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Study on the Enzyme Action Mechanism in the Phospholipid Hydrolysis by Means of small Molecular Inhibitors

Research Project

Project/Area Number 09480145
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Bioorganic chemistry
Research InstitutionKwansei Gakuin University

Principal Investigator

KATSUMURA Shigeo  Kwansei Gakuin University, School of Science, Professor, 理学部, 教授 (70047364)

Co-Investigator(Kenkyū-buntansha) IKEDA Kiyoshi  Osaka University of Pharmaceutical Sciences, Department of Biochemistry, Professor, 薬学部, 教授 (50001053)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 1999: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1998: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1997: ¥2,700,000 (Direct Cost: ¥2,700,000)
Keywordsphospholipase AィイD22ィエD2 / sphingomyelinase / synthesis of enzyme inhibitors / elucidation of inhibitory mechanism / interfacial recognition site / oxazolidinone substrate analog / synthesis of sphingomyelin / sphingolipid analog inhibitor / スフィンゴミエリナーゼ阻害剤 / メチレン気質類緑体 / 立体選択的合成 / ホフマン転位 / スフィンゴミエリン / 第2世代拮抗的阻害剤 / 2置換オキサゾリジノンリン脂酸 / 立体選択的オキサゾリジノン合成 / アミド型阻害剤とCa^<2+>との結合常数 / pH依存性 / アルデヒドテルペノイドの阻害機構 / ホスホリパーゼA_2阻害剤 / 3-(E)-メトキシカルボニルトリエナ-ル / リジンの選択的修飾 / ジヒドロピリジンの形成 / スフィンゴエミリナーゼ基質 / スフィンゴシンの立体選択的合成
Research Abstract

Phospholipids are classified into glycerophospholipids and sphingophospholipids. Phospholipase AィイD22ィエD2 (PLAィイD22ィエD2) catalyzes the hydrolysis of the ester linkage at the sn-2 position of glycerophospholipids and responsibles for the metabolism of unsaturated fatty acids. Meanwhile, sphingomyelinase is the general term of the enzyme which catalyzes the hydrolysis of the phosphoester linkage of sphingomyelin to produce ceramide, which has been known as a lipid second messenger in mammalian cell membranes.
We found that 3-methoxycarbonyl-2, 4, 6-trienal (A) strongly inactivated phospholipase AィイD22ィエD2 which was isolated from bovine pancreas. The inactivation mechanism of PLAィイD22ィエD2 by the compound A was elucidated by means of the stereocontrolled synthesis of the derivatives of A, structure activity relationship, amino acid analysis of the complex with PLAィイD22ィエD2, and model reactions with amines. Thus, the compound A was found to selectively modify Lys-56 which is included in the … More interfacial recognition site of bovine pancreatic PLAィイD22ィエD2, by the MALDI-TOF-Mass peptide mapping analyses of the complex.
We also synthesized the new cyclic amide analog as the second-generation inhibitor having an oxazolidinone ring, because we had previously synthesized the oxazolidinone phospholipid analog which competitively acted on the catalytic site of PLAィイD22ィエD2.
On the other hand, in the study of sphingomyelinase, we achieved the efficient synthesis of (D)-erythro-sphigomyelin, and found that (D)-erythro stereochemistry is essentially important as the substrate for sphingomyelinase and the double bond in the backbone skeleton was not essential for the hydrolysis by B. cereus sphingomyelinase. Furthermore, we established the stereocontrolled efficient synthesis of sphingomyelin methylene and ethylene analogs, which are the first substrate-analog inhibitors, and they actually inhibited the hydrolytic ability of the enzyme. These analog inhibitors might be useful for the elucidation of the sphingomyelinase hydrolytic mechanism. Less

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (34 results)

All Other

All Publications (34 results)

