2013 Fiscal Year Final Research Report
The study on the structure-based inhibitor mechanism for xanthine oxidoreductase: beyond a lock-key system
| Project/Area Number |
23570198
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Biophysics
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| Research Institution | Nippon Medical School |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
OKAMOTO Ken 日本医科大学, 医学部, 准教授 (60267143)
FUJISAKI Hiroshi 日本医科大学, 医学部, 准教授 (60573243)
FURUTA Tadaomi 東京工業大学, 准教授, 助教 (10431834)
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| Project Period (FY) |
2011 – 2013
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| Keywords | 酸化還元酵素 / 構造・機能予測 / 分子動力学 / キサンチン / 痛風治療薬 / 阻害剤 / フェブキソスタット / 創薬 |
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| Research Abstract |
Xanthine oxidoreductase (XOR) catalyzes the oxidation of hypoxanthine to xanthine followed by oxidation of xanthine to uric acid. Because having too much uric acid in the body causes a disease, gout, human XOR is a target of drugs to treat gout. XOR is found in a wide range of organisms from bacteria to man, and the substrate-binding pockets of mammalian and bacterial XOR are well-conserved as regards catalytically important residues and three-dimensional structure. In this research, we found in terms of the enzymatic experiments that febuxostat, a drug recently developed in Japan inhibits mammalian XOR, but not bacterial XOR. This means that a so-called key-lock system breaks and it is difficult to elucidate this functional differences from the view point of static three-dimensional structure of an inhibitor and an enzyme. However,we succeeded in reproducing the experimental results using MD calculations from the view point of dynamics (Sci. Rep. 2, 331; DOI:10.1038/srep00331 (2012)).
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