Scientists decode how plants make powerful medicinal compounds
Researchers have cracked the genetic recipe for how plants synthesize cyclopeptide alkaloids—complex molecules with painkilling and anxiety-reducing properties. The discovery opens a path to engineer these hard-to-synthesize drugs in labs and crops, potentially lowering costs for pharmaceutical companies and expanding access to therapies derived from plant compounds.
Originaltitel: Biosynthesis 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 N-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 (Ziziphus jujuba), 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-terminal hydroxystyrylamine, and SAM-dependent N-terminal α-N,N-dimethylation. We apply the discovered Z. jujuba enzymes in combination with a clubmoss cyclopeptide alkaloid cyclase for the biosynthesis and diversification of the analgesic adouetine X and the anxiolytic sanjoinine A by combining in planta and in vitro reactions. Our work expands the biocatalytic repertoire of nonheme iron- and 2-oxoglutarate-dependent enzymology to oxidative peptide decarboxylation and primes scaled metabolic engineering and chemoenzymatic synthesis of 14-membered cyclopeptide alkaloids with terminal posttranslational modifications.