Reaction mechanisms and physiological roles of sulfur-containing amino acids degradation enzyme in pathogenic protozoa.

• Project/Area Number: 20590429
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Parasitology (including Sanitary zoology)
• Research Institution: Keio University
• Principal Investigator: SATO Dan Keio University, 政策・メディア研究科, 助教 (50468477)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 寄生性原虫 / 創薬開発 / 含硫アミノ酸 / 結晶構造解析 / メタボロミクス / 原虫 / アミノ酸代謝

Research Abstract

Amoebiasis is one of the major infectious diseases worldwide. We focus on the sulfur-containing amino acids degradation enzymes, which present exclusively in the pathogen but missing in humans. We investigated the reaction mechanism, the characterization as a drug target, and physiological roles of the enzymes. We successfully elucidated the reaction mechanism at crystal structure level, and demonstrated that how the lead compounds exhibited the toxicity to amoeba. Our research will provide the valuable information on the rational design of novel anti-amoebic drugs.

Research Products

• [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): Afzal Husain, Dan Sato, Ghulam Jeelani, Fumika Mi-ichi, Vahab Ali, Makoto Suematsu, Tomoyoshi Soga, Tomoyoshi Nozaki
  • Journal Title: Journal of Biological Chemistry. 285(50) Pages: 39160-39170
  • Peer Reviewed
• [Journal Article] 赤痢アメーバ原虫に対するトリフルオロメチオニン誘導体の有効性 (2010)
  • Author(s): 佐藤暖・野崎智義
  • Journal Title: ビタミン Vol.84 No.5・6 Pages: 250-254
• [Journal Article] Cytotoxic effect of amide derivatives of S-trifluoromethylhomocysteine to the enteric protozoan parasite Entamoeba histolytica. (2010)
  • Author(s): Dan Sato, Seiki Kobayashi, Hiroyuki Yasui, Norio Shibata, Takeshi Toru, Masaichi Yamamoto, Gensuke Tokoro, Vahab Ali, Tomoyoshi Soga, Tsutomu Takeuchi, Makoto Suematsu, Tomoyoshi Nozaki
  • Journal Title: International Journal of Antimicrobial Agent. 35(1) Pages: 56-61
  • Peer Reviewed
• [Journal Article] Two atypical L-cysteine-regulated NADPH-dependent oxidoreductases involved in redox maintenance, L-cystine and iron reduction, and metronidazole activation in the enteric protozoon Entamoeba histolytica. (2010)
  • Author(s): Ghulam Jeelani, Afzal Husain, Dan Sato, Vahab Ali, Makoto Suematsu, Tomoyoshi Soga, Tomoyoshi Nozaki
  • Journal Title: Journal of Biological Chemistry. 285(35) Pages: 26889-26899
  • Peer Reviewed
• [Journal Article] Characterization of two isotypes of L-threonine dehydratase from Entamoeba histolytica. (2010)
  • Author(s): Afzal Husain, Ghulam Jeelani, Dan Sato, Vahab Ali, Tomoyoshi Nozaki
  • Journal Title: Molecular and Biochemical Parasitology. 170(2) Pages: 100-104
  • Peer Reviewed
• [Journal Article] Metabolome analysis revealed increase in S-methylcysteine and phosphati dylisopropanolamine synthesis upon L-cysteine deprivation in the anaerobic protozoan parasite Entamoeba histolytica. (2010)
  • Author(s): Afzal Husain
  • Journal Title: Journal of Biological Chemistry Volume: 285 Pages: 39160-39170
  • Peer Reviewed
• [Journal Article] Two atypical L-cysteine-regulated NADPH-dependent oxidoreductases involved in redox maintenance, L-cystine and iron reduction, and metronidazole activation in the enteric protozoon Entamoeba histolytica. (2010)
  • Author(s): Ghulam Jeelani
  • Journal Title: Journal of Biological Chemistry Volume: 285 Pages: 26889-26899
  • Peer Reviewed
• [Journal Article] 赤痢アメーバ原虫に対するトリフルオロメチオニン誘導体の有効性 (2010)
  • Author(s): 佐藤暖
  • Journal Title: ビタミン Volume: 84 Pages: 250-254
• [Journal Article] Cytotoxic effects of amide derivatives of S-trifluoromethylhomocysteine to the enteric protozoan parasite Entamoeba histolytica (2010)
  • Author(s): 佐藤暖
  • Journal Title: International Journal of Antimicrobial Agent 35 Pages: 56-61
