2014 Fiscal Year Final Research Report
Catechol-O-methyl transferase Activator; Its molecular mechanism of action.
| Project/Area Number |
24590148
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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 |
Drug development chemistry
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| Research Institution | Nihon University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Mamoru 大阪大学, 蛋白質研究所, 准教授 (40280507)
TAKAMIYA Tomoko 日本大学, 薬学部, 助教 (50513917)
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Keywords | カテコールO-メチル転移酵素 / COMT / 生成物阻害 / S-アデノシルホモイステイン |
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| Outline of Final Research Achievements |
Catechol-O-methyl transferase (COMT) plays a critical role in vivo to control peripheral blood concentration of noradrenaline. COMT deficiency is considered to relate with several diseases that include chronic kidney disease, atherosclerosis and cardiac insufficiency. We had discovered compounds that enhance apparent COMT reaction velocity. Enzyme kinetic study revealed that the compounds increase the dissociation of S-adenosylhomocyctein (SAH) from SAH-COMT complex. SAH is a product of COMT reaction and is at the same time a strong inhibitor that competes with S-adenosylmethione. This mechanism was confirmed by isothermal titration calorimetric experiments. Next we studied the structure-activity relationship of the enhancer compounds. During this study we found some compounds that are structurally very similar to the enhancer compounds exhibit inhibition activity. Difference of molecular volume seemed to explain the converse.
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| Free Research Field |
医歯薬学
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