2002 Fiscal Year Annual Research Report

プロテインホスファターゼとその特異的阻害剤の化学生物学的研究

Research Project

Project/Area Number	12045268
Research Institution	The Institute of Physical and Chemical Research
Principal Investigator	長田裕之理化学研究所, 抗生物質研究室, 主任研究員 (80160836)
Co-Investigator(Kenkyū-buntansha)	町田清隆理化学研究所, 抗生物質研究室, 基礎科学特別研究員 (30332266) 清水史郎理化学研究所, 抗生物質研究室, 研究員 (30312268) 掛谷秀昭理化学研究所, 抗生物質研究室, 研究員 (00270596) 関山恭代理化学研究所, 抗生物質研究室, 基礎科学特別研究員 (60342804)
Keywords	phoslactomycin / ホスファターゼ / 阻害剤 / 生合成系 / アポトーシス / Bcl-2 / リン酸化
Research Abstract	我々はこれまでに、phoslactomycin(PLM)類がセリンスレオニンホスファターゼ(PP2A)選択的阻害剤であることを明らかにした。本年度は、放線菌におけるPLM類の生合成系(特にポリケチドのスターターユニットの同定)を解明し、さらにPLMの細胞生物学への応用を図った。 1.PLM類の生合成系解明:[2-^<13>C]シキミ酸、[7-^<13>C]シクロヘキサンカルボン酸、[7-^<13>C]-3-ヒドロキシシクロヘキサンカルボン酸のシス体およびトランス体を合成し、放線菌への取り込み実験を行った。その結果、PLM類はシクロヘキサンカルボン酸をスターターとして生合成され、18位水酸基は生合成の後期(例えばPLM-Bが生成した後)に導入されることが示唆された。 2.PLMを用いたアポトーシス研究:膜貫通領域欠損型Bcl-2(Bcl-2ΔTM)は野生型Bcl-2と異なり恒常的にERKによりリン酸化されていることを明らかにした。すなわち、ミトコンドリア外膜に存在する野生型Bcl-2はERKと結合しており、その結合量は細胞質に局在するBcl-2ΔTMと同量であるが、Bcl-2ΔTMのみ恒常的にリン酸化されていることから、PLMなど各種ホスファターゼ阻害剤を用いて、このホスファターゼがPP2Aであることを明らかにした。さらに、野生型Bcl-2はBcl-2ΔTMに比べてPP2Aとの結合量が多いことを明らかにした。

Research Products
(24 results)

All Other

All Publications (24 results)

