脂質代謝を制御する機能分子プローブの創製

• Project/Area Number: 16073215
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: Kitasato University
• Principal Investigator: 供田 洋 Kitasato University, 薬学部, 教授 (70164043)
• Co-Investigator(Kenkyū-buntansha): 猪腰 淳嗣 北里大学, 薬学部, 准教授 (30151640) ; 小山 信裕 北里大学, 薬学部, 助教 (60439156)
• Project Period (FY): 2004 – 2008
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥28,300,000 (Direct Cost: ¥28,300,000); Fiscal Year 2007: ¥8,000,000 (Direct Cost: ¥8,000,000); Fiscal Year 2006: ¥8,000,000 (Direct Cost: ¥8,000,000); Fiscal Year 2005: ¥8,200,000 (Direct Cost: ¥8,200,000); Fiscal Year 2004: ¥4,100,000 (Direct Cost: ¥4,100,000)
• Keywords: 脂質代謝 / 阻害剤 / 微生物由来機能分子 / 感染症 / 医療・福祉 / コレステロール / 中性脂肪 / トリグリセリド / 循環器・高血圧 / 医療福祉

Research Abstract

・新規プローブの探索研究では、脂質代謝に関する様々な評価系として、1)マクロファージ脂肪滴蓄積阻害を評価する系、2)ジアシルグリセロール転移酵素(DGAT)を評価する系や3)細菌の細胞壁合成に重要なウンデカプレニルピロフォスフェート合成酵素(UPPS)阻害を評価する系について重点的に行った。その結果、以下の真菌由来の3種6成分の新規化合物を発見した。1)からは、インドール環とキナソリン環が架橋したquinadoline類AとBを発見した。2)からは、ジヒドロナフトピラノン環が二量体を形成したdinapinone A とBの立体異性体を発見し、これらの混合比により活性が大幅に変化することを明らかとした。3)からは、スピロを介した5員環をもつspirohexaline類 AとBを発見し、立体化学の解析から、A成分が既知のviridicatumtoxinのエナンチオマーであることを証明した。この他に今期、新規評価系として、ヒト由来のDGAT1あるいはDGAT2を導入した酵母を利用したアッセイ系を構築した。
・プローブの作成と作用メカニズム研究では、脂肪滴形成阻害剤beauveriolideのビオチン標識体による解析から、ミクロソーム画分中に結合タンパク質を数種見出した。その一つは、ACAT抗体による解析から、本標的分子と推定しているACATであることが明らかとなってきた。他のタンパク質については、MALDI-TOF-MSなどにより同定を行なう。さらに、ACAT2に選択的な阻害剤pyripyropene A に関しては、ACAT2の一部領域をACAT1の類似領域へと置換したキメラタンパク質を作製することで、あるモチーフ(492〜494番目のアミノ酸残基QVS)が本化合物のACAT2選択的阻害に重要な役割を果たしていることを明らかにした。

