase, nonheme-iron and 2-oxoglutarate-dependent oxidative decarboxylation affording the C-teJournal of the American Chemical Societyhttps://www.ebi.ac.uk/biostudies/studies/S-EPMC12927610biostudies-literatureBiosynthesis of 14-Membered Cyclopeptide Alkaloids via Nonheme Iron- and 2-Oxoglutarate-Dependent Oxidative Decarboxylation.PMC12927610T32GM140223F32 GM146395R35GM146934R35 GM146934F32GM146395T32 GM140223F31 GM155959F31GM155959Li WShafiq KMydy LSMendoza-Perez LMay GChigumba DNHungerford JYao SKersten RDWang XMcDonough KMOusley DAfalseBiosynthesis of 14-Membered Cyclopeptide Alkaloids via Nonheme Iron- and 2-Oxoglutarate-Dependent Oxidative Decarboxylation.Cyclopeptide alkaloids are an expanding class of plant peptide natural products defined by a macrocyclic ether cross-link via a tyrosine-derived phenol. Classical cyclopeptide alkaloids are characterized by strained 13- to 15-membered cyclophanes and terminal modifications such as <i>N</i>-methylation and C-terminal styrylamine moieties. While synthetic access to many classical cyclopeptide alkaloids has been established, no biosynthetic route has been reported. Here, we elucidate the biosynthetic pathway of a 14-membered cyclopeptide alkaloid, lotusine A, from the Chinese date tree (<i>Ziziphus jujuba</i>), which features peptide cyclization on a ribosomal precursor peptide by a split burpitide cyclase, nonheme-iron and 2-oxoglutarate-dependent oxidative decarboxylation affording the C-te2026-01-01T00:00:00Z2026 Feb2026-07-16T17:48:26.936Z2026-07-09T11:10:07.068ZS-EPMC129276104169805010.1021/jacs.5c23400