1vdv
From Proteopedia
(New page: 200px<br /><applet load="1vdv" size="450" color="white" frame="true" align="right" spinBox="true" caption="1vdv, resolution 1.98Å" /> '''Bovine Milk Xanthine...) |
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| - | [[Image:1vdv.gif|left|200px]]<br /><applet load="1vdv" size=" | + | [[Image:1vdv.gif|left|200px]]<br /><applet load="1vdv" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1vdv, resolution 1.98Å" /> | caption="1vdv, resolution 1.98Å" /> | ||
'''Bovine Milk Xanthine Dehydrogenase Y-700 Bound Form'''<br /> | '''Bovine Milk Xanthine Dehydrogenase Y-700 Bound Form'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Y-700 (1-[3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 1VDV is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with CA, FES, MTE, MOS, FAD, YSH, GOL and ACY as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Xanthine_dehydrogenase Xanthine dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.17.1.4 1.17.1.4] Full crystallographic information is available from [http:// | + | 1VDV is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with <scene name='pdbligand=CA:'>CA</scene>, <scene name='pdbligand=FES:'>FES</scene>, <scene name='pdbligand=MTE:'>MTE</scene>, <scene name='pdbligand=MOS:'>MOS</scene>, <scene name='pdbligand=FAD:'>FAD</scene>, <scene name='pdbligand=YSH:'>YSH</scene>, <scene name='pdbligand=GOL:'>GOL</scene> and <scene name='pdbligand=ACY:'>ACY</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Xanthine_dehydrogenase Xanthine dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.17.1.4 1.17.1.4] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1VDV OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Xanthine dehydrogenase]] | [[Category: Xanthine dehydrogenase]] | ||
| - | [[Category: Eger, B | + | [[Category: Eger, B T.]] |
[[Category: Fukunari, A.]] | [[Category: Fukunari, A.]] | ||
[[Category: Kamezawa, M.]] | [[Category: Kamezawa, M.]] | ||
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[[Category: Nishino, T.]] | [[Category: Nishino, T.]] | ||
[[Category: Okamoto, K.]] | [[Category: Okamoto, K.]] | ||
| - | [[Category: Pai, E | + | [[Category: Pai, E F.]] |
[[Category: Yamada, I.]] | [[Category: Yamada, I.]] | ||
[[Category: ACY]] | [[Category: ACY]] | ||
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[[Category: y-700]] | [[Category: y-700]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:34:13 2008'' |
Revision as of 13:34, 21 February 2008
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Bovine Milk Xanthine Dehydrogenase Y-700 Bound Form
Overview
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.
About this Structure
1VDV is a Single protein structure of sequence from Bos taurus with , , , , , , and as ligands. Active as Xanthine dehydrogenase, with EC number 1.17.1.4 Full crystallographic information is available from OCA.
Reference
Y-700 [1-[3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid]: a potent xanthine oxidoreductase inhibitor with hepatic excretion., Fukunari A, Okamoto K, Nishino T, Eger BT, Pai EF, Kamezawa M, Yamada I, Kato N, J Pharmacol Exp Ther. 2004 Nov;311(2):519-28. Epub 2004 Jun 9. PMID:15190124
Page seeded by OCA on Thu Feb 21 15:34:13 2008
Categories: Bos taurus | Single protein | Xanthine dehydrogenase | Eger, B T. | Fukunari, A. | Kamezawa, M. | Kato, N. | Nishino, T. | Okamoto, K. | Pai, E F. | Yamada, I. | ACY | CA | FAD | FES | GOL | MOS | MTE | YSH | Inhibitor | Xanthine oxidoreductase | Y-700
