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Structure of Molecular Assembles of Bioactive Natural Products Formed in Biomembranes

Research Project

Project/Area Number 15201048
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Living organism molecular science
Research InstitutionOsaka University

Principal Investigator

MURATA Michio  Osaka university, Chemistry, Professor, 理学研究科, 教授 (40183652)

Co-Investigator(Kenkyū-buntansha) OISHI Tohru  Osaka university, Chemistry, Associate Professor, 理学研究科, 助教授 (90241520)
MATSUMORI Nobuaki  Osaka university, Chemistry, Assistant Professor, 理学研究科, 助手 (50314357)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥39,910,000 (Direct Cost: ¥30,700,000、Indirect Cost: ¥9,210,000)
Fiscal Year 2005: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2004: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000)
Fiscal Year 2003: ¥24,310,000 (Direct Cost: ¥18,700,000、Indirect Cost: ¥5,610,000)
Keywordsamphotericin B / solid state NMR / antibiotics / self assemble / molecular aggregate / ergosterol / polyene antibiotics / コレステロール
Research Abstract

Amphotericin B (AmB) is known to assemble together and form an ion channel across biomembranes. The selective toxicity is generally accounted for by its higher affinity for ergosterol than cholesterol. To better understand the ion-channel structure and intermolecular interactions, we prepared various AmB derivatives and measured their activities. AmB dimers which are covalently linked between the amino groups by short chains showed more potent ion-channel activity than that of AmB, indicating that the mutual topology of AmB molecules is a head-to-head orientation. AmB-sterol conjugates were also designed and examined for ion-channel activities. AmB-ergosterol conjugates showed more powerful ion-channel activity than AmB-cholesterol congeners, suggesting that stronger van der Waals interaction between AmB and ergosterol contributes to the higher ion-channel activity. Finally, we prepared conformation-restricted derivatives of AmB, in which the amino and carboxyl groups were bridged with various lengths of alkyl chains. The derivatives successfully gave us information on the active-conformation of the sugar moiety of AmB in membrane. These derivatives are now labeled by ^<13>C and/or ^<19>F to probe the molecular structure of AmB ion channel using solid-state NMR.
The mode of membrane permeabilizing action of amphidinols, dinoflagellate-originating polyene-polyhydroxy compounds, was investigated mainly by NMR methods. The polyhydroxy and polyolefinic parts play roles in the formation of ion channel lining and in binding in the membrane. Detailed NOE measurements in membrane-mimicking systems elucidated that the central part of amphidinols takes a hairpin conformation, which should be, at least in part, accounted for their strong biological activities.

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (44 results)

All 2006 2005 2004 2003 Other

All Journal Article (38 results) Publications (6 results)

  • [Journal Article] 誘導体および同位体標識化合物を用いたアンフォテリシンBイオンチャンネル準造の解明2006

    • Author(s)
      松森信明, 大石 徹, 村田道雄
    • Journal Title

      有機合成化学協会誌 (掲載予定)(印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Derivatization and isotope labeling of amphotericin B aiming at elucidation of the ion-channel structure2006

    • Author(s)
      Matsumori, N., Oishi, T., Murata, M.
    • Journal Title

      Journal of Synthetic Organic Chemistry, Japan (In Press)

    • NAID

      10017486791

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Dominant formation of a single-length channel by amphotericin B in dimyristoylphosphatidylcholline membrane evidenceb by ^<13>C-^<31>P rotational echo double resonance.2005

    • Author(s)
      松岡 茂
    • Journal Title

      Biochemistry 44

      Pages: 704-710

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Hairpin conformation of amphidinol possibly accounting for potent membrane permeabilizing activities.2005

    • Author(s)
      蓮台俊宏
    • Journal Title

      Tetrahedron 61

      Pages: 2795-2802

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Bioactive fluorinated derivative of amphotericin B.2005

    • Author(s)
      松森 信明
    • Journal Title

      J.Am.Chem.Soc. 127

      Pages: 10667-10675

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Bioactive fluorinated derivative of amphotericin B2005

    • Author(s)
      松森信明
    • Journal Title

      Bioorganic and Medicinal Chemesitry Letters. 15

      Pages: 3565-3567

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Isolation and structure elucidation of a new amphidinol with a truncated polyhydroxyl chain from Amphidinium klebsii.2005

