An intramolecular macrocyclase in plant ribosomal peptide biosynthesis.

The biosynthetic dogma of ribosomally synthesized and posttranslationally modified peptides (RiPP) involves enzymatic intermolecular modification of core peptide motifs in precursor peptides. The plant-specific BURP-domain protein family, named after their four founding members, includes autocatalytic peptide cyclases involved in the biosynthesis of side-chain-macrocyclic plant RiPPs. Here we show that AhyBURP, a representative of the founding Unknown Seed Protein-type BURP-domain subfamily, catalyzes intramolecular macrocyclizations of its core peptide during the sequential biosynthesis of monocyclic lyciumin I via glycine-tryptophan crosslinking and bicyclic legumenin via glutamine-tyrosine crosslinking. X-ray crystallography of AhyBURP reveals the BURP-domain fold with two type II copper centers derived from a conserved stapled-disulfide and His motif. We show the macrocyclization of lyciumin-C(sp3)-N-bond formation followed by legumenin-C(sp3)-O-bond formation requires dioxygen and radical involvement based on enzyme assays in anoxic conditions and isotopic labeling. Our study expands enzymatic intramolecular modifications beyond catalytic moiety and chromophore biogenesis to RiPP biosynthesis. © 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

Lisa S Mydy, Jordan Hungerford, Desnor N Chigumba, Jamie R Konwerski, Sarah C Jantzi, Di Wang, Janet L Smith, Roland D Kersten. An intramolecular macrocyclase in plant ribosomal peptide biosynthesis. Nature chemical biology. 2024 Apr;20(4):530-540

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PMID: 38355722

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