Research Products

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• [Journal Article] Selectivity of microbial acyl-CoA : cholesterol acyltransferase inhibitors toward ACAT isozymes. (2007)
  • Author(s): T.Ohshiro et al.
  • Journal Title: J. Antibiot. 60 (1) Pages: 43-51
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  • Author(s): N.Koyama et al.
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  • Journal Title: J. Antibiot. 59 (2) Pages: 93-97
• [Journal Article] Molecular target of decursins in the inhibition of lipid droplet accumulation in macrophages. (2006)
  • Author(s): T.Ohshiro et al.
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• [Journal Article] Biosynthesis of sespendole. (2006)
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• [Journal Article] Structure elucidation of fungal sespendole, an inhibitor of lipid droplet synthesis in macrophage. (2006)
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• [Journal Article] Sespendole, a new inhibitor of lipid droplet formation in macrophage, preduced by Pseudobotrytis terrestris FKA-25. (2006)
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• [Journal Article] Molecular target of decursins in the inhibition of lipid droplet accumulation in macrophages. (2006)
  • Author(s): Ohshiro, T. et al.
  • Journal Title: Biol.Pharm.Bull. (in press)
• [Journal Article] Phenatic acids A and B, new potentiators of antifungal miconazole activity produced by Streptomycesa sp.K03-0132. (2005)
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• [Journal Article] Citridones, new potentiators of antifungal miconazole activity, produced by Penicilliuma sp.FKI-1938. I.Taxonomy, fermentation, isolation and biological properties. (2005)
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• [Journal Article] Spylidone, a novel inhibitor of lipid droplet accumulation in mouse macrophages produced by Phoma sp.FKI-1840. (2005)
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• [Journal Article] New sesquicillins, Insecticidal antibiotics produced Albophoma sp.FKI-1778. (2005)
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• [Journal Article] New insecticidal antibiotics, hydroxyfungerins A and B, Produced by Metarhizium sp.FKI-1079. (2005)
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• [Journal Article] Yaequinolones J1 and J2, novel insecticidal antibiotics from Penicillium sp.FKI-2140. (2005)
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• [Journal Article] 創薬を目指した微生物由来脂質代謝阻害剤 (2005)
  • Author(s): 供田 洋
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  • NAID: 10015464855
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• [Journal Article] Antiatherogenic activity of fungal beauveriolides, inhibitors of lipid droplet accumulation in macrophages. (2004)
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• [Journal Article] Identification of ACATI and ACAT2 specific inhibitors with novel, whole cell-based assay. (2004)
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• [Journal Article] Binding site for fungal β-lactone hymeglusin on cytosolic 3-hydroxy-3-methylglutaryl coenzyme A synthase. (2004)
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• [Journal Article] ACAT 2 is localized to hepatocytes and is the major cholesterol-esterifying enzyme in human liver. (2004)
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  • Journal Title: Circulation 110 Pages: 2017-2023
• [Journal Article] Use of a chiral praseodymium shift reagent in predicting the complete stereostructure of glisoprenin A. (2004)
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  • Journal Title: Org.Lett. 6 Pages: 4719-4722
• [Journal Article] Taxonomy and secondary metabolites of fungal strain FKA-25. (2004)
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  • Journal Title: Mycoscience 45 Pages: 9-16
• [Journal Article] New beauvericins, potentiators of antifungal miconazole activity, produced by Beauveria sp.FKI-1366.I.Taxonomy, fermentation, isolation and biological properties. (2004)
