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膜蛋白質と相互作用する生体機能分子の合成と機能解析

Research Project

Project/Area Number 16073211
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Science and Engineering
Research InstitutionOsaka University

Principal Investigator

大石 徹  Osaka University, 大学院・理学研究科, 准教授 (90241520)

Co-Investigator(Kenkyū-buntansha) 村田 道雄  大阪大学, 大学院・理学研究科, 教授 (40183652)
松森 信明  大阪大学, 大学院・理研究科, 助教 (50314357)
Project Period (FY) 2004 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥28,300,000 (Direct Cost: ¥28,300,000)
Fiscal Year 2007: ¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 2006: ¥8,100,000 (Direct Cost: ¥8,100,000)
Fiscal Year 2005: ¥9,100,000 (Direct Cost: ¥9,100,000)
Fiscal Year 2004: ¥4,200,000 (Direct Cost: ¥4,200,000)
Keywords合成化学 / 分子プローブ / 同位体標識 / 化学合成 / 固体NMR / 天然物 / 生物活性 / 膜蛋白質 / 膜タンパク質
Research Abstract

アンフォテリシンB(AmB)は,重要な抗真菌剤として感染症治療に広く使われており,生体膜中でイオン透過性を持つチャネル複合体を形成して活性を発現すると考えられているが,詳細な構造は不明である。本研究者は,AmBによって形成されるチャネル複合体の構造を明らかにするために,膜系の測定に有効な固体NMR,すなわち,異種核間距離測定法の一つである^<13>C{19F}REDOR法を適用することを計画し,一方を19Fで他方を13Cで標識化したAmBを用い,炭素-フッ素間の距離を測定することにした。天然物からの誘導および化学合成によって調製した19F-AmB誘導体および培養によって得られた13C-AmBを用いて固体NMRを行ったところ有意なREDOR減衰が観測され,本方法論がチャネル複合体の構造解析に有効であることが示された。
サリシリハラミドAは,哺乳類の液胞型ATPアーゼ(V-ATPase)に特異的作用する抗腫瘍性天然物である。V-ATPaseは,ATPの加水分解と共役したプロトンポンプ(膜蛋白質)であり,種々の生命活動において重要な働きを担っている。さらに癌細胞の表面にも存在することが知られており,癌の浸潤や転移などに深く関わっている。本研究では,膜系での構造解析に有効な固体NMRを用いてサリシリハラミドAと液胞型ATPアーゼとの分子複合体の構造を明らかにし,分子レベルでの生理活性発現機構を明らかにすることを目的として,4-19F-標識化サリシリハラミドAを化学合成によって調達した。フッ素標識体は天然物と同等のV-ATPase阻害活性を示し,生理活性発現機構のための分子プローブとして有用であることが明らかとなった。

Report

(4 results)
  • 2007 Annual Research Report
  • 2006 Annual Research Report
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (20 results)

All 2007 2006 2005 2004

All Journal Article (19 results) (of which Peer Reviewed: 4 results) Presentation (1 results)

  • [Journal Article] Conformation and Location of Membrane-Bound Salinomycin-Sodium Complex Deduced from NMR in Isotropic Bicelles.2007

    • Author(s)
      Nobuaki, Matsumori
    • Journal Title

      J. Am. Chem. Soc. 129

      Pages: 14989-14995

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Amphotericin B covalent dimers with carbonyl-amino linkage: a new probe for investigating ion channel assemblies.2007

    • Author(s)
      Yuichi, Umegawa
    • Journal Title

      Tetrahedron Lett. 48

      Pages: 3393-3396

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Conformation and Position of Membrane-Bound Amphotericin B Deduced from NMR in SDS Micelles.2007

    • Author(s)
      Nobuaki, Matsumori
    • Journal Title

      J. Org. Chem. 72

      Pages: 700-706

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synthesis of the JK ring fragments of yessotoxin and 42,43,44,45,46,47,55-heptanor-41-oxoyessotoxin.2007

    • Author(s)
      Koji, Watanabe
    • Journal Title

      Heterocycles 72

      Pages: 207-212

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synthesis of the ABC and IJ ring fragments of yessotoxin.2006

