Studies on Molecular Biology of Prostaglandin Biosynthesis by parasitic Trypanosoma
寄生锥虫前列腺素生物合成的分子生物学研究
基本信息
- 批准号:14370087
- 负责人:
- 金额:$ 8.9万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:2002
- 资助国家:日本
- 起止时间:2002 至 2003
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
In this study our aims are the elucidation of the functions and the three-dimensional structures of prostaglandin (PG) synthetic enzymes in parasitic protozoa (Trypanosoma, Leishmania, and Plasmodia), and the development of anti-parasitic drugs. Trypanosoma brucei prostaglandin (PG) F_<2α> synthase (TbPGFS), an aldo-ketoreductase (AKR), catalyzes the NADPH-dependent reduction of the endoperoxide moiety of PGH_2 into PGF_<2α> whose overproduction during trypanosomiasis causes abortion in infected subjects. Here we report the crystal structure of TbPGFS in complex with NADP^+ and citrate at 2.1 Å resolution. TbPGFS adopts a parallel (αβ)_8-barrel fold lacking the protrudent loops. The core active site structure is hydrophobic to bind hydrophobic substrates and contains tyrosine, lysine, histidine and aspartate known as a catalytic tetrad in other aldo-ketoreductases. Mutagenesis identifies that Tyr 52 and Asp 47 are not concerning to the enzyme reaction, showing His 110 and Lys 77 forms the catalytic dyad to perform an acid-assisted reduction in which His 110 transfers its proton to the substrate. These findings identify a novel catalytic mechanism for the biological reduction of the endoperoxide PGH_2 by an aldo-ketoreductase. The structure should allow for rational design of specific inhibitors useful to investigate the physiological roles of TbPGFS in trypanosomes. The reduction of PGH2 has been known for some time and it has also been shown that PGF_<2α> is enzymatically synthesized by a reductive cleavage of the 9, 11-endoperoxide of PGH_2^<43>. However, how the enzyme operates the reductive cleavage of the 9, 11-endoperoxide of PGH_2 has not been elucidated. We provide here the first structural information of a PGH_2 reductase in protozoa enzymes. This structure should now allow the rational design of specific inhibitors that might help investigate the physiological role of TbPGFS in trypanosomes.
本研究旨在阐明寄生原生动物(锥虫、利什曼原虫和疟原虫)中前列腺素合成酶的功能和三维结构,并开发抗寄生虫药物。布鲁氏锥虫前列腺素(PG) F_<2α>合成酶(TbPGFS)是一种醛酮还原酶(AKR),可催化nadph依赖的PGH_2内过氧化物部分还原为PGF_<2α>,而PGF_<2α>在锥虫病中过量产生,导致被感染者流产。本文以2.1 Å分辨率报道了TbPGFS与NADP^+和柠檬酸盐配合物的晶体结构。TbPGFS采用平行(αβ)_8筒状褶皱,没有突出的环状结构。核心活性位点结构是疏水的,可以结合疏水底物,并含有酪氨酸、赖氨酸、组氨酸和天冬氨酸,在其他醛酮还原酶中被称为催化四聚体。诱变鉴定出Tyr 52和Asp 47与酶反应无关,表明His 110和Lys 77形成催化双元体来进行酸辅助还原,其中His 110将其质子转移到底物上。这些发现确定了一种新的醛酮还原酶生物还原内过氧化物PGH_2的催化机制。该结构应允许合理设计特异性抑制剂,有助于研究TbPGFS在锥虫体内的生理作用。PGH2的还原作用早已为人所知,PGF_<2α>是由PGH_2^<43>的9,11 -内过氧化物的还原裂解酶促合成的。然而,该酶如何作用于PGH_2的9,11 -内过氧化物的还原裂解尚不清楚。本文首次提供了原生动物酶中PGH_2还原酶的结构信息。这种结构现在应该允许合理设计特异性抑制剂,这可能有助于研究TbPGFS在锥虫体内的生理作用。
项目成果
期刊论文数量(144)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Kabututu Z.: "Prostaglandin production from arachidonic acid and evidence for a 9,11-endoperoxide prostaglandin H_2 reductase in Leishmania."Intl.J.Parasitol. 32. 1693-1700 (2003)
Kabututu Z.:“从花生四烯酸中产生前列腺素以及利什曼原虫中 9,11-内过氧化物前列腺素 H_2 还原酶的证据。”Intl.J.Parasitol。
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F.von Delft: "Crystallization and preliminary X-ray crystallographic studies of mavicyanin from Cucurbita pepo medullosa"Structure. 11. 985-996 (2003)
