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Structural basis of glucose-6-phosphate deficiency

Research Project

Project/Area Number 19K23713
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0701:Biology at molecular to cellular levels, and related fields
Research InstitutionUniversity 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
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords酵素異常症 / 構造解析 / G6PD / G6PD欠乏症 / NADPH / NADP / structural defects / enzymopathy / PPP / hemolysis / glucose metabolism / G6PD deficiency
Outline of Research at the Start

グルコース-6-リン酸脱水素酵素(G6PD)欠乏症は、赤血球の崩壊に伴う溶血性貧血などを引き起こす重篤な疾患であり、世界で4億人以上がG6PDの遺伝子変異を有すると推定されている。これまでに、G6PDタンパク質において150以上の患者由来の点変異が報告されているが、それら点変異による酵素活性低下のメカニズムは全く分かっていない。本研究では、G6PD欠乏症の患者由来の変異型G6PDの立体構造を原子レベルで明らかにすることによって、変異による活性低下のメカニズムを解明することを研究目的とする。本研究は、分子標的薬の設計が困難であった変異型G6PDを標的とした創薬研究に大いに貢献するものである。

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.

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。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (6 results)

All 2021 2019 Other

All Int'l Joint Research (4 results) Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (1 results)

  • [Int'l Joint Research] Stanford University/SLAC National Accelerator Laboratory(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Universidad de Concepcion(チリ)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Stanford University/SLAC National Accelerator Laboratory(米国)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] Universidad de Concepcion(チリ)

    • Related Report
      2019 Research-status Report
  • [Journal Article] Long-range structural defects by pathogenic mutations in most severe glucose-6-phosphate dehydrogenase deficiency2021

    • Author(s)
      Horikoshi Naoki、Hwang Sunhee、Gati Cornelius、Matsui Tsutomu、Castillo-Orellana Carlos、Raub Andrew G.、Garcia Adriana A.、Jabbarpour Fatemeh、Batyuk Alexander、Broweleit Joshua、Xiang Xinyu、Chiang Andrew、Broweleit Rachel、Vohringer-Martinez Esteban、Mochly-Rosen Daria、Wakatsuki Soichi
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 118 Issue: 4

    • DOI

      10.1073/pnas.2022790118

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Structural basis of the glucose-6-phosphate dehydrogenase deficiency2019

    • Author(s)
      Horikoshi, N., Jabbarpour, F., Hwang, S., Raub, A.G., Mochly-Rosen, D., Wakatsuki Soichi.
    • Organizer
      The 92nd Annual meeting of the Japanese Biochemical Society
    • Related Report
      2019 Research-status Report

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Published: 2019-09-03   Modified: 2022-01-27  

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