    • Author(s)
      Nagy Morsy
    • Journal Title

      Tetrahedron 61

      Pages: 8606-8610

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Dominant formation of a single-length channel by amphotericin B in dimyristoylphosphatidylcholline membrane evidenced by ^<13>C-^<31>P rotational echo double resonance.2005

    • Author(s)
      Matsuoka, S., Ikeuchi, H., Matsumori, N., Murata, M.
    • Journal Title

      Biochemistry 44

      Pages: 704-710

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Hairpin conformation of amphidinol possibly accounting for potent membrane permeabilizing activities.2005

    • Author(s)
      Houdai, T., Matsuoka, S., Morsy, N., Matsumori, N., Satake, M., Murata, M.
    • Journal Title

      Tetrahedron 61

      Pages: 2795-2802

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Bioactive fluorinated derivative of amphotericin B.2005

    • Author(s)
      Matsumori, N., Umegawa, Y, Oishi, T., Murata, M.
    • Journal Title

      Bioorg.Med.Chem.Lett. 15

      Pages: 3565-3567

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Mycosamine orientation of amphotericin B controlling interaction with ergosterol : sterol-dependent activity of conformation-restricted derivatives with an amino-carbonyl bridge.2005

    • Author(s)
      Matsumori, N., Sawada, Y., Murata, M.
    • Journal Title

      J.Am.Chem.Soc. 127

      Pages: 10667-10675

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Isolation and structure elucidation of a new amphidinol with a truncated polyhydroxyl chain from Amphidinium klebsii.2005

    • Author(s)
      Morsy, N., Matsuoka, S., Houdai, T., Matsumori, N., Adachi, S., Murata, M., Iwashita, T., Fujita, T.
    • Journal Title

      Tetrahedron. 61

      Pages: 8606-8610

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Dominant formation of a single-length channel by amphotericin B in dimyristoylphosphatidylcholline membrane evidenced by ^<15>C-^<31>P rotational echo double resonance.2005

    • Author(s)
      松岡 茂
    • Journal Title

      Biochemistry 44

      Pages: 704-710

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Hairpin conformation of amphidinol possibly accounting for patent membrane permeabilizing activities.2005

    • Author(s)
      蓬台俊宏
    • Journal Title

      Tetrahedron 61

      Pages: 2795-2802

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

    • Author(s)
      森 めぐみ
    • Journal Title

      Bioorg.Med.Chem. 13

      Pages: 5099-5103

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

    • Author(s)
      松森 信明
    • Journal Title

      Bioorg.Med.Chem.Lett. 15

      Pages: 3565-3567

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Mycosamine orientation of amphotericin B controlling interaction with ergosterol : sterol-dependent activity of conformation-restricted derivatives with an amino-carbonyl bridge.2005

    • Author(s)
      松森 信明
    • Journal Title

      J.Am.Chem.Soc. 127

      Pages: 10667-10675

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Isolation and structure elucidation of a new amphidinol with a truncated polyhydroxyl chain from Amphidinium klebsii.2005

    • Author(s)
      Nagy Morsy
    • Journal Title

      Tetrahedron. 61

      Pages: 8606-8610

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Dominant formation of a single-length channel by amphotericin B in dimyristoylphosphatidylcholline membrane evidenced by ^<13>C-^<31>Protational echo double resonance.2005

    • Author(s)
      Matsuoka, S.
    • Journal Title

      Biochemistry 44

      Pages: 704-710

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Hairpin conformation of amphidinol possibly accounting for potent membrane permeabilizing activities.2005

    • Author(s)
      Houdai, T.
    • Journal Title

      Tetrahedron 61

      Pages: 2795-2802

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Amphotericin B covalent dimers bearing tertarate linkage2004

    • Author(s)
      松森信明
    • Journal Title

      Chemistry and Biodiversity 1

      Pages: 346-352

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 「研究成果報告書概要(和文)」より2004

    • Author(s)
      松森信明
    • Journal Title

      Chemistry and Biology 11

      Pages: 673-679

    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Membrane permeabilizing activities of amphidinol 3, polyene-polyhydroxy antifungal from marine dinoflagellate2004

    • Author(s)
      蓮台俊宏
    • Journal Title

      Biochimica et Biophysica Acta 1667

      Pages: 91-100

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Amphotericin B covalent dimers bearing tartrate linkage2004

    • Author(s)
      Matsumori, N., Masuda, R., Murata, M.
    • Journal Title

      Chem.Biodiver. 1

      Pages: 346-352

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] An Amphotericin B-ergosterol covalent conjugate with powerful membrane permeabilizing activity.2004

