1VDV

Bovine Milk Xanthine Dehydrogenase Y-700 Bound Form

Summary for 1VDV

• Entry DOI: 10.2210/pdb1vdv/pdb
• Descriptor: Xanthine dehydrogenase/oxidase, CALCIUM ION, FE2/S2 (INORGANIC) CLUSTER, ... (10 entities in total)
• Functional Keywords: xanthine oxidoreductase, y-700, inhibitor, oxidoreductase
• Biological source: Bos taurus (cattle)
• Cellular location: Cytoplasm (By similarity): P80457
• Total number of polymer chains: 2
• Total formula weight: 300186.43

Authors

Fukunari, A.,Okamoto, K.,Nishino, T.,Eger, B.T.,Pai, E.F.,Kamezawa, M.,Yamada, I.,Kato, N. (deposition date: 2004-03-25, release date: 2004-12-21, Last modification date: 2023-12-27)

Primary citation

Fukunari, A.,Okamoto, K.,Nishino, T.,Eger, B.T.,Pai, E.F.,Kamezawa, M.,Yamada, I.,Kato, N.
Y-700 [1-[3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid]: a potent xanthine oxidoreductase inhibitor with hepatic excretion
J.Pharmacol.Exp.Ther., 311:519-528, 2004

PubMed Abstract: Y-700 (1-[3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid) is a newly synthesized inhibitor of xanthine oxidoreductase (XOR). Steady-state kinetics with the bovine milk enzyme indicated a mixed type inhibition with K(i) and K(i) ' values of 0.6 and 3.2 nM, respectively. Titration experiments showed that Y-700 bound tightly both to the active sulfo-form and to the inactive desulfo-form of the enzyme with K(d) values of 0.9 and 2.8 nM, respectively. X-ray crystallographic analysis of the enzyme-inhibitor complex revealed that Y-700 closely interacts with the channel leading to the molybdenum-pterin active site but does not directly coordinate to the molybdenum ion. In oxonate-treated rats, orally administered Y-700 (1-10 mg/kg) dose dependently lowered plasma urate levels. At a dose of 10 mg/kg, the hypouricemic action of Y-700 was more potent and of longer duration than that of 4-hydroxypyrazolo(3,4-d)pyrimidine, whereas its action was approximately equivalent to that of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid, a nonpurine inhibitor of XOR. In normal rats, orally administered Y-700 (0.3-3 mg/kg) dose dependently reduced the urinary excretion of urate and allantoin, accompanied by an increase in the excretion of hypoxanthine and xanthine. Y-700 (1 mg/kg) was absorbed rapidly by the oral route with high bioavailability (84.1%). Y-700 was hardly excreted via the kidneys but was mainly cleared via the liver. These results suggest that Y-700 will be a promising candidate for the treatment of hyperuricemia and other diseases in which XOR may be involved.

PubMed: 15190124
DOI: 10.1124/jpet.104.070433

Experimental method

X-RAY DIFFRACTION (1.98 Å)