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Studies on the NADPH oxidase system responsible for anti-infectious activity of phagocytes

Research Project

Project/Area Number 10670151
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionNational Children's Medical Research Center

Principal Investigator

TSUNAWAKI Shohko  National Children's Medical Research Center, Dept. of Infectious Disease Senior Research Associate, 小児医療研究センター・感染症, 研究員 (00211384)

Co-Investigator(Kenkyū-buntansha) FUJII Hirotada  Sapporo Medical University, Dept. of Chemistry, Professor, 保健医療学部, 教授 (70209013)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1999: ¥1,000,000 (Direct Cost: ¥1,000,000)
Keywordsneutrophils / NADPH oxidase / cytochrome b558 / gliotoxin / FAD / chronic granulomatous disease / Aspergillus / superoxide anion / gp91 / フラビン
Research Abstract

We are studying the mechanisms of the NADPH oxidase system responsible for anti-infectious activity of phagocytes. Patients with chronic granulomatous disease (CGD), a genetic disorder in this system, fail to generate superoxide anion and suffer from recurrent infections.
1.Gp91, the redox center of the NADPH oxidase, had been considered to contain both heme and FAD in its molecule. However, this flavocytochrome concept was only based on the similarities between the amino acid sequences of gp91 and other flavoproteins, without any direct evidence. The main reason for this was that most of the mutations in gp91 lead complete absence of its protein. We discovered a rare CGD patient who expressed a gp91 apoprotein. Analysis of cDNA revealed the mutation of His-338 to Try, which resided in a predicted domain for FAD-binding. The biochemical analysis of the patient revealed that the lost FAD completely, and the addition of reagent FAD in vitro could not corrected his superoxide-generating activity. These resulted indicate that His-338 is a very critical for FAD incorporation into the NADPH oxidase. This was the first such mutation found in CGD.
2. There have not been studies, which inquired the NADPH oxidase in relation to microorganism-derived toxins. Here, we investigated the effect of gliotoxin from Aspergillus on the NADPH oxidase. This toxin, bearing S-S bond in its structure, prevented the onset of superoxide generation by the neutrophil NADPH oxidase in response to PMA. Gliotoxin affected the activation process, but not the catalysis of the activated enzyme. The inhibitory mode was suggested to be direct interaction of S-S bond in gliotoxin with vicinal SH group in the NADPH oxidase.

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Yoshida, L. S. et al.: "Mutation at histidine 338 of gp91^<phox>depletes FAD and affects expression of cytochrome b558 of the human NADPH oxidase"J. Bio. Chem.. 273. 27879-27886 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Teshima, S. et al.: "Helicobacter pylori lipoplysaccharide enhances the expression of NADPH oxidase components in cultured guinea pig gastric mucosal cells"FEBS Lett.. 452. 243-246 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] FAD結合: "Fungous gliotoxin targets the onset of superoxide-generating NADPH oxidase of human neutrophils"BBRC. 268. 716-723 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 綱脇祥子: "食細胞NADPHオキシダーゼ : 新奇サイトゾル因子"p40""臨床免疫. 30. 267-272 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 吉田ルシア幸子,綱脇祥子: "FAD欠損を導く好中球NADPHoxidase系,gp91^<phox>,の変異"磁気共鳴と医学. (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yoshida L. S.: "Mutation at histidine 338 of gp91ィイD1phoxィエD1 depletes FAD and affects expression of cytochrome bィイD2558ィエD2 of the human NADPH oxidas"J. Biol. Chem.. 273. 27879-27886 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Teshima S.: "Helicobacter pylori lipoplysaccharide enhances the expression of NADPH oxidase components in cultured guinea pig gastric mucosal cells."FEBS Lett.. 452. 243-246 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yoshida L. S.: "Fungous gliotoxin targets the onset of superoxide-generating NADPH oxidase of human neutrophils."Biochemical Biophysical Research Commun.. 268. 716-723 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Teshima, S. et al.: "Helicobacter pylori lipoplysaccharide enhances the expression of NADPH oxidase components in cultured guinea pig gastric mucosal cells"FEBS Lett.. 452. 243-246 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yoshida, L. S. et al.: "Fungous gliotoxin targets the onset of superoxide-generating NADPH oxidase of human neutrophils"BBRC. 268. 716-723 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 吉田ルシア幸子,網脇祥子: "FAD欠損を導く好中球NADPH oxidase系,gp91^<phox>,の変異"磁気共鳴と医学. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yoshida,L.S.et al.: "Mutation at histidine 338 of gp91^<phox> depletes FAD and affects expression of cytochrome b558 of the human NADPH oxidase" J.Biol.Chem.273. 27879-27886 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fujii,H.et al.: "Nitric oxide: prospects and perspectives of in vivo detection by L-band EPR spectroscopy" Phys.Med.Biol.43. 1949-1956 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 網脇祥子: "食細胞NADPHオキシダーゼ:新奇サイトゾル因子“p40"" 臨床免疫. 30. 267-272 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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