ArticleProceedings of the National Academy of Sciences of the United States of America2015
Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 53 citations in OpenAlex.
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- An NADH/NADApplied and environmental microbiology · 2024Article
- Characterization of Dichloroisoeverninic Acid Biosynthesis and Chemoenzymatic Synthesis of New Orthosomycins.ACS chemical biology · 2024Article
- Oxidative modification of free-standing amino acids by Fe(II)/αKG-dependent oxygenases.Engineering microbiology · 2023Review
- Orthoester formation in fungal meroterpenoid austalide F biosynthesis.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Article
- Molecular insights into the unusually promiscuous and catalytically versatile Fe(II)/α-ketoglutarate-dependent oxygenase SptF.Nature communications · 2022Article
- HygY Is a Twitch Radical SAM Epimerase with Latent Dehydrogenase Activity Revealed upon Mutation of a Single Cysteine Residue.Journal of the American Chemical Society · 2021Article
- Molecular insights into the endoperoxide formation by Fe(II)/α-KG-dependent oxygenase NvfI.Nature communications · 2021Article
- Microbial Oligosaccharides with Biomedical Applications.Marine drugs · 2021Review
- Activation modes in biocatalytic radical cyclization reactions.Journal of industrial microbiology & biotechnology · 2021Review
- Bifunctional Nitrone-Conjugated Secondary Metabolite Targeting the Ribosome.Journal of the American Chemical Society · 2020Article
- Hydrogen Donation but not Abstraction by a Tyrosine (Y68) during Endoperoxide Installation by Verruculogen Synthase (FtmOx1).Journal of the American Chemical Society · 2019Article
- The Structure of the Bifunctional Everninomicin Biosynthetic Enzyme EvdMO1 Suggests Independent Activity of the Fused Methyltransferase-Oxidase Domains.Biochemistry · 2018Article
- Novofumigatonin biosynthesis involves a non-heme iron-dependent endoperoxide isomerase for orthoester formation.Nature communications · 2018Article
- Amazing Diversity in Biochemical Roles of Fe(II)/2-Oxoglutarate Oxygenases.Trends in biochemical sciences · 2018Review
- Vanadyl as a Stable Structural Mimic of Reactive Ferryl Intermediates in Mononuclear Nonheme-Iron Enzymes.Inorganic chemistry · 2017Article
- Oxidative Cyclization in Natural Product Biosynthesis.Chemical reviews · 2017Review
- Divergent non-heme iron enzymes in the nogalamycin biosynthetic pathway.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
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Abstract
Orthosomycins are oligosaccharide antibiotics that include avilamycin, everninomicin, and hygromycin B and are hallmarked by a rigidifying interglycosidic spirocyclic ortho-δ-lactone (orthoester) linkage between at least one pair of carbohydrates. A subset of orthosomycins additionally contain a carbohydrate capped by a methylenedioxy bridge. The orthoester linkage is necessary for antibiotic activity but rarely observed in natural products. Orthoester linkage and methylenedioxy bridge biosynthesis require similar oxidative cyclizations adjacent to a sugar ring. We have identified a conserved group of nonheme iron, α-ketoglutarate-dependent oxygenases likely responsible for this chemistry. High-resolution crystal structures of the EvdO1 and EvdO2 oxygenases of everninomicin biosynthesis, the AviO1 oxygenase of avilamycin biosynthesis, and HygX of hygromycin B biosynthesis show how these enzymes accommodate large substrates, a challenge that requires a variation in metal coordination in HygX. Excitingly, the ternary complex of HygX with cosubstrate α-ketoglutarate and putative product hygromycin B identified an orientation of one glycosidic linkage of hygromycin B consistent with metal-catalyzed hydrogen atom abstraction from substrate. These structural results are complemented by gene disruption of the oxygenases evdO1 and evdMO1 from the everninomicin biosynthetic cluster, which demonstrate that functional oxygenase activity is critical for antibiotic production. Our data therefore support a role for these enzymes in the production of key features of the orthosomycin antibiotics.
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