[Publications] C.B.Cui, et al.: "A new polyphenolic compound from Rubus aleaefolius and its inhibitory activity on mammalian cell cycle at G0/G1 phase"Chinese Chem. Lett.. 13. 327-330 (2002)
[Publications] H.Kakeya, et al.: "Epoxyquinol A, a highly functionalized pentaketide dimer with antiangiogenic activity isolated from fungal metabolites"J. Am. Chem. Soc.. 124. 3496-3497 (2002)
[Publications] Y.Hayashi, et al.: "Asymmetric total synthesis of (-)-azaspirene, a novel angiogenesis inhibitor"J. Am. Chem. Soc.. 124. 12078-12079 (2002)
[Publications] Y.Asami, et al.: "Azaspirene : a novel angiogenesis inhibitor containing a 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skeleton produced by a fungi Neosartorya sp."Organic Lett.. 4. 2845-2848 (2002)
[Publications] Y.Miyamoto, et al.: "Identification of Saccharomyces cerevisiae isoleucyl-tRNA synthetase as target of G1-specific inhibitor reveromycin A"J. Biol. Chem.. 277. 28810-28814 (2002)
[Publications] K.Machida, et al.: "A novel adenine nucleotide translocase inhibitor, MT-21, induces cytochrome c release by a mitochondrial permeability transition-independent mechanism"J. Biol. Chem.. 277. 31243-31248 (2002)
[Publications] N.Takahashi-Ando, et al.: "A novel lactonohydrolase responsible for the detoxification of zealalenone. -Enzyme purification and gene cloning"Biochem. J.. 365. 1-6 (2002)
[Publications] K.Ueda, et al.: "4-Isoavenaciolide covalently binds and inhibits VHR, a dual-specificity phosphatase"FEBS Lett.. 525. 48-52 (2002)
[Publications] M.Shoji, et al.: "Total synthesis of (+)-epoxyquinols A and B"Angew. Chem. Int. Ed.. 41. 3192-3194 (2002)
[Publications] Y.Takanami-Ohnishi, et al.: "Essential role of p38 mitogen-activated protein kinase in contact hypersensitivity"J. Biol. Chem.. 277. 37896-37903 (2002)
[Publications] H.Kakeya, et al.: "Epoxyquinol B, a fungal metabolite with a potent antiangiogenic activity"J. Antibiot.. 55. 829-831 (2002)
[Publications] Y.Tanaka, et al.: "Reveromycin A inhibits antigen receptor-mediated antigen presentation by B lymphoma cells via its effect on intracellular trafficking of the antigen"J. Antibiot.. 55. 904-913 (2002)
[Publications] T.Sudo, et al.: "Stress meets development in p38 MAP kinase"Molecular anatomy of cellular systems. 22. 3-11 (2002)
[Publications] T.Shimizu, et al.: "Chemical modification of reveromycin A and its biological activities"Bioorg. Med. Chem. Lett.. 12. 3363-3366 (2002)
[Publications] J.K.Prasain, et al.: "Rapid screening and identification of cytochalasins by electrospray tandem mass spectrometry"J. Mass Spectrom.. 37. 283-291 (2002)
[Publications] H.Kakeya, et al.: "Biotransformation of the mycotoxin zearalenone to a non-estrogenic compound by a fungal strain Clonostachys sp."Biosci. Biotechnol. Biochem.. 66. 2723-2726 (2002)
[Publications] M.S.Lee et al.: "Inhibition of VHR Dual-Specificity Protein Tyrosine Phosphatase Activity by Flavonoids Isolated from Scutellaria baicalensis : Structure-Activity Relationships"Planta Med.. 68. 1063-1065 (2002)
[Publications] A.Matsuyama, et al.: "In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation"EMBO J.. 21. 1-12 (2002)
[Publications] P.R.Sebahar, et al.: "Asymmetric, stereocontrolled total synthesis of (+) and (-) -spirotryprostatin B via a diastereoselective azomethine ylide[1,3]-dipolar cycloaddition reaction"Tetrahedron. 58. 6311-6322 (2002)
[Publications] M.Shoji, et al.: "A practical total synthesis of both enantiomers of epoxyquinols A and B"Tetrahedron Lett.. 43. 9155-9158 (2002)
[Publications] S.Sirirath, et al.: "Bitungolides A-F, New Polyketides from the Indonesian Sponge Theonella cf. Swinhoei"J. Nat. Prod.. 65. 1820-1823 (2002)
[Publications] 掛谷秀昭他: "がん征圧と化学-最新抗がん剤事情"化学と工業. 55. 555-559 (2002)
[Publications] 長田裕之: "微生物からの贈り物・バイオプローブ"ファルマシア. 39. 44-48 (2003)
[Publications] T.Sudo, et al.: "Molecular anatomy of cellular systems (Ed. I. Endo et al.)"Elsevier. 231 (2002)

2002 Fiscal Year Annual Research Report

プロテインホスファターゼとその特異的阻害剤の化学生物学的研究

Principal Investigator

長田 裕之 理化学研究所, 抗生物質研究室, 主任研究員 (80160836)

Research Products

[Publications] C.B.Cui, et al.: "A new polyphenolic compound from Rubus aleaefolius and its inhibitory activity on mammalian cell cycle at G0/G1 phase"Chinese Chem. Lett.. 13. 327-330 (2002)

[Publications] H.Kakeya, et al.: "Epoxyquinol A, a highly functionalized pentaketide dimer with antiangiogenic activity isolated from fungal metabolites"J. Am. Chem. Soc.. 124. 3496-3497 (2002)

[Publications] Y.Hayashi, et al.: "Asymmetric total synthesis of (-)-azaspirene, a novel angiogenesis inhibitor"J. Am. Chem. Soc.. 124. 12078-12079 (2002)

[Publications] Y.Asami, et al.: "Azaspirene : a novel angiogenesis inhibitor containing a 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skeleton produced by a fungi Neosartorya sp."Organic Lett.. 4. 2845-2848 (2002)