    • Author(s)
      Tohru Oishi
    • Journal Title

      Tetrahedron Lett. 47(24)

      Pages: 3975-3978

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Synthesis of 28-^<19>F-amphotericin B methyl ester2006

    • Author(s)
      Hiroshi Tsuchikawa
    • Journal Title

      Tetrahedron Lett. 47(35)

      Pages: 6187-6191

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Convergent synthesis of the CDEF ring system of yessotoxin via α-cyan ethers.2006

    • Author(s)
      Tohru Oishi
    • Journal Title

      Heterocycles 69

      Pages: 91-98

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Design and synthesis of an artificial ladder-shaped polyether that interacts with glycophorin A.2006

    • Author(s)
      Kohei Torikai
    • Journal Title

      Bioorg. Med. Chem. Lett. 16(24)

      Pages: 6355-6359

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Structures of new amphidinols with truncated polyhydroxyl chain and their membrane-permeabilizing activities.2006

    • Author(s)
      Nagy Morsy
    • Journal Title

      Bioorg. Med. Chem. 14(19)

      Pages: 6548-6554

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Synthesis of artificial ladder-shaped polyethers containing a 6/7 cis-fused ring system.2006

    • Author(s)
      Kohei Torikai
    • Journal Title

      Heterocycles 70

      Pages: 161-167

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Ladder-shaped polyether compound, desulfated yessotoxin, interacts with membrane-integral α-helix peptides.2005

    • Author(s)
      Megumi Mori
    • Journal Title

      Bioorg.Med.Chem. 13・17

      Pages: 5099-5013

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Bioactive fluorinated derivative of amphotericin B.2005

    • Author(s)
      Nobuaki Matsumori
    • Journal Title

      Bioorg.Med.Chem.Lett. 15・15

      Pages: 3565-3567

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Convergent synthesis of the FGHI ring system of yessotoxin : stereoselective construction of the G ring.2005

    • Author(s)
      Koji Watanabe
    • Journal Title

      Tetrahedron Lett. 46・23

      Pages: 3991-3995

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Intact glycation end products containing carboxymethyl-lysine and glyoxal lysine dimer obtained from synthetic collagen model peptide.2004

    • Author(s)
      Hiroaki Yamada et al.
    • Journal Title

      Bioorg.Med.Chem.Lett. 14

      Pages: 5677-5680

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Stereocontrolled synthesis of the ABCDE ring moiety of ciguatoxin CTX3C.2004

    • Author(s)
      Shoji Kobayashi et al.
    • Journal Title

      Tetrahedron 60

      Pages: 8375-8396

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Synthesis and identification of an endogenous sperm activating and attracting factor isolated from eggs of the ascidian Ciona intestinalis, an example of nanomolar-level structure elucidation of novel natural compound.2004

    • Author(s)
      Tohru Oishi et al.
    • Journal Title

      Tetrahedron 60

      Pages: 6971-6980

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Synthesis and conformation of deuterated spermidine for investigating weak interaction with polyanionic biomolecules.2004

    • Author(s)
      Keisuke Maruyoshi et al.
    • Journal Title

      Tetrahedron 60

      Pages: 5163-5170

    • Related Report
      2004 Annual Research Report
  • [Journal Article] An amphotericin B-ergosterol covalent conjugate with powerful membrane permeabilizing activity.2004

    • Author(s)
      Nobuaki Matsumori et al.
    • Journal Title

      Chem.Biol. 11

      Pages: 673-679

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Glycoglycerolipid from the membranes of Acholeplasma laidlawii binds to human immunodeficiency virus-1 (HIV-1) and accelerates its entry into cells.2004

    • Author(s)
      Takashi Shimizu et al.
    • Journal Title

      Current Microbiology 48

      Pages: 182-188

    • Related Report
      2004 Annual Research Report
  • [Presentation] Synthetic Studies of Yessotoxin2007

    • Author(s)
      Tohru, Oishi
    • Organizer
      International Symposium on Catalysts and Fine Chemicals
    • Place of Presentation
      Nanyang Technological University, シンガポール
    • Year and Date
      2007-12-17
    • Related Report
      2007 Annual Research Report

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Published: 2004-04-01   Modified: 2018-03-28  

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