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Pathophysiological roles of prostaglandin F synthase

前列腺素 F 合酶的病理生理作用

基本信息

批准号：
13670152
负责人：
WATANABE Kikuko
金额：
$ 2.3万
依托单位：
University of East Asia
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670152/
关键词：
prostaglandin PGE PGF PGF synthase mPGE synthase-2 cancer tertiary structure inhibitor PGE合成酵素組織化学

项目摘要

Prostaglandin (PG)s regulate diverse biological functions during both homeostasis and inflammation, and are synthesized through the enzymatic conversion of arachidonic acid to PGH_2 by cyclooxygenase (COX). PGF_2 and E_2, which are primary PGs, are widely distributed in various organs, and exhibits various biological actions such as smooth muscle contraction, pain transmission, and so forth. Watanabe, K., who is a head investigator of this project, discovered PGF synthase and mPGE synthase-2. PGF synthase is a dual function enzyme, which catalyzes the reduction of not only PGD_2 but also that of PGH_2 in the presence of NADPH. It forms 9α, 11β-PGF_2, a stereoisomer of PGF_<2α>, from PGD_2 and PGF_<2α> from PGH_2 on the same molecule. Watanabe, K.has characterized the enzymatic and molecular properties of PGF synthase for a long time. On the other hand, many PGE synthases including the membrane-associated PGE synthase (mPGE synthase)-1 and cytosolic PGE synthase (cPGE synthase) require glutathione (GSH) for their synthase activity, and they thus belong to the GSH S-transferase family. In contrast, mPGE synthase-2 has a broad specificity in its thiol requirement for catalytic activity, and its amino acid sequence places it in the redoxin family. We have crystallized mPGE synthase-2 as well as PGF synthase, and determined the active site for each substrate for both enzymes. Moreover, we studied the localization of both enzymes and COX-1 and -2 in kidney and renal cell carcinoma, and suggest that these enzymes contribute to the syntheses of PGF and E in renal cell carcinoma.

前列腺素（PG）通过环氧化酶（COX）将花生四烯酸转化为PGH_2而合成，在体内平衡和炎症过程中具有多种生物学功能。PGF_2和E_2是主要的pg，广泛分布于各个器官，并表现出平滑肌收缩、疼痛传递等多种生物学作用。Watanabe， K.是该项目的首席研究员，他发现了PGF合成酶和mPGE合成酶-2。PGF合成酶是一种双功能酶，在NADPH存在的情况下，它不仅能催化PGD_2的还原，还能催化PGH_2的还原。在同一分子上由PGD_2生成PGF_<2α>的立体异构体9α， 11β-PGF_2，由PGH_2生成PGF_<2α>。Watanabe, k .对PGF合成酶的酶学和分子特性进行了很长时间的研究。另一方面，许多PGE合成酶，包括膜相关PGE合成酶（mPGE合成酶）-1和细胞质PGE合成酶（cPGE合成酶），其合成酶活性需要谷胱甘肽（GSH），因此它们属于谷胱甘肽s转移酶家族。相比之下，mPGE合成酶-2在催化活性所需的硫醇方面具有广泛的特异性，其氨基酸序列将其置于氧化还氧蛋白家族中。我们已经结晶了mPGE合成酶-2和PGF合成酶，并确定了这两种酶的每个底物的活性位点。此外，我们研究了这两种酶以及COX-1和cox -2在肾脏和肾细胞癌中的定位，表明这些酶参与了肾细胞癌中PGF和E的合成。