原虫感染における含硫アミノ酸代謝の役割

2010 Fiscal Year Annual Research Report

• Project Area: Matrix of Infection Phenomena
• Project/Area Number: 18073001
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: 野崎 智義 国立感染症研究所, 寄生動物部, 部長 (60198588)
• Co-Investigator(Kenkyū-buntansha): 佐藤 暖 慶應義塾大学, 政策・メディア研究科, 特任助教 (50468477)
• Keywords: メタボローム / トランスクリプトーム / 感染症 / 含硫アミノ酸 / 赤痢アメーバ

Research Abstract

本研究は、腸管寄生虫赤痢アメーバをモデル原虫として感染における含硫アミノ酸代謝の変化をトランスクリプトーム、プロテオーム、メタボロームを融合させた統合的アプローチを用いて解明することにより、感染・寄生及ひ病原機構における含硫アミノ酸代謝の役割を理解することを目的としている。更にこの目的の達成をもって、長期的には、「感染における含硫アミノ酸代謝」という新たな代謝学の一分野を創造することを目標としている。本年度は、感染伝播に不可欠である細胞分化(嚢子化)過程のメタボローム・トランスクリプトーム解析をヘビの腸に寄生し、赤痢アメーバと同様の病態を示すEntamoebainvadensを用いて行った。キャピラリー電気泳動飛行時間計測型質量分析計によるメタボローム解析により、解糖経路の代謝活性が全般的に抑制され、解糖経路の代謝産物が嚢子壁の主要構成成分であるキチンの生合成に振り向けられることが明らかとなった。更に、これまで存在しないと考えられていたポリアミン代謝経路における代謝中間産物などが発見され、赤痢アメーバにおける新しい創薬標的が提供された,また、更に、含硫アミノ酸代謝の主要酵素であるシステイン合成酵素、セリンアセチル転移酵素の発現抑制体を作成し、増殖、分化、寄生適応能力、病原性などにおける役割を検証したところ、システインの枯渇下での増殖が抑圧されることが示され、本経路の生理的重要性が確認された。