  • [Publications] Tanaka, T. ; Katsumura, S.: "Novel Synthesis of the Ocular Age Pigment A2-E : New Method for Substituted Pyridine Synthesis via Azacyclization"Organic Letters. 2. 373-375 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 田中 克典、勝村 成雄: "アルデヒドテルペノイドによるホスホリパーゼA_2不活性化機構"有機合成化学協会誌. 57. 867-887 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Furuichi, N. ; Kato, M. ; Katsumura, S.: "Stereocontrolled Synthesis of (+)-Acuminolide and Determination of Its Absolute Configuration"Chemistry Letters. 1247-1248 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fujii, S. ; Ogata, K. ; Katsumura, S. et al.: "Roles of Asp 126 and Asp 156 in the Enzyme Function of Sphingomyelinase from Bacillus cereus"Journal of Biochemistry. 126. 90-97 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hata, T. ; Tanaka, K. ; Katsumura, S.: "First Synthesis of (-)-Spongianolide A and Determination of Its Absolute Structure"Tetrahedron Letters. 40. 1731-1734 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tanaka, K. ; Kamatani, M. ; Mori, H. ; Fujii, S. ; Ikeda, K. ; Katsumura, S.: "The Inhibitory Machanism of Bovine Pancreatic Phospholipase A_2 by Aldehyde Terpenoids"Tetrahedron. 55. 1657-1686 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Asano, K. ; Hakogi, T. ; Iwama, S. ; Katsumura, S.: "New Entry for Asymmetric Deoxyazasugar Synthesis : Syntheses of Deoxymannojirimycin, Deoxyaltrojirimycin and Deoxygalactostatin"Chemical Communication. 41-42 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Iwama, S. ; Segawa, M.; Fujii, S. ; Ikeda, K. ; Katsumura, S.: "Design and Synthesis of New Secretory Phospholipase A_2 Inhibitor of a Phospholipid Analog"Bioorg. Medic. Chem. Lett.. 8. 3495-3498 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fujii, S. ; Tani, T. ; Inoue, S. ; Iwama, S. ; Katsumura, S. : Ikeda, K.: "pH Dependence of the Reaction Rate of p-Bromophenacyl Bromide and the Binding Constant of Ca^<2+> and an Amide-Type Substrate Analog to Bovine Pancreatic Phospholipase A_2"Arch. Biochem. Biophys.. 354. 73-82 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tanaka, K. et al.: "Synthesis of a New Phospholipase A_2 Inhibitor of an Aldehyde Terpenoid and its Possible Inhibitory Mechanism"Tetrahedron Letters. 39. 1185-1188 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tomoo, K. et al.: "X-Ray Crystal Structure Determination and Molecular Dynamics Simulation of Phospholipase A_2 Inhibited by Amide-type Substrate Analogues"Biochimica et Biophysica Acta. 1340. 178-186 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Murakami, M. et al.: "An Efficient Synthesis of Short-chain Spingomyelin Analogs and their Susceptibility to Hydrolysis Catalyzed by Spingomyelinase"Bioorg. Medic. Chem. Lett.. 7. 1725-1728 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Inoue, S. et al.: "Specificity of two types of phospholipase A_2 inhibitors from the plasma of venomous snakes"Biochemistry and Molecule Biology International. 41. 529-537 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ohkura, N. et al.: "Purification and characterization of three distinct types of phospholipase A_2 inhibitors from the blood plasma of the Chinese mamushi, Agkistrondon blomhoffii siniticus"Biochemical Journal. 325. 527-531 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Inoue, S. et al.: "Dopaminergic transmitter up-regulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) synthesis in mouse astrocytes in culture"Biochemical and Biophysical Research Communication. 238. 468-472 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tanaka, K.; Katsumura, S.: "The Inhibitory Mechanism of Phospholipase AィイD22ィエD2 by Aldehyde Terpenoids."JOURNAL OF SYNTHETIC ORGANIC CHMISTRY, JAPAN.. 57. 867-887 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fujii, S.; Ogata, K.; Katsumura, S. et al.: "Roles of Asp 126 and Asp 156 in the Enzyme Function of Sphingomyelinase from Bacillus cereus."Journal of Biochemistry. 126. 