[Publications] Y.Miyamoto, et al.: "Identification of Saccharomyces cerevisiae isoleucyl-tRNA synthetase as target of G1-specific inhibitor reveromycin A"J. Biol. Chem.. 277. 28810-28814 (2002)

[Publications] K.Machida, et al.: "A novel adenine nucleotide translocase inhibitor, MT-21, induces cytochrome c release by a mitochondrial permeability transition-independent mechanism"J. Biol. Chem.. 277. 31243-31248 (2002)

[Publications] N.Takahashi-Ando, et al.: "A novel lactonohydrolase responsible for the detoxification of zealalenone. -Enzyme purification and gene cloning"Biochem. J.. 365. 1-6 (2002)

[Publications] K.Ueda, et al.: "4-Isoavenaciolide covalently binds and inhibits VHR, a dual-specificity phosphatase"FEBS Lett.. 525. 48-52 (2002)

[Publications] M.Shoji, et al.: "Total synthesis of (+)-epoxyquinols A and B"Angew. Chem. Int. Ed.. 41. 3192-3194 (2002)

[Publications] Y.Takanami-Ohnishi, et al.: "Essential role of p38 mitogen-activated protein kinase in contact hypersensitivity"J. Biol. Chem.. 277. 37896-37903 (2002)

[Publications] H.Kakeya, et al.: "Epoxyquinol B, a fungal metabolite with a potent antiangiogenic activity"J. Antibiot.. 55. 829-831 (2002)

[Publications] Y.Tanaka, et al.: "Reveromycin A inhibits antigen receptor-mediated antigen presentation by B lymphoma cells via its effect on intracellular trafficking of the antigen"J. Antibiot.. 55. 904-913 (2002)

[Publications] T.Sudo, et al.: "Stress meets development in p38 MAP kinase"Molecular anatomy of cellular systems. 22. 3-11 (2002)

[Publications] T.Shimizu, et al.: "Chemical modification of reveromycin A and its biological activities"Bioorg. Med. Chem. Lett.. 12. 3363-3366 (2002)

[Publications] J.K.Prasain, et al.: "Rapid screening and identification of cytochalasins by electrospray tandem mass spectrometry"J. Mass Spectrom.. 37. 283-291 (2002)

[Publications] H.Kakeya, et al.: "Biotransformation of the mycotoxin zearalenone to a non-estrogenic compound by a fungal strain Clonostachys sp."Biosci. Biotechnol. Biochem.. 66. 2723-2726 (2002)

[Publications] M.S.Lee et al.: "Inhibition of VHR Dual-Specificity Protein Tyrosine Phosphatase Activity by Flavonoids Isolated from Scutellaria baicalensis : Structure-Activity Relationships"Planta Med.. 68. 1063-1065 (2002)

[Publications] A.Matsuyama, et al.: "In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation"EMBO J.. 21. 1-12 (2002)

[Publications] P.R.Sebahar, et al.: "Asymmetric, stereocontrolled total synthesis of (+) and (-) -spirotryprostatin B via a diastereoselective azomethine ylide[1,3]-dipolar cycloaddition reaction"Tetrahedron. 58. 6311-6322 (2002)

[Publications] M.Shoji, et al.: "A practical total synthesis of both enantiomers of epoxyquinols A and B"Tetrahedron Lett.. 43. 9155-9158 (2002)

[Publications] S.Sirirath, et al.: "Bitungolides A-F, New Polyketides from the Indonesian Sponge Theonella cf. Swinhoei"J. Nat. Prod.. 65. 1820-1823 (2002)

[Publications] 掛谷 秀昭 他: "がん征圧と化学-最新抗がん剤事情"化学と工業. 55. 555-559 (2002)

[Publications] 長田 裕之: "微生物からの贈り物・バイオプローブ"ファルマシア. 39. 44-48 (2003)

[Publications] T.Sudo, et al.: "Molecular anatomy of cellular systems (Ed. I. Endo et al.)"Elsevier. 231 (2002)

長田裕之理化学研究所, 抗生物質研究室, 主任研究員 (80160836)

[Publications] 掛谷秀昭他: "がん征圧と化学-最新抗がん剤事情"化学と工業. 55. 555-559 (2002)

[Publications] 長田裕之: "微生物からの贈り物・バイオプローブ"ファルマシア. 39. 44-48 (2003)