  • Peer Reviewed
• [Journal Article] 赤痢アメーバ原虫の薬剤標的酵素・メチオニンγリアーゼ-薬剤リード化合物・トリフルオロメチオニンと生理的基質に対する反応性- (2009)
  • Author(s): 佐藤暖・山形渉・原田繁春・野崎智義
  • Journal Title: ビタミン Vol.83 No.5・6 Pages: 292-295
• [Journal Article] Methionine gamma-lyase : the unique reaction mechanism, physiological roles, and therapeutic applications against infectious diseases and cancers. (2009)
  • Author(s): Dan Sato, Tomoyoshi Nozaki
  • Journal Title: IUMBM Life. 61(11) Pages: 1019-1028
  • Peer Reviewed
• [Journal Article] Methionine gamma-lyase : the unique reaction mechanism, physiological roles, and therapeutic applications against infectious diseases and cancers (2009)
  • Author(s): 佐藤暖
  • Journal Title: IUMBM Life 61 Pages: 1019-1028
  • Peer Reviewed
• [Journal Article] 赤痢アメーバ原虫の薬剤標的酵素・メチオニンγリアーゼ -薬剤リード化合物・トリフルオロメチオニンと生理的基質に対する反応性- (2009)
  • Author(s): 佐藤暖
  • Journal Title: ビタミン 83 Pages: 292-295
• [Journal Article] Crystallization and preliminary X-ray analysis of L-methionine gamma-lyase 1 from Entamoeba histolytica. (2008)
  • Author(s): Dan Sato, Tsuyoshi Karaki, Akira Shimizu, Kaeko Kamei, Shigeharu Harada, Tomoyoshi Nozaki
  • Journal Title: Acta Crystallographica Section F. 64(Pt8) Pages: 697-699
  • Peer Reviewed
• [Journal Article] Kinetic characterization of methionine-lyases from the enteric protozoan parasite Entamoeba histolytica against physiological substrates and trifluoromethionine, a promising lead compound against amoebiasis. (2008)
  • Author(s): Dan Sato, Wataru Yamagata, Shigeharu Harada, Tomoyoshi Nozaki
  • Journal Title: FEBS Journal. 275(3) Pages: 548-560
  • Peer Reviewed
• [Journal Article] Crystallization and preliminary X-ray analysis of L-methionine gamma-lyase 1 from Entamoeba histolytica. (2008)
  • Author(s): Dan Sato
  • Journal Title: Acta Crystallographica Section F. 64 Pages: 697-699
  • Peer Reviewed
• [Journal Article] Kinetic characterization of methionine gamma-lyases from the enteric protozoan parasite Entamoeba histolytica against physiological substrates and trifluoromethionine, a promising lead compound against amoebiasis. (2008)
  • Author(s): Dan Sato
  • Journal Title: FEBS Journal. 275 Pages: 548-560
  • Peer Reviewed
• [Presentation] 腸管寄生性原虫赤痢アメーバにおけるL-システイン欠乏条件下でのメタボローム解析 (2010)
  • Author(s): 佐藤暖アフザルフセイン、ジラニグラム、末松誠、曽我朋義、野崎智義
  • Organizer: 第5回メタボロームシンポジウム
  • Place of Presentation: 山形県鶴岡市
• [Presentation] Metabolomic analysis of the human enteric parasite Entamoeba histolytica : Discovery of unique pathways and potential targets for chemotherapeutics. (2010)
  • Author(s): Dan Sato, Afzal Husain, Ghulam Jeelani, Makoto Suematsu, Tomoyoshi Soga, Tomoyoshi Nozaki
  • Organizer: The 6^<th> Metabolomics Society Conference 2010
  • Place of Presentation: Amsterdam, the Netherlands(Amsterdam, the Netherlands)
• [Presentation] Metabolomics of parasite differentiation : metabolomic profiling of the human enteric protozoan parasite Entamoeba histolytica revealed activation of unpredicted pathways during differentiation of the proliferative into dormant stage. (2010)
  • Author(s): Ghulam Jeelani, Dan Sato, Afzal Husain, Makoto Suematsu, Tomoyoshi Soga, Tomoyoshi Nozaki
  • Organizer: The 6^<th> Metabolomics Society Conference 2010
  • Place of Presentation: Amsterdam, the Netherlands(Amsterdam, the Netherlands)
• [Presentation] 赤痢アメーバ原虫のトレオニン脱水酵素の酵素学的解析 (2010)
  • Author(s): 佐藤暖、アフザルフセイン、ジラニグラム、バハブアリ、野崎智義
  • Organizer: 日本ビタミン学会第62回大会
  • Place of Presentation: 岩手県盛岡市
• [Presentation] S-methylcysteine and phosphatidylisopropanolamine biosynthesis under L-cysteine deprived condition in the anaerobic protozoan parasite Entamoeba histolytica (2010)
  • Author(s): 佐藤暖
  • Organizer: BMB2010(第33回日本分子生物学会年会・第83回日本生化学会大会 合同大会)
  • Place of Presentation: 兵庫県神戸市
