{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Morgan GL"],"funding":["Eunice Kennedy Shriver National Institute of Child Health and Human Development","NICHD NIH HHS","NCI NIH HHS","University of North Carolina at Chapel Hill","Rita Allen Foundation","David and Lucile Packard Foundation","NIGMS NIH HHS"],"pagination":["2776-2786"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8917869"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["16(12)"],"pubmed_abstract":["Nonribosomal peptide synthetases (NRPSs) are typically multimodular enzymes that assemble amino acids or carboxylic acids into complex natural products. Here, we characterize a monomodular NRPS, PvfC, encoded by the <i>Pseudomonas virulence factor</i> (<i>pvf</i>) gene cluster that is essential for virulence and signaling in different bacterial species. PvfC exhibits a unique adenylation-thiolation-reductase (ATR) domain architecture that is understudied in bacteria. We show that the activity of PvfC is essential in the production of seven leucine-derived heterocyclic natural products, including two pyrazines, a pyrazinone, and a rare disubstituted imidazole, as well as three pyrazine <i>N</i>-oxides that require an additional <i>N-</i>oxygenation step. Mechanistic studies reveal that PvfC, without a canonical peptide-forming domain, makes a dipeptide aldehyde intermediate en route to both the pyrazinone and imidazole. Our work identifies a novel biosynthetic route for the production of pyrazinones, an emerging class of signaling molecules and virulence factors. Our discovery also showcases the ability of monomodular NRPSs to generate amino acid- and dipeptide-aldehydes that lead to diverse natural products. The diversity-prone biosynthesis by the <i>pvf</i>-encoded enzymes sets the stage for further understanding the functions of <i>pvf</i> in bacterial cell-to-cell signaling."],"journal":["ACS chemical biology"],"pubmed_title":["Enzymatic Synthesis of Diverse Heterocycles by a Noncanonical Nonribosomal Peptide Synthetase."],"pmcid":["PMC8917869"],"funding_grant_id":["T32 GM008570","P30 CA016086","DP2 HD094657","DP2HD094657"],"pubmed_authors":["Aube J","Crawford DM","Morgan GL","Li B","Li K"],"additional_accession":[]},"is_claimable":false,"name":"Enzymatic Synthesis of Diverse Heterocycles by a Noncanonical Nonribosomal Peptide Synthetase.","description":"Nonribosomal peptide synthetases (NRPSs) are typically multimodular enzymes that assemble amino acids or carboxylic acids into complex natural products. Here, we characterize a monomodular NRPS, PvfC, encoded by the <i>Pseudomonas virulence factor</i> (<i>pvf</i>) gene cluster that is essential for virulence and signaling in different bacterial species. PvfC exhibits a unique adenylation-thiolation-reductase (ATR) domain architecture that is understudied in bacteria. We show that the activity of PvfC is essential in the production of seven leucine-derived heterocyclic natural products, including two pyrazines, a pyrazinone, and a rare disubstituted imidazole, as well as three pyrazine <i>N</i>-oxides that require an additional <i>N-</i>oxygenation step. Mechanistic studies reveal that PvfC, without a canonical peptide-forming domain, makes a dipeptide aldehyde intermediate en route to both the pyrazinone and imidazole. Our work identifies a novel biosynthetic route for the production of pyrazinones, an emerging class of signaling molecules and virulence factors. Our discovery also showcases the ability of monomodular NRPSs to generate amino acid- and dipeptide-aldehydes that lead to diverse natural products. The diversity-prone biosynthesis by the <i>pvf</i>-encoded enzymes sets the stage for further understanding the functions of <i>pvf</i> in bacterial cell-to-cell signaling.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Dec","modification":"2025-04-26T18:45:22.837Z","creation":"2025-04-06T15:52:03.71Z"},"accession":"S-EPMC8917869","cross_references":{"pubmed":["34767712"],"doi":["10.1021/acschembio.1c00623"]}}