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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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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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 Research at the Start |
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、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。そこでがん病理の理解および生体の恒常性維持機構の理解に向けて、hOGG1の触媒機構の解明に挑む。hOGG1の活性残基としては、Lys249とAsp268が触媒残基と目されている。しかしこれらの触媒残基の化学的役割については未同定の部分が多い。そこで上記活性残基の触媒機構上の役割の解明を目指し、hOGG1タンパク質と基質DNA複合体についてNMRによる物性解析およびX線結晶構造解析を実施する。
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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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| 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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Report
(4 results)
Research Products
(17 results)
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[Journal Article] Effect of cytosine-Ag+-cytosine base pairing on the redox potential of the Ag+/Ag couple and the chemical reduction of Ag+ to Ag by tetrathiafulvalene2021
Author(s)
Takenori Dairaku, Rika Kawai, Teppei Kanaba, Tetsuya Ono, Kentaro Yoshida, Hajime Sato, Kanako Nozawa-Kumada, Yoshinori Kondo, Jiro Kondo, Akira Ono, Yoshiyuki Tanaka and Yoshitomo Kashiwagi
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Journal Title
Dalton Transactions
Volume: -
Issue: 22
Pages: 7633-7639
DOI
Related Report
Peer Reviewed
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