    • Author(s)
      Matsumori, N., Eiraku, N., Matsuoka, S., Oishi, T., Murata, M., Aoki, T., Ide, T.
    • Journal Title

      Chem.Biol. 11

      Pages: 673-679

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Membrane permeabilizing activities of amphidinol 3,polyene-polyhydroxy antifungal from marine dinoflagellate.2004

    • Author(s)
      Houdai, T., Matsuoka, S., Matsumori, N., Murata, M
    • Journal Title

      Biochim.Biophys.Acta. 1667

      Pages: 91-100

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Synthesis and identification of an endogenous sperm activating and attracting factor isolated from the ascidian Ciona Intestinals ; an example of nanomolar-level structure elucidation of novel natural compound2004

    • Author(s)
      Oishi, T.
    • 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 biomolecules2004

    • Author(s)
      Maruyoshi, K.
    • Journal Title

      Tetrahedron 60

      Pages: 5163-5170

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Intact glycation end products containing carboxylmethyl-lysine and glyoxal lysine dimerobtained from synthetic collagen model peptide2004

    • Author(s)
      Yamada, H.
    • Journal Title

      Bloor.Med.Chem.Lett. 14

      Pages: 5677-5680

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Membrane permeabilizing activities of amphidinol 3, polyene-polyhydroxy antifungal from marine dinoflagellate2004

    • Author(s)
      Houdai, T.
    • Journal Title

      Biochim.Biophys.Acta. 1667

      Pages: 91-100

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Membrane permeabilizing activity of amphotericin B is affected by chain length of phosphatidylcholine added as minor constituent.2003

    • Author(s)
      松岡 茂
    • Journal Title

      Biochimica et Biophysica Acta 1617

      Pages: 109-115

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Amphotericin of B-phospholipid covalent conjugates : dependence of membrane- permeabilizing activitiy on acyl-chain length.2003

    • Author(s)
      松岡 茂
    • Journal Title

      Orgic and Biomolecular Chemistry 1

      Pages: 3882-3884

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 生物現象鍵物質の微量構造決定2003

    • Author(s)
      村田道雄
    • Journal Title

      化学と生物 41

      Pages: 114-117

    • NAID

      10012133104

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] NMRの技術進歩と海洋天然物2003

    • Author(s)
      村田道雄
    • Journal Title

      先端化学シリーズ 5

      Pages: 50-54

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Membrane permeabilizing activity of amphotericin B is affected by chain length of phosphatidylcholine added as minor constituent.2003

    • Author(s)
      Matsuoka, S., Murata, M.
    • Journal Title

      Biochim.Biophys.Acta 1617

      Pages: 109-115

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Amphotericin B-phospholipid covalent conjugates : dependence of membrane- permeabilizing activitiy on acyl-chain length.2003

    • Author(s)
      Matsuoka, S., Matsumori, N., Murata, M.
    • Journal Title

      Org.Biomol.Chem. 1

      Pages: 3882-3884

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Structure determination of bioactive key compounds with a small sample amount2003

    • Author(s)
      Murata, M.
    • Journal Title

      Kagaku to Seibutsu 41

      Pages: 114-117

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Technical advances in NMR and marine natural products2003

    • Author(s)
      Murata, M.
    • Journal Title

      Frontier Chemistry Series 5

      Pages: 5-54

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Publications] 大石 徹: "Synthesis of endogenous sperm-activating and attracting factor isolated from ascidian Ciona intestinalis"Tetrahedron Lett.. 44. 6387-6389 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 泉川 美穂: "Coning of modular type I polyketide synthase genes from Salinomycin producing strain of Streptomyces albus"Bioorg.Med.Chem.. 11. 3401-3405 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 松岡 茂: "Membrane permeabilizing activity of amphotericin B is affected by chain length of phosphatidylcholine added as minor constituent"Biophys.Biochim.Acta.. 1617. 109-115 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 松岡 茂: "Amphotericin B-phospholipid covalent conjugates : dependence of membrane- permeabilizing activity on acyl-chain length"Org.Biomol.Chem.. 1. 3882-3884 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 松森 信明: "Amphotericin B covalent dimers bearing tertrate linkage"Chem.Biodiver.. (印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 松森 信明: "Amphotericin B-ergosterol conjugate exceeding its cholesterol homologue in membrane permeabilizing activity"Chem.Biol.. (印刷中). (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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