The studies of reaction mechanism of cyanide-insensitive alternative oxidase from Trypanosoma brucei (TAO), a promising drug target

2013 Fiscal Year Final Research Report

• Project/Area Number: 23570131
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: Kyoto Institute of Technology
• Principal Investigator: SHIBA Tomoo 京都工芸繊維大学, 工芸科学研究科, 准教授 (80401206)
• Project Period (FY): 2011 – 2013
• Keywords: トリパノソーマ / diironタンパク質 / 膜表在型タンパク質 / アスコフラノン / X線結晶構造解析

Research Abstract

Trypanosoma brucei is the causative agent of human African sleeping sickness (trypanosomiasis). The cyanide-insensitive alternative oxidase from T. brucei (TAO) is a membrane-bound diiron carboxylate protein which is located on the inner surface of the inner mitochondrial membrane Since TAO is absent from the mammalian host it is a promising target for the development of anti-trypanosomal drugs.
I have reported on the first crystal structure of TAO in the presence and absence of an ascofuranone (AF)-derivative at 2.6 and 2.85 angstrom resolution, respectively (Shiba T et al. Proc. Natl. Acad. Sci. USA, 2013). The structures reveal a membrane binding region and an active-site containing 4 glutamate and 2 histidine residues which are buried in a 4-helix bundle. The binding of the AF-inhibitor results in major conformational changes at the active site.

