ArticleProceedings of the National Academy of Sciences of the United States of America2016
Divergent non-heme iron enzymes in the nogalamycin biosynthetic pathway.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 54 citations in OpenAlex.
- Complete Pathway Refactoring and Combinatorial Biosynthesis of Anthracyclines for Modulation of Histone Eviction and DNA Damage Bioactivities.Angewandte Chemie (International ed. in English) · 2026Article
- Three distinct strategies lead to programmable aliphatic C-H oxidation in bicyclomycin biosynthesis.Nature communications · 2025Article
- Discovery of Noncanonical Iron and 2-Oxoglutarate Dependent Enzymes Involved in C-C and C-N Bond Formation in Biosynthetic Pathways.ACS bio & med chem Au · 2025Review
- Progress toward the Total Synthesis of Nogalamycin Using a Benzyne Cycloaddition Strategy.The Journal of organic chemistry · 2024Article
- A BioBricks Metabolic Engineering Platform for the Biosynthesis of Anthracyclinones inACS synthetic biology · 2022Article
- Molecular insights into the unusually promiscuous and catalytically versatile Fe(II)/α-ketoglutarate-dependent oxygenase SptF.Nature communications · 2022Article
- Activation and discovery of tsukubarubicin from Streptomyces tsukubaensis through overexpressing SARPs.Applied microbiology and biotechnology · 2021Article
- Pathway Engineering of Anthracyclines: Blazing Trails in Natural Product Glycodiversification.The Journal of organic chemistry · 2020Article
- Hydrogen Donation but not Abstraction by a Tyrosine (Y68) during Endoperoxide Installation by Verruculogen Synthase (FtmOx1).Journal of the American Chemical Society · 2019Article
- Evolutionary Trajectories for the Functional Diversification of Anthracycline Methyltransferases.ACS chemical biology · 2019Article
- Induction of HRR genes and inhibition of DNMT1 is associated with anthracycline anti-tumor antibiotic-tolerant breast carcinoma cells.Molecular and cellular biochemistry · 2019Article
- Selective C-H halogenation over hydroxylation by non-heme iron(iv)-oxo.Chemical science · 2018Article
- Enzymatic Synthesis of the C-Glycosidic Moiety of Nogalamycin R.ACS chemical biology · 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
- Coculture of Marine Invertebrate-Associated Bacteria and Interdisciplinary Technologies Enable Biosynthesis and Discovery of a New Antibiotic, Keyicin.ACS chemical biology · 2017Article
- Oxidative Cyclization in Natural Product Biosynthesis.Chemical reviews · 2017Review
- Dioxygen activation by nonheme iron enzymes with the 2-His-1-carboxylate facial triad that generate high-valent oxoiron oxidants.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2017Review
- How Are Substrate Binding and Catalysis Affected by Mutating GluFrontiers in chemistry · 2017Article
- New insights into bacterial type II polyketide biosynthesis.F1000Research · 2017Review
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Nogalamycin, an aromatic polyketide displaying high cytotoxicity, has a unique structure, with one of the carbohydrate units covalently attached to the aglycone via an additional carbon-carbon bond. The underlying chemistry, which implies a particularly challenging reaction requiring activation of an aliphatic carbon atom, has remained enigmatic. Here, we show that the unusual C5''-C2 carbocyclization is catalyzed by the non-heme iron α-ketoglutarate (α-KG)-dependent SnoK in the biosynthesis of the anthracycline nogalamycin. The data are consistent with a mechanistic proposal whereby the Fe(IV) = O center abstracts the H5'' atom from the amino sugar of the substrate, with subsequent attack of the aromatic C2 carbon on the radical center. We further show that, in the same metabolic pathway, the homologous SnoN (38% sequence identity) catalyzes an epimerization step at the adjacent C4'' carbon, most likely via a radical mechanism involving the Fe(IV) = O center. SnoK and SnoN have surprisingly similar active site architectures considering the markedly different chemistries catalyzed by the enzymes. Structural studies reveal that the differences are achieved by minor changes in the alignment of the substrates in front of the reactive ferryl-oxo species. Our findings significantly expand the repertoire of reactions reported for this important protein family and provide an illustrative example of enzyme evolution.
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