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1996 Fiscal Year Final Research Report Summary

Development of A New Cholesterol Lowering Drug to Prevent Atherosclerosis

Research Project

Project/Area Number 07557342
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section試験
Research Field Circulatory organs internal medicine
Research InstitutionHokkaido University

Principal Investigator

OKAMOTO Hiroshi  Hokkaido Univ., Medical Hospital, Assistant, 医学部・附属病院, 助手 (50260394)

Co-Investigator(Kenkyū-buntansha) SAKAKIBARA Jun  Niigata Univ., Fac.of Med., Assistant, 医学部, 助手 (90242403)
ONO Teruo  Niigata Univ., Fac.of Med., Professor, 医学部, 教授 (00000927)
KAWAGUCHI Hideaki  Hokkaido Univ., Fac.of Med., Professor, 医学部, 教授 (70161297)
KITABATAKE Akira  Hokkaido Univ., Fac.of Med., Professor, 医学部, 教授 (00124769)
Project Period (FY) 1995 – 1996
Keywordscholesterol / squalene epoxidase / gene / atherosclerosis / inhibitors / DNA cloning
Research Abstract

Squalene epoxidase (SE) (EC 1.14.99.7) catalyzes the first oxygenation step in sterol biosynthesis and is suggested to be one of the rate-limiting enzymes in this pathway. Rat SE cDNA was isolated by selecting yeast transformants expressing rat cDNA in the presence of transformants expressing rat cDNA in the presence of terbinafine, an inhibitor specific for fungal SE.Mouse and human SE cDNA was isolated by library screening using rat SE cDNA as a probe. SE polypeptide deduced from the nucleotide sequence contains 573 amino acids, and its molecular weight is 63,950 Da. The amino acid sequence reveals one potential transmembrane domain, a hydrophobic segment (Leu27 to Tyr43) in the NH2-terminal region. This region also contains a beta 1-alpha A-bata 2 motif, which is the consensus sequence for an FAD binding domain. This deduced rat SE sequence is 30.2% identical to the ERG 1 gene, which encodes SE from an allylamine-resistant Saccharomyces cerevisiae mutant. The cDNA had an open reading frame for a 572 amino acid polypeptide with a calculated molecular mass of 63.8 kDa. The predicted amino acid sequence of the mouse enzyme contained an FAD-binding motif, and was 93%, 83% identical to those of the rat and human enzymes, respectively. Blotting analyzes showed that the mRNA is 2.8 kb in size and that a single copy of the gene is present in the mouse genome. PCR revealed that human SE gene to chromosomes 8 by using the NIGMS Human/Rodent Somatic Cell Hybrid Mapping Panel 2 as templates. To refine the localization of the human SE gene showed that the human SE gene linked with the micro-satellite marker D8S508 which was reported to be localized in 8q 24.13-q telomere (Lod score 7.87). Moreover, fluorescence in situ hybridization also map the human SE gene to 8q 24.13.

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Sakakibara J.: "Molecular cloning and expression of rat epoxidase" J.Biol.Chem.270(1). 17-20 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kosuga K.: "Nucleotide sequence of a1 cDNA for mouse epoxidase." Biochim Biophys Acta. 126. 345-348 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nagano A: "Purification and characterization of recombinant squalene epoxidase" J Lipid Res. 36. 1489-1497 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoneya K.: "Angiotensin-coverting engymegene polymorphism in Japanese patieuts with HCM." Am Heart J. 130. 1089-1093 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Endo-Mochizuki Y.: "Expression of renin" Heart and Vessels. 10. 285-293 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakamura Y.: "Transcriptional regulation of squalene epoxidase by sterols and inhibitors in Hela cells." J Biol.Chem.271(14). 8053-8056 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sakakibara J., Watanabe R., Kanai Y., Ono T.: "Molecular cloning and expression of rat epoxidase." J Biol Chem. 270 (1). 17-20 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kosuga K., Hata S., Osumi T., Sakakibara J., Ono T.: "Nucleotide sequence of a cDNA for mouse epoxidase." Biochim Biophys Acta. 1260. 345-348 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nagumo A., Kamei T., Sakakibara J., Ono T.: "Purification and characterization of recombinant squalene epoxidase." J Lipid Res.36. 1489-1497 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoneya K,Okamoto H,Machida M,Onozuka H,Noguchi M,Mikami T,Kawaguchi H,Murakami M,Ueda T,Kitabatake A.: "Angiotensin-converting enzyme gene polymorphism in Japanese patients with hypertrophic cardiomyopathy." Am Heart J. 130. 1089-1093 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Endo-Mochizuki Y,Mochizuki N,Sawa H,Takada A,Okamoto H,Kawaguchi H,Nagashima K,Kitabatake A.: "Expression of renin and anglotensin-converting enzyme in human hearts." Heart and Vessels. 10. 285-293 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakamura Y., Sakakibara J., Izumi T., Shibata A., Ono T.: "Transcriptional regulation of squalene epoxidase by sterols and inhibitors in Hela cells." J Biol Chem. 271 (14). 8053-8056 (1996)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-16  

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