2021 Fiscal Year Final Research Report
Activation of dysfunctional metabolic enzymes in G6PD deficiency causing hemolytic anemia
Project/Area Number |
20K15741
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 43030:Functional biochemistry-related
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Research Institution | The University of Tokyo (2021) University of Tsukuba (2020) |
Principal Investigator |
Horikoshi Naoki 東京大学, 定量生命科学研究所, 准教授 (60732170)
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Project Period (FY) |
2020-04-01 – 2022-03-31
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Keywords | G6PD欠乏症 / 溶血性貧血 / 構造解析 |
Outline of Final Research Achievements |
Glucose-6-phosphate dehydrogenase (G6PD) plays a key role in the pentose phosphate pathway. In cells, G6PD is essential for regulating reactive oxygen species (ROS), which are involved in oxidative damage to DNA and proteins as well as many signaling pathways. More than 160 mutations on the G6PD gene have been reported worldwide. Some mutations, which are categorized as Class I and II, cause severe symptoms including hemolytic anemia, kernicterus, sepsis, and jaundice. Molecular mechanisms of activity loss caused by Class I and II mutations have remained elusive. In this study, we analyzed the structures and characteristics of G6PD Class I mutants and elucidated a mechanism of activity loss. We also found that additional mutations, which stabilize the tetramerization of G6PD, increase the enzymatic activity of Class I mutants. These findings would pave the way for future drug discovery for Class I mutants in G6PD deficiency.
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Free Research Field |
機能生物化学
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Academic Significance and Societal Importance of the Research Achievements |
これまでに、G6PD欠乏症における最も重篤なクラスIに対する活性化分子は同定されていない。本研究によって、世界で初めてクラスI変異による活性低下機構の解明及びクラスI変異体の活性化に成功した。今後、本研究によって得られた知見やG6PD変異体の構造情報を用いて、クラスIに対する新規の治療薬の開発につながることが期待される。また、本研究は酵素活性レベルは同程度にも関わらず症状が異なるクラスI及びクラスIIの変異に関する研究に対しても重要な知見を与えた。以上のことから、本研究は学術的及び社会的に非常に意義深いと考えられる。
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