title: Chemical nature and reaction mechanisms of the molybdenum cofactor of xanthine oxidoreductase.
abstract: Xanthine oxidoreductase (XOR), a complex flavoprotein, catalyzes the metabolic reactions leading from hypoxanthine to xanthine and from xanthine to urate, and both reactions take place at the molybdenum cofactor. The enzyme is a target of drugs for therapy of gout or hyperuricemia. We review the chemical nature and reaction mechanisms of the molybdenum cofactor of XOR, focusing on molybdenum-dependent reactions of actual or potential medical importance, including nitric oxide (NO) synthesis. It is now generally accepted that XOR transfers the water-exchangeable -OH ligand of the molybdenum atom to the substrate. The hydroxyl group at OH-Mo(IV) can be replaced by urate, oxipurinol and FYX-051 derivatives and the structures of these complexes have been determined by xray crystallography under anaerobic conditions. Although formation of NO from nitrite or formation of xanthine from urate by XOR ischemically feasible, it is not yet clear whether these reactions have any physiological significance since the reactions are catalyzed at a slow rate even under anaerobic conditions.
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School, 1-1-5 Sendagi, Bunkyouku, Tokyo 113-8602, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Okamoto
authors.forename: Teruo
authors.initials: T
authors.lastname: Kusano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishino
mesh_terms: D000818:Animals; D003067:Coenzymes / Q000737:chemistry* / Q000378:metabolism*; D055808:Drug Discovery; D004579:Electron Transport; D006801:Humans; D006860:Hydrogen Bonding; D006900:Hydroxylation; D008667:Metalloproteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D000090006:Molybdenum Cofactors; D009569:Nitric Oxide / Q000096:biosynthesis; D010084:Oxidation-Reduction; D011485:Protein Binding; D011621:Pteridines / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity; D014527:Uric Acid / Q000378:metabolism; D019820:Xanthine / Q000378:metabolism; D014968:Xanthine Dehydrogenase / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D003067:Coenzymes; D008667:Metalloproteins; D000090006:Molybdenum Cofactors; D009569:Nitric Oxide; D011621:Pteridines; D014527:Uric Acid; D019820:Xanthine; D014968:Xanthine Dehydrogenase; C022261:molybdopterin