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Structure, Function and Regulation of Lung-Specific Carbonyl Reductase

Research Project

Project/Area Number 01571220
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Biological pharmacy
Research InstitutionGifu Pharmaceutical University

Principal Investigator

HARA Akira  Gifu Pharmaceutical University, Assistant professor, 薬学部, 助教授 (00094334)

Co-Investigator(Kenkyū-buntansha) NAKAGAWA Makoto  Gifu Pharmaceutical University, Assistant, 薬学部, 助手 (30188908)
Project Period (FY) 1989 – 1991
Project Status Completed (Fiscal Year 1991)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1991: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1990: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1989: ¥1,100,000 (Direct Cost: ¥1,100,000)
Keywordscarbonyl reductase / lung / cDNA / coenzyme binding / lipid metabolism / cooperativity / fatty acid / allosteric effector / アミノ酸配列 / アロステリック酵素 / 活性調節 / 肺障害 / 免疫組織化学 / アルデヒド酸化 / 化学修飾 / 酵素構造 / 活性化剤
Research Abstract

Carbonyl reductase(EC 1.1.1.184)is one of several NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds. Lungs of pig, mouse and guinea-pig specifically contain an oligomeric carbonyl reductase different from the monomeric enzymes in other mammalian tissues. In this study, we purified the oligomeric carbonyl reductase from these animal lungs, and characterized its structural and functional properties, localization in lung, and regulation of the enzyme activity by effectors, in order to elucidate its role in pulmonary metabolism of xenobiotic and endogenous carbonyl compounds.
1. Structure. The pulmonary carbonyl reductase was a tetramer with a Mr of 103, 000, consisting of apparent identical subunits of Mr 24, 000. A CDNA clone for carbonyl reductase was isolated from a pig lung CDNA library by use of a specific antibody to the pulmonary enzyme, and the nucleotide sequence of the clone was determined. The predicted amino acid sequence was confirmed by partial se … More quence analysis of the enzyme protdin, and also localized a putative coenzyme binding region similar to that of many other pyridine nucleotide-dependent dehydrogenases. Chemical modification study suggested the presence of essential lysyl and histidyl residues at or near the active center of the enzyme.
2. Function. The enzyme reduced various aliphatic and aromatic carbonyl compounds including 3-ketosteroids and fatty aldehydes, and oxidized aldehydes to carboxylic acids. Immunohistochemical study revealed that the enzyme was localized in the Clara cells, ciliated cells, and Type II alveolar cells in these animal lungs. Thus, the enzyme may play roles in dismutation of carbonyl compounds derived from lipid peroxidation, steroid metabolism, and biosynthesis of ether lipids, as well as drug metabolism.
3. Regulation. The enzyme exhibited negative cooperativity with respect to the carbonyl substrates. Fatty acids acted as allosteric effectors abolishing the negative interaction. Especially, cis-unsaturated fatty acids such as oleic acid and arachidonic acid were most effective activators showing Ka values of 2.2-14 muM. The fatty acid effect may be important in the regulation of the synthesis of ether lipids from fafiy acids by the enzyme, and the low Ka values for the fatty acids suggests an additional function that the enzyme acts as a lung-specific binding protein for fatty acids. Less

Report

(4 results)
  • 1991 Annual Research Report   Final Research Report Summary
  • 1990 Annual Research Report
  • 1989 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] 松浦 一也: "Pulmonary carbonyl reductase: Metabolism of carbonyl products in lipid peroxidation." Alan R.Liss Inc.,"Enzymology and MoMolecular Biology of Carbonyl Metabolism 2"".335-349 (1689)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] 松浦 一也: "Localization of pulmonary carbonary carbonyl reductase in quinea pig and mouse:Eyzyme histochemical and immunohemical studies." J.Histochem.Cytochem.38. 217-223 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] 原 明: "Aldehyde dismutation catalyzed by pulmonary carbonyl reductase: Kinnetic ctudies of chloral hydrate metabolism to trichloroacetic acid and trichloroethanol." Biochim.Biophys.Acta. 1075. 61-67 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] 析谷 博幸: "Purification and characterization of pig lung carbonyl reductase." Arch.Biochem.Biophys.292. 539-547 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] 原 明: "Activation of carbonyl reductase from pig lung by fatty acids." Arch.Biochem.Biophys.292. 548-554 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] 原 明: "Activation of pulmonary carbonyl reductase of puimeaーpig and pig by basic aromatic compounds."

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] 出屋敷 喜宏: "Cloning and sequencing of cDNA encording pig lung carbonyl reductase."

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] 松浦 一也: "Ultrastructural localization of carbonyl reductase in mouse lung."

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Matsuura, Kazuya, Alan R. Liss Inc.: ""Enzymology and Molecular Biology of Carbonyl Metabolism 2"" 335-349 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Matsuura, Kazuya, Localizatin of pulmonary carbonyl reductase in guinea pig and mouse: "Enzyme histochemica and immunochemical studies." J. Histochem. Cytochem.38. 217-223 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Hara, Akira: "Aldehyde dismutation catalyzed by pulmonary carbonyl reductase : Kinetic studies of Chloral hydrate metabolism to trichloroacetic acid and trichloroethanol." Biochem. Biophys. Acta. 1075. 61-67 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Oritani, Hiroyuki: "Purification and characterization of pig lung carbonyl reductase." Arch. Biochem. Biophys.292. 539-547 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Hara, Akira: "Activation of carbonyl reductase from pig lung by fatty acids." Arch. Biochem. Biophys.292. 548-554 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Hara, Akira: "Activation of pulmonary carbonyl reductase of guinea-pig and pig by basic aromatic compounds."

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Dayashiki, Yoshihiro: "Cloning and sequencing of cDNA envording pig lung carbonyl reductase."

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Matsuura, Kazuya: "Ultrastructural localization of carbonyl reductase in mouse lung."

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] 出屋敷 喜宏: "Cloning and sequencing of cDNA encording pig lung carbonyl reductase."

    • Related Report
      1991 Annual Research Report
  • [Publications] 松浦 一也: "Ultrastructural localization of carbonyl reductase in mouse lung."

    • Related Report
      1991 Annual Research Report
  • [Publications] 松浦 一也: "Localization of pulmonary carbonyl reductase in guinea pig and mouse:Enzyme histochemistry and immunohistochemical studies" The Journal of Histochemistry and Cytochemistry. 38. 217-223 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 原 明: "Aldehyde dismutation by pulmonary carbonyl reductase." Biochimica Biophysica et Acta.

    • Related Report
      1990 Annual Research Report
  • [Publications] 折谷 博幸: "Purification and characterization of carbonyl reductase in pig lung" Archives of Biochemistry and Biophysics.

    • Related Report
      1990 Annual Research Report
  • [Publications] 原 明: "Activation of pulmonary carbonyl reductase by fatty acids." Archives of Biochemistry and Biophysics.

    • Related Report
      1990 Annual Research Report
  • [Publications] 松浦 一也: "Immunochemical localization of carbonyl reductase in the Clara cells and Type II alveaolar pneumocytes of guinea pig and mouse lung." Histochemistry.

    • Related Report
      1990 Annual Research Report
  • [Publications] 松浦一也: "Localization of pulmonary carbonyl reductase in guinea pig and mose:Enzyme histochemical and immunohistochemical studies" The Journal of Histochemistry and Cytochemistry.

    • Related Report
      1989 Annual Research Report

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Published: 1989-04-01   Modified: 2016-04-21  

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