title: Flavin-mediated dual oxidation controls an enzymatic Favorskii-type rearrangement.
abstract: Flavoproteins catalyse a diversity of fundamental redox reactions and are one of the most studied enzyme families. As monooxygenases, they are universally thought to control oxygenation by means of a peroxyflavin species that transfers a single atom of molecular oxygen to an organic substrate. Here we report that the bacterial flavoenzyme EncM catalyses the peroxyflavin-independent oxygenation-dehydrogenation dual oxidation of a highly reactive poly(β-carbonyl). The crystal structure of EncM with bound substrate mimics and isotope labelling studies reveal previously unknown flavin redox biochemistry. We show that EncM maintains an unexpected stable flavin-oxygenating species, proposed to be a flavin-N5-oxide, to promote substrate oxidation and trigger a rare Favorskii-type rearrangement that is central to the biosynthesis of the antibiotic enterocin. This work provides new insight into the fine-tuning of the flavin cofactor in offsetting the innate reactivity of a polyketide substrate to direct its efficient electrocyclization.
authors.affiliation: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California, 92093, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Teufel
authors.affiliation: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California, 92093, USA.
authors.forename: Akimasa
authors.initials: A
authors.lastname: Miyanaga
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Michaudel
authors.affiliation: Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Stull
authors.affiliation: Howard Hughes Medical Institute, The Salk Institute for Biological Studies, Jack H. Skirball Center for Chemical Biology and Proteomics, La Jolla, California 92037, USA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Louie
authors.affiliation: Howard Hughes Medical Institute, The Salk Institute for Biological Studies, Jack H. Skirball Center for Chemical Biology and Proteomics, La Jolla, California 92037, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Noel
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Phil S
authors.initials: PS
authors.lastname: Baran
authors.affiliation: Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Palfey
authors.affiliation: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California, 92093, USA.|Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Moore
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D055162:Biocatalysis; D001952:Bridged-Ring Compounds / Q000378:metabolism; D018360:Crystallography, X-Ray; D003500:Cyclization; D005415:Flavins / Q000378:metabolism*; D005420:Flavoproteins / Q000737:chemistry / Q000378:metabolism*; D007553:Isotope Labeling; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000378:metabolism*; D008956:Models, Chemical; D008958:Models, Molecular; D010084:Oxidation-Reduction; D061065:Polyketides / Q000378:metabolism; D011487:Protein Conformation; D013302:Streptomyces / Q000201:enzymology* / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001952:Bridged-Ring Compounds; D005415:Flavins; D005420:Flavoproteins; D061065:Polyketides; C012306:enterocin; D006899:Mixed Function Oxygenases