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Mechanistic Study of Allosteric Inhibition of PPARgamma Serine Phosphorylation

Research Project

Project/Area Number 25860090
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Drug development chemistry
Research InstitutionShowa Pharmaceutical University

Principal Investigator

ITOH Toshimasa  昭和薬科大学, 薬学部, 准教授 (80536110)

Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
KeywordsPPARgamma / 構造生物学 / メディシナルケミストリー / 高度不飽和脂肪酸 / PPAR / X線結晶構造解析 / タンパク質NMR / インスリン抵抗性 / インスリン抵抗性改善作用 / 脂肪酸合成 / PPARγ / X-線結晶構造解析
Outline of Final Research Achievements

To understand how PPARgamma ligands inhibit Ser245 phosphorylation, we have done several experiments. 1H-15N HSQC NMR experiment showed that some residues were significantly shifted by PPARgamma ligand. A signaling pathway from ligand to the shifted residues was revealed by using PPARgamma mutants. This is supported by circular dichroism spectroscopic experiments. To integrate our results, we used modeling software Sybyl-X and we proposed the main signaling pathway and mechanism of inhibition of Ser245 phspholylation by ligand.
Based on the mechanism, we planed to design and synthesis of partial agonist for PPARgamma. We established facile synthesis of 17-(S)HDHA then synthesized 17-oxoDHA, which showed PPARgamma partial agonistic activity, as we predicted.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (9 results)

All 2016 2015 2014 2013 Other

All Int'l Joint Research (1 results) Journal Article (2 results) (of which Peer Reviewed: 2 results,  Acknowledgement Compliant: 2 results) Presentation (4 results) Remarks (2 results)

  • [Int'l Joint Research] Italian National Research Council(イタリア)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Gram scale synthesis of specialized pro-resolving mediator 17(S)-HDHA using lipoxygenase enhanced by water-soluble reducing agent TCEP2016

    • Author(s)
      Toshimasa Itoh, Tomoko Saito, Yoshinori Yamamoto, Hiroaki Ishida, Keiko Yamamoto
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters

      Volume: 26 Issue: 2 Pages: 343345-343345

    • DOI

      10.1016/j.bmcl.2015.12.011

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Characterization of Covalent Bond Formation between PPARγ and Oxo-Fatty Acids2015

    • Author(s)
      Daichi Egawa, Toshimasa Itoh, and Keiko Yamamoto
    • Journal Title

      Bioconjugate Chemistry

      Volume: 26 Issue: 4 Pages: 690698-690698

    • DOI

      10.1021/acs.bioconjchem.5b00021

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] リガンドによるPPARγリン酸化阻害機構における ヘリックス3とβシート間の相互作用に関する研究2014

    • Author(s)
      西方貴美奈, 伊藤俊将, 江川大地, 山本恵子
    • Organizer
      第58回日本薬学会関東支部大会
    • Place of Presentation
      昭和薬科大学,東京
    • Year and Date
      2014-10-04
    • Related Report
      2014 Research-status Report
  • [Presentation] 核内受容体PPARγセリンリン酸化におけるアロステリック阻害機構解明に関する研究2014

    • Author(s)
      西方貴美奈, 伊藤俊将, 江川大地, 粟飯島広乃, Roberta Montanari, Louise Fairall, John Schwabe, Fulvio Loiodice, Giorgio Pochetti, 山本恵子
    • Organizer
      PFシンポジウム
    • Place of Presentation
      つくば国際会議場 (つくば市)
    • Related Report
      2013 Research-status Report
  • [Presentation] Mechanistic Study of Allosteric Inhibition of PPARγ Serine Phosphorylation2013

    • Author(s)
      Toshimasa Itoh, Hirono Awaishima, Daichi Egawa, Roberta Montanari, Fulvio Loiodice , Giorgio Pochetti, and Keiko Yamamoto
    • Organizer
      14th Tetrahedron Symposium
    • Place of Presentation
      Hilton Vienna (Vienna, Austria)
    • Related Report
      2013 Research-status Report
  • [Presentation] Toshimasa Itoh, Daichi Egawa, Hirono Awaishima, Kimina Nishikata, Roberta Montanari, Louise Fairall, John Schwabe, Fulvio Loiodice, Giorgio Pochetti, Keiko Yamamoto2013

    • Author(s)
      Mechanistic Study of Allosteric Inhibition of PPARγ Serine Phosphorylation
    • Organizer
      EMBO Conference
    • Place of Presentation
      Hilton Sorrento Palace (Sorrento, Italy)
    • Related Report
      2013 Research-status Report
  • [Remarks] 総説・総合論文・著書

    • URL

      http://www.shoyaku.ac.jp/labosite/iyaku/2015/03/post_3.html

    • Related Report
      2014 Research-status Report
  • [Remarks] 原著論文 (2003-)

    • URL

      http://www.shoyaku.ac.jp/labosite/iyaku/2015/03/_2003_1.html

    • Related Report
      2014 Research-status Report

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Published: 2014-07-25   Modified: 2019-07-29  

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