1997 Fiscal Year Final Research Report Summary
Studies on the cellular functions of lipid-modified proteins
| Project/Area Number |
07557162
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Biological pharmacy
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| Research Institution | The Kitasato Institute |
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Principal Investigator |
OHMURA Satoshi The Kitasato Institute, Researach Center for Biological Function, President and Professor, 生物機能研究所, 所長 (90050426)
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| Co-Investigator(Kenkyū-buntansha) |
ARAI Hiroyuki The University of Tokyo Graduate School of Pharmaceutical Sciences, Associate Pr, 大学院・薬学系研究科, 助教授 (40167987)
MASUMA Rokuro The Kitasato Institute, Researach Center for Biological Function, Chief Research, 生物機能研究所, 室長 (90219353)
MORIKAWA Yuko The Kitasato Institute, Researach Center for Basic Research, Chief Researcher, 基礎研究所, 室長 (20191017)
INOKOSHI Junji Kitasato University, School of Pharmaceutical Sciences, Associate Professor, 薬学部, 講師 (30151640)
TOMODA Hiroshi The KItasato Institute, Researach Center for Biological Function, Chief Research, 生物機能研究所, 副所長 (70164043)
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| Project Period (FY) |
1995 – 1997
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| Keywords | Myristoylation / Farnesyltransferase / HIV Gag protein / Triacsin / Acly-Coa synthetase / Inhibitor / Ras protein / Andrastin |
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| Research Abstract |
Many cellular proteins are modified with lipids such as acyl(palmitoyl or myristoly)and/or prenly(farnesly or geranylgeranyl)residues. In this researach project, the biochemical functions of lipid-modified proteins were studied and searaach for microbial inhibitors of their formation wes carried out as a new approach for anticancer or antiviral agents.
HIV Gag protein is myrisstoylataed at the N-terminal glycine residue, which plays an important role in virus particlebdding. The myristoylation levels were controlled to investigate the effect on the particle budding by using the specifiv acyl-CoA synthetase inhibitor triacsin previousy discovered by our group. We showed that the inhibition of Gag myristoylation by triacsin follows dose-dependent kinetics but that the particle budding exhibits sudden shutoff kinetics, suggesting that only a relatively small proportion of total Gag molecules need to be myristoylated for efficient budding and indicating that total inhibition of myristoylation will be required for effective anti-HIV therapy.
Oncogene product Ras proteins are posttranslationally farnesylated at the cysteine residue near the C-terminus, in which protein farnesyltransferase(PFTase)is involved. PFTase is expected as a novel target of inhibition since the inhibition causes altering membrane localization and blocking activation of Ras proteins. An efficient screening system was conducted by utilizing Saccharomyces cerevisiae, resulting in discovery of two series of new PTFase inhibitors, andrastins produced by Penicillium sp.FO-3929 and kurasoins by Paecilomyces sp.FO-3684. The structure elucidation including stereochemistries, biosynthesis of andrastin and total sylnthesis of kurasoin were studied. Their inhibitory activity against PFTase (IC_<50>) was 10-60muM.
It still remains to be investigated whether or not these compounds inhibit PFTase in cells and show in fvivo anticancer activity.
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[Publications] Morikawa, Y., Hinata, S., Tomoda, H., Gogo, TA., Nakai, M., Aizawa, T., Tanaka, H.& Ohmura, S.: ""Completre inhibition of human immunodeficiency virus Gag myristoylation is necessary for inhibition of particle budding."" J.Bio.Chem.271. 2868-2873 (1996)
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「研究成果報告書概要(欧文)」より
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[Publications] Shiomi, K., Uchida, R., Inokoshi, J., Tanaka, H., Iwai, Y.& Ohmura, S.: ""Andrastins A-C,new protein farnesyltransferase inhibitors, produced by Penicillium sp.FO-3929."" Tetrahedron Lett.37. 1265-1268 (1996)
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「研究成果報告書概要(欧文)」より
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[Publications] Ohmura, S., Inokoshi, J., Uchida, R., Shiomi, K,Masuma, R., Kawakubo, T., Tanaka, H., Iwai, Y., Kosemura, S.& Yamamura, S.: ""Andrastins A-C,nes protein farnesyltransferase inhibitors, produced by Penicillium sp.FP-3929.I.Producing strain, fermentation, isolation and biological activities."" J.Antibiot.49. 414-417 (1996)
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「研究成果報告書概要(欧文)」より
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[Publications] Uchida, AR., Shiomi, K., Inokoshi, J., Sunazuka, T., Tanaka, H., Iwai, Y., Takayanagi, H.& Ohmura, S.: ""Andrastins A-C,new protein faranesyltransferase inhibitors, produced by Penicillium sp.RO-3929.II.Structure elucidation and biosynthesis."" 49. 49. 418-424 (1996)
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「研究成果報告書概要(欧文)」より
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[Publications] Uchida, R., Shiomi, K., Inokoshi, J., Masuma, R., Kawakubo, T., Tanaka, H., Iwai, Y.& Ohmura, S.: ""Kurasoins A and B,new protein farnesyltransferase inhibitors prodiced by Paecilomyces sp.FO-3684.I.Prodicing strain, fermentation, isolation and biological activities."" J.Antibiot.49. 932-934 (1996)
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「研究成果報告書概要(欧文)」より
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[Publications] Uchida, R., Shiomi, K., Sunazuka, T., Inokoshi, J., Nishizawa, A., Hirose, T., Tanaka, H., Iwai, Y.& Ohmura, S.: ""Kurasoins A and B,new protein farnesyltransferase inhibitors produced by Paecilomyces sp.FO-3684.II.Structure elucidation and total synthesis."" J.Antibiot.49. 886-889 (1996)
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「研究成果報告書概要(欧文)」より
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[Publications] Uchida, R., Shiomi, K., Inokoshi, J., Tanaka, H., Iwai, Y.& Ohmura, S.: ""Andrastin D,novel protein farnesyltransferase inhibitor produced by Penickillium sp.FO-3929."" J.Antibiot.49. 1278-1280 (1996)
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「研究成果報告書概要(欧文)」より
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[Publications] Sunazuka, T., Hirose, T., Tian, Z.-M., Uchida, AR., Shiomi, K., Harigaya, Y.& Ohmura, S.: ""Syntheses and absolute structures of novel protein farnesyltransferase inhibitors, kurasoins A and B."" J.Antibiot.50. 453-455 (1997)
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