  • Author(s): Fukuda, T. et al.
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• [Journal Article] New beauvericins.potentiators of antifungal miconazole activity, produced by Beauveria sp.FKI-1366.II.Structure elucidation. (2004)
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• [Journal Article] Total syntheses of (+)-chloropuupehenone and (+)-chloropuupehenol, and their analogs and evaluation of their bioactivities. (2004)
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• [Journal Article] Epohelmins A an B, novel lanosterol synthase inhibitors from a fungal strain FKI-0929. (2004)
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• [Journal Article] 中性脂質合成酵素とそれを制御する微生物由来低分子化合物 (2004)
  • Author(s): 供田 洋
  • Journal Title: ファルマシア 40 Pages: 714-718
• [Presentation] 黒胡椒成分piperineによるマクロファージ内脂肪滴蓄積阻害作用 (2008)
  • Author(s): 松田 大介, ら
  • Organizer: 日本薬学会
  • Place of Presentation: 横浜
• [Presentation] ACC1阻害剤による脂肪的蓄積阻害活性 (2008)
  • Author(s): 小林 翔, ら
  • Organizer: 日本薬学会
  • Place of Presentation: 横浜
• [Presentation] カイコを利用した感染簡易in VIVO 評価による抗真菌剤探索研究 (2008)
  • Author(s): 山口 史哲, ら
  • Organizer: 日本薬学会
  • Place of Presentation: 横浜
• [Presentation] Stemphone誘導体の生物活性研究(1) MRSAに対するイミペネム活性増強 (2008)
  • Author(s): 山崎 寛之, ら
  • Organizer: 日本薬学会
  • Place of Presentation: 横浜
• [Presentation] Stemphone誘導体の生物活性研究(2)マクロファージ脂肪油蓄積阻害活性 (2008)
  • Author(s): 小山 信裕, ら
  • Organizer: 日本薬学会
  • Place of Presentation: 横浜
• [Presentation] Sphingofungin類による amphotericin B の抗真菌活性増強作用に関する研究 (2008)
  • Author(s): 坂部 泰成, ら
  • Organizer: 日本薬学会
  • Place of Presentation: 横浜
• [Presentation] 真菌 FHI-3864 株の生産する新規トジアシルグリセロール生成阻書物に関する研究 (2008)
  • Author(s): 大手 聡, ら
  • Organizer: 日本薬学会
  • Place of Presentation: 横浜
• [Presentation] 真菌 FHエー3864 株の生産する undecaprenyl pyrophosphate synthase 阻害物質に関する研究 (2008)
  • Author(s): 中村 雄一郎, ら
  • Organizer: 日本薬学会
  • Place of Presentation: 横浜
• [Presentation] 真菌 FKI-1746株が生産する新規マクロファージ脂肪滴蓄積阻害物質の研究 (2008)
  • Author(s): 井上 勇佑, ら
  • Organizer: 日本薬学会
  • Place of Presentation: 横浜
• [Presentation] F0-2942株の生産する新しいamidepsine成分に関する研究 (2008)
  • Author(s): 高木 陽一, ら
  • Organizer: 日本薬学会
  • Place of Presentation: 横浜
• [Presentation] β-ラクタム剤の抗MRSA活性増強作用を示す新規KB-3346-5物質の単離、および活性 (2008)
  • Author(s): 福本 敦, ら
  • Organizer: 日本薬学会
  • Place of Presentation: 横浜
• [Presentation] 海洋由来脂質代謝阻害剤を用いたケミカルバイオロジー (2007)
  • Author(s): 松田 大介、 供田 洋
  • Organizer: 第10回マリンバイオテクノロジー学会
  • Place of Presentation: 仙台
• [Presentation] Selectivity of pyripyropene derivatives, ACAT inhibitors, toward the ACAT2 isozyme (2007)
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  • Organizer: SIM Annual Meeting & Exhibition
  • Place of Presentation: Denver
• [Presentation] Bioactive products from marine-derived microorgamsm as probes in chemical biology (2007)
  • Author(s): Tomoda, H. & Matsuda, D.
  • Organizer: VI^<TM> us-Japan seminar: frontiers in marine naturalproducts research
  • Place of Presentation: Park city, Utah
• [Patent(Industrial Property Rights)] 新規FKI・1746-1およびFKI-1746・2物質並びにそれらの製造方法 (2008)
  • Inventor(s): 供田 洋, 小山信裕, 増間碌郎, 大村智
  • Industrial Property Rights Holder: 北里学園
  • Filing Date: 2008-02-05
• [Patent(Industrial Property Rights)] 新規FKI-3864物質およびその製造方法 (2008)
  • Inventor(s): 供田 洋, 内田龍児, 増間碌郎, 大村智
  • Industrial Property Rights Holder: 北里学園
  • Filing Date: 2008-02-13
• [Patent(Industrial Property Rights)] 新規FKI・3368物質およびその製造方法 (2007)
  • Inventor(s): 供田 洋, 猪腰淳嗣, 増間縁郎, 大村智
  • Industrial Property Rights Holder: 北里学園
  • Filing Date: 2007-09-14
• [Patent(Industrial Property Rights)] 新規FKI-1840物質及びその製造法 (2004)
  • Inventor(s): 供田洋, 増間碌郎, 大村智
  • Industrial Property Rights Holder: 社団法人北里研究所
  • Filing Date: 2004-01-12
• [Patent(Industrial Property Rights)] FKI-1938瀕およびその製造法 (2004)
  • Inventor(s): 供田洋, 増間碌郎, 大村智
  • Industrial Property Rights Holder: 社団法人北里研究所
  • Filing Date: 2004-10-28
• [Patent(Industrial Property Rights)] 新規K03-0132物質およびその製造法 (2004)
  • Inventor(s): 供田洋, 高橋洋子, 大村智
  • Industrial Property Rights Holder: 社団法人北里研究所
  • Filing Date: 2004-12-22