Research Products

• [Journal Article] 希少疾病のアカデミア創薬–グローバルオーファンドラッグ創成をめざして– (2014)
  • Author(s): 北潔, 志波智生, 原田繁春
  • Journal Title: 実験医学増刊 Volume: 32(2) Pages: 210-215
  • Peer Reviewed
• [Journal Article] Anemia amelioration by lactose infusion during trypanosomosis could be associated with erythrocytes membrane de-galactosylation (2014)
  • Author(s): Balogun EO, Balogun JAB, Yusuf S, Inuwa HM, Ndams IS, Sheridan P, Inaoka DK, Shiba T, Harada S, Kita K, Esievo KAN, Nok AJ.
  • Journal Title: Veterinary Parasitology Volume: 199 Pages: 259-263
  • Peer Reviewed
• [Journal Article] The alternative oxidases : simple oxidoreductase proteins with complex functions (2013)
  • Author(s): Young L, Shiba T, Harada S, Kita K, Albury MS, Moore AL.
  • Journal Title: Biochem Soc Trans. Volume: 41 Pages: 1305-1311
  • Peer Reviewed
• [Journal Article] Biochemical characterization of highly active Trypanosoma brucei gambiense glycerol kinase, a promising drug target (2013)
  • Author(s): Balogun EO, Inaoka DK, Shiba T, Kido Y, Nara T, Aoki T, Honma T, Tanaka A, Inoue M, Matsuoka S, Michels PA, Harada S, Kita K.
  • Journal Title: J. Biochemistry Volume: 154 Pages: 77-84
  • Peer Reviewed
• [Journal Article] アフリカ睡眠病治療薬の候補化合物と標的タンパク質との複合体構造 (2013)
  • Author(s): 志波智生, 高橋元, 原田繁春, 斎本博之, 城戸康年, 稲岡ダニエル健, 北潔.
  • Journal Title: 日本結晶学会誌 Volume: 55 Pages: 254-259
  • Peer Reviewed
• [Journal Article] Unraveling the heater : new insights into the structure of the alternative oxidase (2013)
  • Author(s): Moore AL, Shiba T, Young L, Harada S, Kita K, Ito K.
  • Journal Title: Annu. Rev Plant Biol. Volume: 64 Pages: 637-663
  • Peer Reviewed
• [Journal Article] Structure of the trypanosome cyanide-insensitive alternative oxidase (2013)
  • Author(s): Shiba T, Kido Y, Sakamoto K, Inaoka DK, Tsuge C, Tatsumi R, Takahashi G, Balogun EO, Nara T, Aoki T, Honma T, Tanaka A, Inoue M, Matsuoka S, Saimoto H, Moore AL, Harada S, Kita K.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 110 Pages: 4580-4585
  • Peer Reviewed
• [Journal Article] Identification and characterization of sialidase-like activity in the developmental stages of Amblyomma variegatum (2013)
  • Author(s): Natala AJ, Balogun EO, Balogun JA, Inuwa HM, Nok AJ, Shiba T, Harada S, Kita K, Agbede RI, Esievo KA.
  • Journal Title: J. of Med. Entomol. Volume: 50 Pages: 85-93
  • Peer Reviewed
• [Journal Article] Structures of cyanobacteriochromes from phototaxis regulators AnPixJ and TePixJ reveal general and specific photoconversion mechanism (2013)
  • Author(s): Narikawa R, Ishizuka T, Muraki N, Shiba T, Kurisu G, Ikeuchi M.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 110 Pages: 918-923
  • Peer Reviewed
• [Journal Article] The role of amino acid residues in the active site of L-methionineγ-lyase from Pseudomonas putida (2012)
  • Author(s): Fukumoto M, Kudou D, Murano S, Shiba T, Sato D, Tamura T, Harada S, Inagaki K.
  • Journal Title: Biosci. Biotechnol. Biochem. Volume: 76 Pages: 1275–1284
  • Peer Reviewed
• [Journal Article] Crystal structure of mitochondrial quinol-fumarate reductase from the parasitic nematode Ascaris suum (2012)
  • Author(s): Shimizu H, Osanai A, Sakamoto K, Inaoka DK, Shiba T, Harada S, Kita K.
  • Journal Title: J. Biochemistry Volume: 151 Pages: 589–592
  • Peer Reviewed
• [Presentation] アフリカトリパノソーマのシアン耐性酸化酵素(TAO)と新規阻害剤:フェルレノールとの複合体の結晶構造 (2013)
  • Author(s): 高橋元, 志波智生, 上田慧, 稲岡ダニエル健, 城戸康年, 坂元君年, 柘植千明, Balogun EO, 奈良武司, 青木孝, 本間光貴, 田仲昭子, 井上将行, 松岡茂, Moore AL, 斎本博之, 原田繁春, 北潔
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 20130911-13
• [Presentation] アフリカトリパノソーマの薬剤標的「シアン耐性酸化酵素Trypanosome Alternative Oxidase (TAO)」の結晶構造解析 (2013)
  • Author(s): 志波智生, 高橋元, 城戸康年, 稲岡ダニエル健, 坂元君年, 柘植千明, 辰巳涼子, Balogun EO, 奈良武司, 青木孝, 本間光貴, 田仲昭子, 井上将行, 松岡茂, Moore AL, 斎本博之, 原田繁春, 北潔
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 20130911-13
• [Presentation] The search for inhibitors of African trypanosomes glycerol kinase (2013)
  • Author(s): Balogun EO, Inaoka DK, Shiba T, Kido Y, Nara T, Aoki T, Honma T, Tanaka A, Inoue M, Matsuoka S, Michels PA, Kita K, Harada S.
  • Organizer: 第13回日本蛋白質科学会年会
  • Place of Presentation: 鳥取
  • Year and Date: 20130612-14
• [Presentation] シアン耐性酸化酵素Trypanosome Alternative Oxidase(TAO)の結晶構造 (2013)
  • Author(s): 志波智生, 城戸康年, 高橋元, 稲岡ダニエル健, 坂元君年, 奈良武司, 青木孝, 本間光貴, 田仲昭子, 井上将行, 松岡茂, 斎本博之, 原田繁春, 北潔
  • Organizer: 第13回日本蛋白質科学会年会
  • Place of Presentation: 鳥取
  • Year and Date: 20130612-14
• [Presentation] アフリカトリパノソーマ症の薬剤標的「シアン耐性酸化酵素Trypanosome Alternative Oxidase (TAO)」の精製と結晶構造解析 (2012)
  • Author(s): 高橋元, 志波智生, 城戸康年, 稲岡ダニエル健, 坂元君年, 奈良武司, 青木孝, 本間光貴, 田仲昭子, 井上将行, 松岡茂, Moore AL, 斎本博之, 原田繁春, 北潔
  • Organizer: 第85回日本生化学会
  • Place of Presentation: 福岡
  • Year and Date: 20121214-16
• [Presentation] Structure-based approach for developing trypanosome-specific glycerol kinase inhibitor(s) (2012)
  • Author(s): Balogun EO, Inaoka DK, Shiba T, Kido Y, Nara T, Aoki T, Honma T, Tanaka A, Inoue M, Matsuoka S, Michels PA, Harada S, Kita K.
  • Organizer: 第12回日本蛋白質科学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 20120620-22
• [Presentation] アフリカトリパノソーマの薬剤標的「シアン耐性酸化酵素Trypanosome Alternative Oxidase(TAO)」の結晶構造 (2012)
  • Author(s): 志波智生, 城戸康年, 稲岡ダニエル健, 坂元君年, 奈良武司, 青木孝, 本間光貴, 田仲昭子, 井上将行, 松岡茂, Moore AL, 斎本博之, 原田繁春, 北潔
  • Organizer: 第12回日本蛋白質科学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 20120620-22
• [Presentation] Structural analysis of glycerol kinase from human African trypanosomes for anti-trypanosomal drug design (2011)
  • Author(s): Balogun EO, 稲岡ダニエル健, 志波智生, 城戸康年, 奈良武司, 青木孝, 本間光貴, 田仲昭子, 井上将行, 松岡茂, Michels PA, 原田繁春, 北潔
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 20110921-24
• [Presentation] トリパノソーマ原虫のミトコンドリアの内膜に局在する「シアン耐性酸化酵素Trypanosome Alternative Oxidase (TAO)」の結晶構造」 (2011)
  • Author(s): 志波智生, 城戸康年, 稲岡ダニエル健, 坂元君年, 奈良武司, 青木孝, 本間光貴, 田仲昭子, 井上将行, 松岡茂, 斎本博之, Moore AL, 原田繁春, 北潔
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 20110921-24
• [Remarks]
  • URL: http://www.kit.ac.jp/01/topics/2012/pressrelease130305.html