ArticleThe Journal of biological chemistry2011
The crystal structure and mechanism of an unusual oxidoreductase, GilR, involved in gilvocarcin V biosynthesis.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 26 citations in OpenAlex.
- Biosynthetic Strategies of Berberine Bridge Enzyme-like Flavoprotein Oxidases toward Structural Diversification in Natural Product Biosynthesis.Biochemistry · 2024Review
- Engineering BioBricks for Deoxysugar Biosynthesis and Generation of New Tetracenomycins.ACS omega · 2023Article
- Biosynthesis of DNA-Alkylating Antitumor Natural Products.Molecules (Basel, Switzerland) · 2022Review
- Characterization of Two VAO-Type Flavoprotein Oxidases from Myceliophthora thermophila.Molecules (Basel, Switzerland) · 2018Article
- Two tyrosine residues, Tyr-108 and Tyr-503, are responsible for the deprotonation of phenolic substrates in vanillyl-alcohol oxidase.The Journal of biological chemistry · 2017Article
- Flavoenzyme CrmK-mediated substrate recycling in caerulomycin biosynthesis.Chemical science · 2016Article
- Oxidation of Monolignols by Members of the Berberine Bridge Enzyme Family Suggests a Role in Plant Cell Wall Metabolism.The Journal of biological chemistry · 2015Article
- Roles of the synergistic reductive O-methyltransferase GilM and of O-methyltransferase GilMT in the gilvocarcin biosynthetic pathway.Journal of the American Chemical Society · 2012Article
- Complexity generation during natural product biosynthesis using redox enzymes.Current opinion in chemical biology · 2012Review
- Delineation of gilvocarcin, jadomycin, and landomycin pathways through combinatorial biosynthetic enzymology.Current opinion in chemical biology · 2012Review
- Enzymatic total synthesis of defucogilvocarcin M and its implications for gilvocarcin biosynthesis.Angewandte Chemie (International ed. in English) · 2012Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
GilR is a recently identified oxidoreductase that catalyzes the terminal step of gilvocarcin V biosynthesis and is a unique enzyme that establishes the lactone core of the polyketide-derived gilvocarcin chromophore. Gilvocarcin-type compounds form a small distinct family of anticancer agents that are involved in both photo-activated DNA-alkylation and histone H3 cross-linking. High resolution crystal structures of apoGilR and GilR in complex with its substrate pregilvocarcin V reveals that GilR belongs to the small group of a relatively new type of the vanillyl-alcohol oxidase flavoprotein family characterized by bicovalently tethered cofactors. GilR was found as a dimer, with the bicovalently attached FAD cofactor mediated through His-65 and Cys-125. Subsequent mutagenesis and functional assays indicate that Tyr-445 may be involved in reaction catalysis and in mediating the covalent attachment of FAD, whereas Tyr-448 serves as an essential residue initiating the catalysis by swinging away from the active site to accommodate binding of the 6R-configured substrate and consequently abstracting the proton of the hydroxyl residue of the substrate hemiacetal 6-OH group. These studies lay the groundwork for future enzyme engineering to broaden the substrate specificity of this bottleneck enzyme of the gilvocarcin biosynthetic pathway for the development of novel anti-cancer therapeutics.
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