F.von Delft:“来自 Cucurbita pepo medullosa 的 mavicyanin 的结晶和初步 X 射线晶体学研究”结构。
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Kubata BK: "A key role for old yellow enzyme in the metabolism of drugs by Trypanosoma cruzi."J Exp Med. 196. 1241-1251 (2002)
Kubata BK:“老黄酶在克氏锥虫药物代谢中发挥着关键作用。”J Exp Med。
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Adachi, H.: "Pre-Stirring Promotes Nucleation of Protein Crystals"Jpn.J.Appl.Phys.. 43. L243-L246 (2004)
Adachi, H.:“预搅拌促进蛋白质晶体的成核”Jpn.J.Appl.Phys.. 43. L243-L246 (2004)
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T.Inoue, Y.Okano, Y.Kado, K.Aritake, D.Irikura, N.Uodome, N.Okazaki, S.Kinugasa, H.Shishitani, H.Matsumura, Y.Kai, Y.Urade: "The First Determination of the Inhibitor Complex Structure of Human Hematopoietic Prostaglandin D Synthase"J.Biochem.. 135. 279-28
T.Inoue、Y.Okano、Y.Kado、K.Aritake、D.Irikura、N.Uodome、N.Okazaki、S.Kinugasa、H.Shishitani、H.Matsumura、Y.Kai、Y.Urade:“
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INOUE Tsuyoshi其他文献
Experimental study on stability of axial direction of Balance Piston mechanism
平衡活塞机构轴向稳定性实验研究
- DOI:
10.1299/transjsme.19-00187 - 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
HIRAKI Hiromichi;INOUE Tsuyoshi;YABUI Shota - 通讯作者:
YABUI Shota
Development of model for stability analysis in a balance piston mechanism in turbopump by using active control
利用主动控制开发涡轮泵平衡活塞机构稳定性分析模型
- DOI:
10.1299/transjsme.18-00445 - 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
YABUI Shota;HIRAKI Hiromichi;INOUE Tsuyoshi - 通讯作者:
INOUE Tsuyoshi
地図上のノード位置を制約とするMoving Horizon Estimationによる自動車位置の補正
使用地图上的节点位置作为约束,使用移动地平线估计来校正车辆位置
- DOI:
- 发表时间:
2021 - 期刊:
- 影响因子:0
- 作者:
HIRAKI Hiromichi;INOUE Tsuyoshi;YABUI Shota;藤間 隆生,野中 謙一郎,関口 和真 - 通讯作者:
藤間 隆生,野中 謙一郎,関口 和真
INOUE Tsuyoshi的其他文献
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{{ truncateString('INOUE Tsuyoshi', 18)}}的其他基金
Development of a Rotor Model Considering the Crack Propagation due to Fatigue and the Method for Vibration Diagnosis and Prognostics of the Crack Growth
考虑疲劳裂纹扩展的转子模型的开发以及裂纹扩展的振动诊断和预测方法
- 批准号:
23560257 - 财政年份:2011
- 资助金额:
$ 8.9万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Toward understanding the initial conditions of star formation using realistic magnetohydrodynamics simulations
使用真实的磁流体动力学模拟来了解恒星形成的初始条件
- 批准号:
23740154 - 财政年份:2011
- 资助金额:
$ 8.9万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Neutron structure analysis of human PGD synthase for elucidation of the reaction mechanism activated by metal ions
人 PGD 合成酶的中子结构分析,阐明金属离子激活的反应机制
- 批准号:
22550152 - 财政年份:2010
- 资助金额:
$ 8.9万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Development of the identification method of both the depth and position of the breathing crack in the rotating shaft
转轴呼吸裂纹深度和位置识别方法的研制
- 批准号:
20560214 - 财政年份:2008
- 资助金额:
$ 8.9万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Exploration of connection rules regulating synchronous firing in the thalamus
调节丘脑同步放电连接规则的探索
- 批准号:
20770128 - 财政年份:2008
- 资助金额:
$ 8.9万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Development ofenzyme inlulkar far infectious diseace including malaria and clarification ofthe inlubitor activity
疟疾等远距离传染病酶的研制及其抑制剂活性的阐明
- 批准号:
18350086 - 财政年份:2006
- 资助金额:
$ 8.9万 - 项目类别:
Grant-in-Aid for Scientific Research (B)