90-97 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tanaka, K.; Kamatani, M.; Mori, H.; Fujii, S.; Ikeda, K.; katsumura, S.: "The Inhibitory Mechanism of Bovine Pancreatic Phospholipase AィイD22ィエD2 by Aldehyde Terpenoids."Tetrahedron. 55. 1657-1686 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Iwama, S.; Segawa, M.; Fujii, S.; Ikeda, K.; Katsumura, S.: "Design and Synthesis of New Secretory Phospholipase AィイD22ィエD2 Inhibitor of a Phospholipid Analog."Bioorg. Medic. Chem. Lett.. 8. 3495-3498 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Murakami, M.; Iwama, S.; Fujii, S.; Ikeda, K.; Katsumura, S.: "An Efficient Synthesis of Short-chain Sphingomyeline Analogs and Their Susceptibility to Hydrolysis Catalyzed by Sphingomyelinase."Bioorg. Medic. Chem. Lett.. 7. 1725-1728 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 田中克典、勝村成雄: "アルデヒドテルペノイドによるホスホリパーゼA_2不活性化機構"有機合成化学協会誌. 57. 867-887 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Furuichi,N.;Kato,Katsumura,S.: "Stereocontrolled Synthesis of (+)-Acuminolide and Determination of Its Absolute Configuration"Chemistry Letters. 1247-1248 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Fujii, S. ; Ogata, K. ; Katsumura, S. et al: "Role of Asp 126 and Asp156 in the Enzyme Fuction of Sphingomyelinase from Bacillus cereus"Journal of Biochemistry. 126. 90-97 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hata,T.;Tanaka,K.;Katsumura,S.: "First Synthesis of (-)-Spongianolide and Determination of Its Absolute Configuration" Tetrahedron Letters. 40. 1731-1734 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tanaka,K;Kamatani,M.;Mori,H.;Fujii,S.;Ikeda,K.;Katsumura,S.: "The Inhibitory Mechanism of Bovine Pancreatic Phospholipase A2 by Aldehyde Terpenoids" Tetrahedron. 55. 1657-1686 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Asano,K.;Hakogi,T.;Iwama,S.;Katsumura,S.: "New Entry for Asymmetric Deoxyazasugar Synthesis:Synthesis of Deoxymannojirimycin,Deoxyaltrojirimycin and Deoxygalactostatin" Chemical Communication. 41-42 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Iwama,S.;Segawa,M.;Fujii,S.;Ikeda,K.;Katsumura,S.: "Design and Synthesis of New Secretory Phospholipase A_2 Inhibitor of a Phospholipid Analog" Bioorg.Medic.Chem.Lett.8. 3495-3498 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fujii,S.;Tani,T.:Inoue,S.;Iwama,S.;Katsumura,S.;Ikeda,K.: "pH Dependence of the Reaction Rate of p-Bromophenacyl Bromide and of the Binding Constant of Ca^<2+> and an Amide-Type Substrate Analog to Bovine Panacreatic Phospholopase A_2," Arch.Biochem.Biophys.354. 73-82 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tanaka,K.: "Synthesis of a New Phospholipase A_2 Inhibitor of an Aldehyde Terpenoid and its Possible Inhibitory Mechanism." Teterahedron Letters. 39. 1185-1188 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tomoo,K.: "X-Ray Crystal Structure Determination and Molecular Dynamics Simulation of Phospholipase A_2 Inhibited by Amide-type Substrate Analogues." Biochimimica et Biophysica Acta. 1340. 178-186 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Murakami,M.: "An Efficient Synthesis of Short-chain Spingomyelin Analogs and their Susceptibility to Hydrolysis Catalyzed by Sphingomyelinase." Bioorganic & Medicinal Chemistry Letters. 7. 1725-1728 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Inoue,S.: "Specificity of two types of phospholipase A2 inhibitors from inhibitors from the plasma of venomous snakes." Biochemistry and Molecule Biology International. 41. 529-537 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ohkura,N.: "Purification and characterization of three distinct types of phospholopase A2 inhibitors from the blood plasma of the Chinese mamushi, Agkistrondon blomhoffii siniticus." Biochemical Journal. 325. 527-531 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Inoue,S.: "Dopaminergic transmitter up-regulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) synthesis in mouse astrocytes in culture." Biochemical and Biophysical Research Communication. 238. 468-472 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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