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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| Project Status |
Completed (Fiscal Year 2013)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2013: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2012: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2011: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
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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 / ｷｻﾝﾁﾝ |
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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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Report
(4 results)
Research Products
(48 results)
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[Journal Article] The Tryptophan Residue at the Active Site Tunnel Entrance of Trichoderma reesei Cellobiohydrolase Ce17A Is Important for Initiation of Degradation of Crystalline Cellulose2013
Author(s)
Akihiko Nakamura, Tsukada, T., Auer, S., Furuta, T., Wada, M., Koivula, A., Igarashi, K. and Samejima M.
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Journal Title
Journal of Biological Chemistry
Volume: 288
Issue: 19
Pages: 13503-13510
DOI
Related Report
Peer Reviewed
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