Structural highlights
FunctionPublication Abstract from PubMedYcaO enzymes catalyze ATP-dependent post-translation modifications on peptides, including the installation of (ox/thi)azoline, thioamide and/or amidine moieties. Here we demonstrate that, in the biosynthesis of the bis-methyloxazolic alkaloid muscoride A, the YcaO enzyme MusD carries out both ATP-dependent cyclodehydration and peptide bond cleavage, which is a mechanism unprecedented for such a reaction. YcaO-catalyzed modifications are proposed to occur through a backbone O-phosphorylated intermediate, but this mechanism remains speculative. We report, to our knowedge, the first characterization of an acyl-phosphate species consistent with the proposed mechanism for backbone amide activation. The 3.1-A-resolution cryogenic electron microscopy structure of MusD along with biochemical analysis allow identification of residues that enable peptide cleavage reaction. Bioinformatics analysis identifies other cyanobactin pathways that may deploy bifunctional YcaO enzymes. Our structural, mutational and mechanistic studies expand the scope of modifications catalyzed by YcaO proteins to include peptide hydrolysis and provide evidence for a unifying mechanism for the catalytically diverse outcomes. YcaO-mediated ATP-dependent peptidase activity in ribosomal peptide biosynthesis.,Zheng Y, Nair SK Nat Chem Biol. 2022 Oct 24. pii: 10.1038/s41589-022-01141-0. doi:, 10.1038/s41589-022-01141-0. PMID:36280794[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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