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Structure analyses of key enzymes from trypanosoma and malaria for the development of new drugs

Research Project

Project/Area Number 19370043
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Structural biochemistry
Research InstitutionNagasaki University

Principal Investigator

YOSHIMOTO Tadashi  Nagasaki University, 理工学部, 教授 (60088870)

Co-Investigator(Kenkyū-buntansha) ITO Kiyoshi  長崎大学, 医歯薬学総合研究科, 准教授 (50201926)
NAKAJIMA Yoshitaka  長崎大学, 医歯薬学総合研究科, 助教 (80372770)
Project Period (FY) 2007 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Fiscal Year 2010: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2009: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2008: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2007: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
Keywordsマラリア / トリパノソーマ / オリゴペプチダーゼB / 阻害剤 / 医薬品 / アミノペプチダーゼ / メチオニンアミノペプチダーゼ / 治療薬 / 構造生物学 / 酵素 / 立体構造 / X線結晶構造解析 / プロテアーゼ / 感染症 / 結晶解析
Research Abstract

Since there is no effective medicine for infectious disease caused by Trypanosoma and malaria, many peoples live in tropical were killed. In order to develop new drugs for these, we focused to metabolic enzymes in Trypanosoma and malalia as target, and studied specific inhibitors.
(1) Methionine aminopeptidase from P. falciparum ; We develop new assay method of methionine aminopeptidase using prolyl aminopeptidase. We cloned the enzyme gene and expressed in E. coli. Using the new assay method, specific inhibitor have been screened. A family of structurally related inhibitors containing a 2-(2pyridinyl)- pyrimidine was identified in compound library. Inhibitors were also found in microbial products and plant extract.
(2) Oligopeptidase B from trypanosomiasis : The enzyme plays a key role in the pathogenesis of trypanosomiasis. We found protamine act unique and potent inhibitor for oligopeptidase B from trypanosoma. In order to clarify the mechanism of inhibition, we crystallized the enzyme and studied X-ray crystallography. The crystallographic parameters were a=b=123.9, C=248.0 A gamma=120 degree and p hexagonal.
(3) Specific inhibitors for aminopeptidase N and prolyl oligopeptidase from them were also studied.

Report

(6 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report   Self-evaluation Report ( PDF )
  • 2008 Annual Research Report
  • 2007 Annual Research Report
  • Research Products

    (34 results)

All 2010 2009 2008 2007

All Journal Article (18 results) (of which Peer Reviewed: 7 results) Presentation (14 results) Book (2 results)

  • [Journal Article] Substitution of Glu122 by glutamine revealed the function of the second water molecule as a proton donor in the binuclear metal enzyme, creatininase2010

    • Author(s)
      Yamashita K., Nakajima Y., Matsushita H., Nishiya Y., Yamazawa R., Wu Y., Matsubara F., Oyama H., Ito K., Yoshimoto T.
    • Journal Title

      J.Mol.Biol.

    • NAID

      120006984734

    • Related Report
      2010 Final Research Report
  • [Journal Article] Substitution of Glu122 by glutamine revealed the function of the second water molecule as a proton donor in the binuclear metal enzyme, creatininase2010

    • Author(s)
      YL
    • Journal Title

      J.Mol.Biol..

      Volume: 396 Pages: 1081-1096

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Substitution of Glu122 by glutamine revealed the function of the second water molecule as a proton donor in the binuclear metal enzyme, creatininase2010

    • Author(s)
      Yamashita, K., Nakajima, Y., Matsushita, H., Nishiya, Y., Yamazawa, R., Wu, Y., Matsubara, F., Oyama, H., Ito, K., Yoshimoto, T.
    • Journal Title

      J.Mol.Biol. 396

      Pages: 1081-1096

    • NAID

      120006984734

    • Related Report
      2009 Self-evaluation Report
  • [Journal Article] ペプチド最終分解系に関与するエキソペプチダーゼの構造と機能2009

    • Author(s)
      伊藤潔、中嶋義隆、田中信忠、芳本忠
    • Journal Title

      生化学 81

      Pages: 5-16

    • NAID

      10024915560

    • Related Report
      2010 Final Research Report
  • [Journal Article] Structure of aminopeptidase N from Escherichia coli complexed with the transition state alnalogue aminophosphinic inhibitor PL250, Marie-Claude Fournie-Zaluski, Herve Poras and Bernard P.Roques2009

    • Author(s)
      中嶋義隆, 伊藤潔, 芳本忠
    • Journal Title

      Acta Crystal.D. 65

      Pages: 814-822

    • Related Report
      2010 Final Research Report
  • [Journal Article] Closed Complex of the D-3-Hydroxybutyrate Dehydrogenase Induced by an Enantiomeric Competitive Inhibitor : Importance of Gln196 in Stable Ternary Complex Formation.2009