Research Products

• [Journal Article] Global Analysis of gene expression in response to L-cysteine deprivation in the anaerobic protozoan parasite Entamoeba histolytica (2011)
  • Author(s): Husain, A., Jeelani, G., Sato, D., Nozaki, T.
  • Journal Title: BMC Genomics Volume: 12 Pages: 275
  • Peer Reviewed
• [Journal Article] Mechanism of trifluoromethionine resistance in Entamoeba histolytica (2011)
  • Author(s): Penuliar, G.M., Furukawa, A., Sato, D., Nozaki, T.
  • Journal Title: J.Antimicrob.Chemother. Volume: 66 Pages: 2045-2052
  • Peer Reviewed
• [Journal Article] Cytotoxic effect of amide derivatives of trifluoromethionine to the enteric protozoan parasite Entamoeba histolytica (2010)
  • Author(s): Sato., D., Kobayashi, S., Yasui, H., Shibata, N., Toru, T., Yamamoto, M., Tokoro, G., Ali, V., Soga, T., Takeuchi, T., Suematsu, M., Nozaki, T.
  • Journal Title: Int.J.Antimicrob.Agents. Volume: 35 Pages: 56-61
  • Peer Reviewed
• [Journal Article] (2010) Bacterial-type oxygen detoxification and iron-sulphur cluster assembly in amoebal relict mitochondria (2010)
  • Author(s): Maralikova, B., Ali, V., Nakada-Tsukui, K., Nozaki, T., van der Giezen, M., Henze, K., Tovar, J.
  • Journal Title: Cell.Microbiol. Volume: 12 Pages: 331-342
  • Peer Reviewed
• [Journal Article] Characterization of two isotypes of L-threonine dehydratase from Entamoeba histolytica (2010)
  • Author(s): Husain, A., Jeelani, G., Sato, D., Ali, V., Nozaki, T.
  • Journal Title: Mol.Biochem.Parasitol. Volume: 170 Pages: 100-104
  • Peer Reviewed
• [Journal Article] Localization and targeting of unusual pyridine nucleotide transhydrogenase in Entamoeba histolytica (2010)
  • Author(s): Yousuf, M.A., Mi-ichi, F., Nakada-Tsukui, K., Nozaki, T.
  • Journal Title: Eukaryot.Cell Volume: 9 Pages: 926-933
  • Peer Reviewed
• [Journal Article] Conservation and function of Rab small GTPases in Entamoeba : annotation of E.invadens Rab and its use for the understanding of Entamoeba biology (2010)
  • Author(s): Nakada-Tsukui, K., Saito-Nakano, Y., Husain, A., Nozaki, T.
  • Journal Title: Exp.Parasitol. Volume: 126(Review) Pages: 337-347
  • Peer Reviewed
• [Journal Article] Two Atypical L-cysteine-regulated NADPH-dependent oxidoreductases involved in redox maintenance, L-cystine reduction, and metronidazole activation in the enteric protozoon Entamoeba histolytica (2010)
  • Author(s): Jeelani, G., Husain, A., Sato, D., Ali, V., Suematsue, M., Soga, T., Nozaki, T.
  • Journal Title: J.Biol.Chem. Volume: 285 Pages: 26889-26899
  • Peer Reviewed
• [Journal Article] Metabolome analysis revealed increase in S-methylcysteine and phosphatidylisopropanolamine synthesis upon L-cysteine deprivation in the anaerobic protozoan parasite Entamoeba histolytica (2010)
  • Author(s): Husain, A., Sato, D., Jeelani, G., Suematsu, M., Soga, T., Nozaki, T.
  • Journal Title: J.Biol.Chetn. Volume: 285 Pages: 39160-39170
  • Peer Reviewed
• [Journal Article] Sulfate activation in mitosomes plays a crucial role in the proliferation of Entamoeba histolytica (2010)
  • Author(s): Mi-ichi, F., Makiuchi, T., Furukawa, A., Sato, D., Nozaki, T.
  • Journal Title: PLoS Negl.Trop.Dis. Volume: 5 Pages: e1263
  • Peer Reviewed
• [Presentation] Function and transport of the highly divergent mitochondrion-related organelle from the anaerobic parasitic protist Entamoeba histolytica (2011)
  • Author(s): Nozaki, T.
  • Organizer: The 1st As i an Conference of Prosistology
  • Place of Presentation: Jeju, Korea
  • Year and Date: 20111003-20111006
• [Presentation] A novel class of hydrolase receptors involved in the lysosomal trafficking of virulence factors in Entamoeba histolytica (2011)
  • Author(s): Nozaki, T., Nakada-Tsukui, K., Furukawa, A.
  • Organizer: The 1st Asian Conference of Prosistology
  • Place of Presentation: Jeju, Korea
  • Year and Date: 20111003-20111006
• [Presentation] A novel import machinery of the highly divergent mitochondrion-related organelle from the anaerobic parasitic protist Entamoeba histolytica (2011)
  • Author(s): Nozaki, T.
  • Organizer: International Union of Microbiological Societies
  • Place of Presentation: Sapporo, Japan
  • Year and Date: 20110908-20110910
• [Presentation] Novel receptor family proteins mediate transport of lysosomal enzymes in the enteric protozoan parasite Entamoeba histolytica (2011)
  • Author(s): Nakada-Tsukui, K., Tsuboi, K., Furukawa, A., Yamada, Y., Nozaki, T.
  • Organizer: International Union of Microbiological Societies
  • Place of Presentation: Sapporo, Japan
  • Year and Date: 20110908-20110910
• [Presentation] Metabolomic analysis during differentiation of enteric protozoan Parasite Entamoeba histolytica into the infectious cyst stage (2011)
  • Author(s): Jeelani, G., Sato, D., Husein, A., Suematsu, M., Soga, T., Nozaki, T.
  • Organizer: The 45^<th> US-Japan Cooperative Medical Science Program
  • Place of Presentation: Tokyo
  • Year and Date: 20110110-20110112
• [Presentation] Gene silencing of mitosomal proteins causes growth inhibition and suggests essentiality of mitosomes in Entamoeba histolytica (2011)
  • Author(s): Mi-ichi, F, Yousuf, A., Makiuchi, T., Nakada-Tsukui, K., Nozaki, T.
  • Organizer: The 45^<th> US-Japan Cooperative Medical Science Program
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 20110110-20110112
• [Presentation] Metabolomic analysis of sulfur containing amino acid metabolism in E.histolytica (2011)
  • Author(s): Husain, A., Sato, D., Jeelani, G., Mi-ichi, F., Ali, V., Suematsu, M., Soga, T., Nozaki, T.
  • Organizer: The 45^<th> US-Japan Cooperative Medical Science Program
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 20110110-20110112
• [Presentation] Analysis of the protein import machinery in the Entamoeba mitochondrial remnant (2011)
  • Author(s): Makiuchi, T., Mi-ichi, F., Nakada-Tsukui, K., Nozaki, T.
  • Organizer: The 45^<th> US-Japan Cooperative Medical Science Program
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 20110110-20110112
• [Presentation] Metabolomic analysis of Entamoeba : discovery of unique pathways and potential targets for chemotherapy (2010)
  • Author(s): Nozaki, T, Husain, A., Jeelni, G, Sato, D., Suematsu, M., Soga, T.
  • Organizer: Amebiasis Workshop 2010, "Molecular Approaches and Clinical Aspects"
  • Place of Presentation: Montreal, Canada
  • Year and Date: 20100922-20100924
• [Presentation] Mitosomes from the enteric protozoan parasite Entamoeba histolytica possess unique functions and minimal import machinery (2010)
  • Author(s): Nozaki, T.
  • Organizer: The XIIth International Congeress of Parasitology
  • Place of Presentation: Melbourne Australia
  • Year and Date: 20100815-20100820
• [Presentation] Unprecedented role of the mitosome in Entamoba histolytica (2010)
  • Author(s): Nozaki, T.
  • Organizer: The 18^<th> Meeting of the International Society for Evolutionary Protistology
  • Place of Presentation: Kanazawa, Japan
  • Year and Date: 20100702-20100707
• [Presentation] Metabolic analysis of the human enteric parasite Entamoeba histolytica : Discovery of unique pathways and potential targets for chemotherapeutics (2010)
  • Author(s): Sato, D., Husain, A., Jeelani, G., Suematsu, M., Soga, T., Nozaki, T.
  • Organizer: Metabolomics 2010
  • Place of Presentation: Amsterdam, The Netherlands
  • Year and Date: 20100627-20100701
• [Presentation] Metabolomics of parasite differentiation : metabolomic profiling of the human enteric protozoan parasite Entamoeba histolyitca revealed activation of unpredicted pathways during differentiation of the proliferative into dormant stage (2010)
  • Author(s): Jeelani, G., Sato, D., Jusain, A., Suematsu, M., Soga, T., Nozaki, T.
  • Organizer: Metabolomics 2010
  • Place of Presentation: Amsterdam, The Netherlands
  • Year and Date: 20100627-20100701
• [Remarks]
  • URL: http://www.nih.go.jp/niid/ja/2011-05-26-00-03-52.html