• [Presentation] 一連の酵素反応中間体との複合体構造に基づいたEntamoeba histolytica由来メチオニンγ-リアーゼ1の酵素反応機構 (2010)
  • Author(s): 村野祥子
  • Organizer: BMB2010(第33回日本分子生物学会年会・第83回日本生化学会大会 合同大会)
  • Place of Presentation: 兵庫県神戸市
• [Presentation] Metabolomic analysis of the human enteric parasite Entamoeba histolytica : Discovery of unique pathways and potential targets for chemotherapeutics. (2010)
  • Author(s): Dan Sato
  • Organizer: The 6^<th> Metabolomics Society Conference 2010
  • Place of Presentation: オランダ アムステルダム
• [Presentation] Metabolomics of parasite differentiation : metabolomic profiling of the human enteric protozoan parasite Entamoeba histolytica revealed activation of unpredicted pathways during differentiation of the proliferative into dormant stage (2010)
  • Author(s): Ghulam Jeelani
  • Organizer: The 6^<th> Metabolomics Society Conference 2010
  • Place of Presentation: オランダ アムステルダム
• [Presentation] 赤痢アメーバ原虫に対するトリフルオロメチオニン誘導体の薬効について (2009)
  • Author(s): 佐藤暖
  • Organizer: 日本ビタミン学会第61回大会
  • Place of Presentation: 京都学園大学(京都府亀岡市)
  • Year and Date: 2009-05-31
• [Presentation] 腸管寄生原虫赤痢アメーバにおける酸化ストレス応答のメタボローム解析 (2009)
  • Author(s): アフザルフセイン、ジラニグラム、佐藤暖、見市文香、ババブアリ、曽我朋義、末松誠、野崎智義
  • Organizer: 第4回メタボロームシンポジウム
  • Place of Presentation: 神奈川県横浜市鶴見区
• [Presentation] Biochemical and physiological function of a novel reductase from the microaerophilic protozoan parasite Entamoeba histolytica. (2009)
  • Author(s): Ghulam Jeelani, Afzal Husain, Dan Sato, Makoto Suematsu Vahab Ali, Tomoyoshi Nozaki
  • Organizer: The 9^<th> Awaji International Forum on Infection and Immunity.
  • Place of Presentation: Awaji, Japan
• [Presentation] Metabolomic and transcriptomic analysis of sulfur-containing amino acid metabolism in enteric protozoan parasite Entamoeba (2009)
  • Author(s): Afzal Husain, Ghulam Jeelani, Dan Sato, Fumika Mi-ichi, Tomoyoshi Soga, Makoto Suematsu, Vahab Ali, Yasuyoshi Ike, Tomoyoshi Nozaki
  • Organizer: The 9^<th> Awaji International Forum on Infection and Immunity.
  • Place of Presentation: Awaji, Japan
• [Presentation] 赤痢アメーバ原虫に対するトリフルオロメチオニン誘導体の薬効について (2009)
  • Author(s): 佐藤暖、小林正規、安井宏有貴、柴田哲男、山本雅一、曽我朋義、竹内勤、末松 誠、野崎智義
  • Organizer: 日本ビタミン学会第61回大会
  • Place of Presentation: 京都府亀岡市(Awaji, Japan)
• [Presentation] 含硫アミノ酸分解酵素・メチオニンγ-リアーゼを標的とした新規抗赤痢アメーバ薬の開発 (2008)
  • Author(s): 佐藤 暖
  • Organizer: BMB2008(第31回日本分子生物学会年会・第81回日本生化学会大会合同大会)
  • Place of Presentation: 神戸ポートアイランド神戸国際展示場
  • Year and Date: 2008-12-12
• [Presentation] 寄生性原虫の含硫アミノ酸代謝の重要性-メタボローム解析からのアプローチ- (2008)
  • Author(s): 佐藤 暖
  • Organizer: 第3回メタボロームシンポジウム
  • Place of Presentation: 山形県慶應義塾大学先端生命科学研究所
  • Year and Date: 2008-11-01
• [Presentation] Characterization of methionine gamma-lyases from enteric protozoan parasite, Entamoeba histolytica, as a potential drug target against amoebiasis (2008)
  • Author(s): Dan Sato
  • Organizer: The 8^<th> Awaji International Forum on Infection and Immunity
  • Place of Presentation: 兵庫県淡路夢舞台国際会議場
  • Year and Date: 2008-09-10
• [Presentation] Metabolomic and transcriptomic analysis of sulfur containing amino acid metabolism in enteric protozoan parasite Entamoeba histolytica (2008)
  • Author(s): Afzal Husain
  • Organizer: The 8^<th> Awaji International Forum on Infection and Immunity
  • Place of Presentation: 兵庫県淡路夢舞台国際会議場
  • Year and Date: 2008-09-10
• [Presentation] 寄生性原虫の含硫アミノ酸代謝の重要性-メタボローム解析からのアプローチ- (2008)
  • Author(s): 佐藤暖、アフザルフセイン、曽我朋義、末松誠、野崎智義
  • Organizer: 第3回メタボロームシンポジウム
  • Place of Presentation: 山形県鶴岡市
• [Presentation] 硫黄含有アミノ酸生合成・分解経路を標的とする抗赤痢アメーバ薬の開発-メチオニンγリアーゼの立体構造と阻害剤の結合様式- (2008)
  • Author(s): 唐木剛、清水顕、佐藤暖、亀井加恵子、原田繁春、野崎智義
  • Organizer: 第7回分子寄生虫・マラリア研究フォーラム
  • Place of Presentation: 愛媛県松山市
• [Remarks]
  • URL: http://vu9.sfc.keio.ac.jp/faculty_profile/cgi/f_profile.cgi?id=65e8ff37c7822cfc