    • Author(s)
      Kanako Nakashima, Kiyoshi Ito, Yoshitaka Nakajima, Ryuji Yamazawa, Syunsuke. Miyakawa, Tadashi Yoshimoto
    • Journal Title

      J.Biochem. 145,(4)

      Pages: 467-479

    • Related Report
      2010 Final Research Report
  • [Journal Article] Closed Complex of the D-3-Hydroxybutyrate dehydrogenase induced by an enantiomeric competitive inhibitor : Importance of Gln196 in stable ternary complex formation2009

    • Author(s)
      Nakashima, K., Ito, K., Nakajima, Y., Yamazawa, R., Miyakawa, S., Yoshimoto, T.
    • Journal Title

      J.Biochem. 145(4)

      Pages: 467-479

    • Related Report
      2009 Self-evaluation Report
  • [Journal Article] Structure of aminopeptidase N from Escherichia coli complexed with the transition state alnalogue aminophosphinic inhibitor PL2502009

    • Author(s)
      Fournie-Zaluski, M. C., Poras, H., Roques, B P., Nakajima, Y., Ito, K., Yoshimoto, T.
    • Journal Title

      Acta Crystal.D 65

      Pages: 814-822

    • Related Report
      2009 Self-evaluation Report
  • [Journal Article] Closed Complex of the D-3-Hydroxybutyrate Dehydrogenase Induced by an Enantiomeric Competitive Inhibitor2009

    • Author(s)
      Nakashima, Y., et al
    • Journal Title

      J.Biochem.. 145

      Pages: 467-479

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Structure of aminopeptidase N from Escherichia coli complexed with the transition state alnalogue aminophosphinic inhibitor PL2502009

    • Author(s)
      Zaluski, M-C.F., et al.
    • Journal Title

      Acta Crystal. D 65

      Pages: 814-822

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ペプチド最終分解系に関するエキソペプチダーゼの構造と機能2009

    • Author(s)
      伊藤潔, 中嶋義隆, 田中信忠, 芳本 忠
    • Journal Title

      生化学 81

      Pages: 5-16

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dipeptidyl Aminopeptidase IV from Stenotrophomonas maltophilia Exhibited 4-Hydroxyproline Residue.2008

    • Author(s)
      Nakajima Y., Ito K., Toshima T., Egawa T., Zheng. H., Oyama H., Wu Y-F., Takahashi E., Kyono. K., Yoshimoto T.
    • Journal Title

      J.Bacteriol. 190(23)

      Pages: 7819-7829

    • Related Report
      2010 Final Research Report
  • [Journal Article] Novel Inhibitor for Prolyl Tripeptidyl aminopeptidase from Porphyromonas gingivalis and details of substrate-recognition mechanism2008

    • Author(s)
      Xu, Y., Nakajima, Y., Ito, K., Zheng, H., Oyama, H., Heiser, U., Hoffmann, T., Gartner, U-T., Demuth. H-U., Yoshimoto, T.
    • Journal Title

      J.Mol.Biol. 375(3)

      Pages: 708-719

    • NAID

      120006984748

    • Related Report
      2009 Self-evaluation Report
  • [Journal Article] Dipeptidyl aminopeptidase IV from Stenotrophomonas maltophilia exhibited an activity against substrate containing 4-hydroxyproline residue2008

    • Author(s)
      Nakajima, Y., Ito, K., Toshima, T. Egawa, T., Zheng. H., Oyama, H., Wu, Y-F., Takahashi, E., Kyono. K., Yoshimoto, T.
    • Journal Title

      J.Bacteriol. 190(23)

      Pages: 7819-7829

    • Related Report
      2009 Self-evaluation Report
  • [Journal Article] Dipeptidyl aminopeptidase IV from Stenotrophomonas maltophilia exhibited an activity against substrate containing 4-hydroxyproline residue.2008

    • Author(s)
      Nakajima, Y., et al
    • Journal Title

      J. Bacteriol. 190

      Pages: 7819-7829

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel inhibitor for prolyl tripeptidyl aminopeptidase from Porphyromonas gingivalis and details of substrate-recognition mechanism2008

    • Author(s)
      Xu, et. al.
    • Journal Title

      J.Mol.Biol. 375

      Pages: 708-719

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 微生物酵素の生化学的および構造生物学的研究と医療への応用2007

    • Author(s)
      芳本忠
    • Journal Title

      薬学雑誌 127

      Pages: 1035-1045

    • Related Report
      2010 Final Research Report
  • [Journal Article] 微生物酵素の生化学的および構造生物学的研究と医療への応用2007

    • Author(s)
      芳本 忠
    • Journal Title

      薬学雑誌 127

      Pages: 1035-1045

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Presentation] Crystal structure of the G179S mutant creatininase revealed a possible substrate entry mechanism2010

    • Author(s)
      黒川裕美, 芳本忠, 伊藤潔
    • Organizer
      日本生化学会
    • Place of Presentation
      神戸
    • Year and Date
      2010-12-07
    • Related Report
      2010 Annual Research Report
  • [Presentation] Crystal Structure of FAD-dependent D-Glucose Dehydrogenase complexed with an inhibitor2010

