Structural basis of glucose-6-phosphate deficiency

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K23713
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0701:Biology at molecular to cellular levels, and related fields
• Research Institution: University of Tsukuba
• Principal Investigator: Horikoshi Naoki 筑波大学, 生存ダイナミクス研究センター, 助教 (60732170)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Keywords: 酵素異常症 / 構造解析 / G6PD

Outline of Final Research Achievements

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common enzymopathy in the world. More than 160 missense mutations in the G6PD gene have been reported, and those mutations cause loss of enzymatic activity and severe symptoms such as hemolytic anemia. Many ClassI mutations in G6PD deficiency are localized in the dimer interface distant from the active site, and mechanisms of loss of activity have been unclear. In this study, we have successfully solved the structures of the most severe Class I mutants and elucidated mechanisms of loss of activity. This study paves the way for the development of a novel drug for G6PD deficiency.

Free Research Field

機能生物化学

Academic Significance and Societal Importance of the Research Achievements

G6PD欠乏症は溶血性貧血、黄疸、ビリルビン脳症、敗血症などを引き起こす疾患である。世界でおよそ４億人がG6PD遺伝子に変異を有しており、変異によってはG6PDの活性に甚大な影響を及ぼす。多くの場合、通常では無症状であるものの、ウイルス感染、薬の投与、特定の食物によって細胞に過剰な酸化ストレスが生じた際に溶血性貧血などの症状を呈する。現在までに、G6PD欠乏症に対する有効な治療薬は存在せず、創薬研究が急務である。本研究課題では、最も重篤なクラスI変異体の立体構造及び活性低下のメカニズムの解明に成功した。今後、本研究で得られた知見に基づいてG6PD欠乏症に対する治療薬の開発が期待される。