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Analysis of the processing mechanism of endothelin-converting enzyme and the development of its inhibitors as novel therapeutics for vascular complications.

Research Project

Project/Area Number 08671167
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 内分泌・代謝学
Research InstitutionKYUSHU UNIVERSITY

Principal Investigator

TAKAYANAGI Ryoichi  Kyushu University, Faculty of Medicine, Assistant Professor, 医学部, 講師 (30154917)

Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1997: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1996: ¥1,200,000 (Direct Cost: ¥1,200,000)
KeywordsEndothelin / Endothelin-converting enzyme / Endothelial cell / Big endothelin / ECE / ET / GFP
Research Abstract

1. Big ET-1 analogues with the inhibitory activity on endothelin-converting enzyme-1 (ECE-1). Two big endothelin-1(big ET-1) analogues with the inhibitory activity on ECE-1, [F^<21>]big ET-1(18-34) and [A^<31>]big ET-1(18-34), were found by various amino acid substitution of big ET-1. Kinetics analyses showed that [F^<21>]big ET-1(18-34) is a competitive inhibitor and [A^<31>]big ET-1 (18-34) is a non-competitive inhibitor, suggesting that ECE-1 recognizes the P1 position and the C-terminal portion in a different fashon.
2. Clarification of intracellular site for big ET-1-conversion. It is important for the drug design to know where in the cell the big ET-1 is converted, however, the intracellular site for the conversion of big ET-1 has been controversial. In the present study, using a chimera of ECE-1 and green fluorescent protein (GFP), visible signal in living cells, it was revealed that endogenous big ET-1 is converted intracellularly, not on the cell surface.
3. Analyses of the properties of ECE-1 by mutagenesis of ECE-1 cDNA.Mutagenesis of human cDNA revealed that glycosylation of the extracellular C-terminal domain of ECE-1 is essential to the enzymatic activity, and that the transmembrane domain plays an important role in the completion of normal glycosylation.

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Tanaka S: "1,25-dihydroxyvitamin D3 enhances the enzymatic activity and expression of the messenger ribonucleic acid for aromatase cytochrome P450 synergistically with dexamethasone depending on the vitamin D receptor level in cultured human osteoblasts." Endocrinology. 137. 1860-1869 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Liu W: "[Phe^<21>]big endothelin-1(18-34)and[Ala^<31>]big endothelin-1(18-34)inhibit the human endothelin-converting enzyme-1(ECE-1)expressed in CHO-Kl cells in a different fashon." FEBS Lett. 420. 103-106 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takayanagi R: "Big endothelin analogues with inhibitory activity on endothelin-converting enzyme-1." J Cardivasc Pharmacol. 31. 62-63 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Natori S: "Chromogranin B(secretogranin I),a neuroendocrine-regulated secretory protein,is sorted to exocrine secretory granules in transgenic mice." EMBO J. 17. 3277-3289 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 高柳 涼一: "エンドセリン変換酵素" 内分泌・糖尿病科. 4. 61-67 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takayanagi,R: "Molecular Biology of Endothelin-converting Enzyme(ECE)" Highsmith,RF,Humana Press,Totowa,NJ,USA, 18 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Tanaka S et al.: "1,25-dihydroxyvitamin D3 enhances the enzymatic activity and expression of the messenger ribonucleic acid for aromatase cytochrome P450 synergistically with dexamethasone depending on the vitamin D receptor level in cultured human osteoblasts." Endocrinology. 137. 1860-1869 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Liu W et al.: "[Phe^<21>] big endothelin-1 (18-34) and [Ala^<31>] big endothelin-1 (18-34) inhibit the human endothelin-converting enzyme-1 (ECE-1) expressed in CHO-K1 cells in a different fashon." FEBS Lett. 420. 103-106 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takayanagi R et al.: "Big endothelin analogues with inhibitory activity on endothelin-converting enzyme-1." J Cardivasc Pharmacol. 31. S62-S63 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Natori S et al.: "Chromogranin b (secretogranin I), a neuroendocrine-regulated seretory protein, is sorted to exocrine secretory granules in transgenic mice." EMBO J. 17. 3277-3289 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takayanagi, Ret al.: "Molecular Biology of Endothelin-converting Enzyme (ECE)" Endothelin, Molecular Biology, Physiology, and Pathology. (Highsmith, R.F.ed) Humana Press (Totowa, U.S.A). 75-92 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 高柳 涼一: "エンドセリン変換酵素の臨床的意義" ホルモンと臨床. 44巻. 50-60 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] 高柳 涼一: "エンドセリン変換酵素" 内分泌・糖尿病科. 4. 61-67 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Liu,W.et al.: "[Phe^<21>]big endothelin-1(18-34)and[Ala^<31>]big endothelin-1(18-34)inhibit the human endothelin-converting enzyme-1(ECE-1)expressed in CHO-Kl cells in a different fashion." FEBS Letters. 420. 103-106 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takayanagi R.et al.: "Big endothelin analogues eith inhibitory activity of endothelin-convertihg enzyme." J.Cardiovasc.Pharmancol.31. 62-63 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takayanagi R.et al.: "Molecular Biology of Endothelin-Converting Enzyme(ECE)." R.F.Highsmith,Humana Press Inc.,Totowa,NJ,USA, 18 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 高柳涼一: "エンドセリン変換酵素の臨床的意識" ホルモンと臨床. 44巻. 50-60 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 高柳涼一: "エンドセリン変換酵素" 内分泌・糖尿病科. 4. 61-67 (1997)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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