    • Author(s)
      中嶋義隆, 西矢芳昭, 芳本忠, 伊藤潔
    • Organizer
      日本生化学会
    • Place of Presentation
      神戸
    • Year and Date
      2010-12-07
    • Related Report
      2010 Annual Research Report
  • [Presentation]2009

    • Organizer
      Sixth General Meeting of the International Proteolysis Society
    • Place of Presentation
      Gold Coast(Australia)
    • Year and Date
      2009-10-28
    • Related Report
      2010 Final Research Report
  • [Presentation] 4-Hys基質に活性を示すS.maltophilia由来ジペプチジルアミノペプチダーゼIVの構造的特徴2009

    • Author(s)
      Ito, K., 他
    • Organizer
      Sixth General Meeting of the International Proteolysis Society
    • Place of Presentation
      Gold Coast(Australia)
    • Year and Date
      2009-10-28
    • Related Report
      2009 Annual Research Report
  • [Presentation]2009

    • Organizer
      プロリン特異性ペプチダーゼ生化学会シンポジウム
    • Place of Presentation
      神戸
    • Year and Date
      2009-10-22
    • Related Report
      2010 Final Research Report
  • [Presentation] プロリン特異性ペプチダーゼ2009

    • Author(s)
      芳本忠, 他
    • Organizer
      生化学会シンポジウム
    • Place of Presentation
      神戸
    • Year and Date
      2009-10-22
    • Related Report
      2009 Annual Research Report
  • [Presentation] 歯周病菌プロリルトリペプチジルアミノペプチダーゼの基質N末端認識に関与するGlu6362008

    • Organizer
      第13回病態と治療におけるプロテアーゼとインヒビター学会学術集
    • Place of Presentation
      大阪
    • Year and Date
      2008-08-22
    • Related Report
      2010 Final Research Report 2008 Annual Research Report
  • [Presentation] 4-Hys基質に活性を示すS.maltophilia由来ジペプチジルアミノペプチダーゼIVの構造的特徴2008

    • Organizer
      日本生化学会九州支部例会九州大学
    • Place of Presentation
      福岡
    • Year and Date
      2008-05-17
    • Related Report
      2010 Final Research Report
  • [Presentation] 4 - Hys基質に活性を示すS. maltophilia由来ジペプチジルアミノペプチダーゼIVの構造的特徴2008

    • Author(s)
      中嶋義隆, 他
    • Organizer
      日本生化学会九州支部例会
    • Place of Presentation
      九州大学(福岡)
    • Year and Date
      2008-05-17
    • Related Report
      2008 Annual Research Report
  • [Presentation] 大腸菌アミノペプチダーゼNの基質認識機構2008

    • Organizer
      日本薬学会第128年会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2008-03-27
    • Related Report
      2010 Final Research Report 2007 Annual Research Report
  • [Presentation] The three dimensional structure of aminopeptidase N and wide substrate recognition mechanism2007

    • Organizer
      International Proteolysis Society
    • Place of Presentation
      パトラス(ギリシャ)
    • Year and Date
      2007-10-23
    • Related Report
      2010 Final Research Report
  • [Presentation] The three dimensional structure of aminopeptidase N and wide substrate recoenition mechanism2007

    • Author(s)
      芳本 忠
    • Organizer
      International Proteolysis Society
    • Place of Presentation
      パトラス (ギリシャ)
    • Year and Date
      2007-10-23
    • Related Report
      2007 Annual Research Report
  • [Presentation] Streptococcus 由来プリンヌクレオシドホスホリラーゼの構造と基質特異性2007

    • Author(s)
      武吉智也, 中嶋義隆, 伊藤潔, 芳本忠
    • Organizer
      平成19年度 第24回日本薬学会九州支部大会
    • Place of Presentation
      福岡
    • Related Report
      2009 Self-evaluation Report
  • [Presentation] Hyp基質に活性を示すS. maltophilia ジペプチジルアミノペプチダーゼIVの構造的特徴2007

    • Author(s)
      十島翼, 中嶋義隆, 伊藤潔, 尾山廣, 芳本忠
    • Organizer
      平成19年度第24回日本薬学会九州支部大会
    • Place of Presentation
      福岡
    • Related Report
      2009 Self-evaluation Report
  • [Book] 生化学辞典(今堀和友、山川民夫監修)2008

    • Author(s)
      芳本忠
    • Publisher
      東京化学同人
    • Related Report
      2010 Final Research Report
  • [Book] 構造生物学(倉光、杉山編)(病原菌の戦い)2007

    • Author(s)
      伊藤潔、中嶋義隆、芳本忠
    • Publisher
      共立出版
    • Related Report
      2010 Final Research Report

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Published: 2007-04-01   Modified: 2016-04-21  

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