2021 Fiscal Year Final Research Report
Mechanistic Study on Gene Repair Enzyme
| Project/Area Number |
19K05705
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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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| Review Section |
Basic Section 37010:Bio-related chemistry
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| Research Institution | Tokushima Bunri University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | 酵素反応機構解析 / 構造化学 / NMR / X線結晶構造解析 / タンパク質核酸複合体 |
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| Outline of Final Research Achievements |
Human 8-OxoGuanine Glycosylase 1 (hOGG1) is a central enzyme within the gene-repair system that is related with the pathology of cancer and the homeostasis in living organisms. To understand the relationship between those biological activities and its enzymatic activity, we tried to reveal the catalytic mechanism of hOGG1. In hOGG1, Lys249 (K249) and Asp268 (D268) are considered to be catalytic residues at its active site. However, there are many uncertainties about the chemical role of these catalytic residues.
Based on this understanding, the following research was conducted. 1) An hOGG1 mutant was prepared, and its enzymatic pKa value was determined from the pH-dependent changes in enzyme activity. 2) Using the above mutant, its pKa values of the active residue was directly determined with NMR spectroscopy.
From these experiments, the enzymatic activity of the mutant and pKa values were explored. Then, the possible enzymatic pathway was considered.
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| Free Research Field |
生物物理化学
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| Academic Significance and Societal Importance of the Research Achievements |
遺伝子修復は生体の恒常性維持機構であり、その異常はがんの病理とも深くかかわる。中でも、損傷塩基として頻度の高い 8-oxoguanineを除去修復する酵素: ヒト 8-OxoGuanine Glycosylase 1 (hOGG1) は修復系で中核的役割を果たす酵素である。本研究では、hOGG1の触媒機構の解明に挑んだが、これは分子論的な立場から、がんに対する防御機構を理解すること、および、生体の恒常性維持機構を解明することにつながる 。また遺伝子修復系を標的としたがん治療薬の開発も進んでおり、がん治療薬の開発にも将来的に資する研究と考えられる。
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