GLUTATHIONE PEROXIDASE ACTION AND INHIBITION

谷胱甘肽过氧化物酶的作用和抑制

基本信息

批准号：
3296550
负责人：
PETER G.W. GETTINS
金额：
$ 12.32万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-02-01 至 1991-06-30
项目状态：
已结题

项目摘要

Selenium is an essential nutrient for man, in large part through the crucial part it plays in the mechanism of action of glutathione peroxidase. This enzyme seems to serve an important role in protecting cell membranes from oxidative damage by peroxides through reduction of the peroxide at the expense of glutathione. A less direct and negative role for the enzyme may occur in the etiology of rheumatoid arthritis. There is evidence to link some of the most effective drugs used in treatment of rheumatoid arthritis, including the gold drugs, with potent inhibition of glutathione peroxidase. At present, although the structure of the enzyme from bovine erythrocytes is known, the details of functioning of the selenium moiety, both in its normal enzymatic degradation of peroxides and in its inhibition by arthritis drugs is far from clear. By examining the molecular species and interactions of the selenium and its immediate environment in glutathione peroxidase, both with substrates and inhibitors, a much better understanding of both the functional need for selenium (cf. sulfur) and the mechanism whereby gold drugs and others are effective in arthritis treatment should be obtained. This understanding is the long term goal of this project. It is proposed: 1. To use 77-Se NMR as a very sensitive means of following changes in oxidation state of selenium in glutathione peroxidase during the catalytic cycle and to identify the species involved. 2. To characterize the binding sites on the enzyme for reduced and oxidized glutathione by 1-H NMR difference spectroscopy. 3. To obtain evidence concerning subunit interactions from equivalence of 77-Se resonances and 1-H difference spectra. 4. To investigate in model systems and in glutathione peroxidase the interactions between gold, and other arthritis drugs, and selenocysteamine and its seleninic acid, using 77-Se and 199-Hg NMR. 5. To compare the bovine enzyme with the human, ovine and rat liver enzymes by 1-H NMR difference spectroscopy. 6. To compare the mechanism of action of a synthetic low molecular weight glutathione peroxidase mimic (PZ-51) with that of the enzyme using 1-H and 77-Se NMR.

硒是人类的重要营养素，在很大程度上是它在谷胱甘肽的作用机理中起着至关重要的部分过氧化物酶。这种酶似乎在保护细胞膜免受过氧化物的氧化损伤通过以谷胱甘肽为代价减少过氧化物。酶可能会出现不直接和负面作用类风湿关节炎病因。有证据可以连接一些用于治疗类风湿的最有效药物关节炎，包括金药物，有效抑制谷胱甘肽过氧化物酶。目前，尽管牛红细胞的酶是已知的硒部分的功能，都以正常的酶促过氧化物及其因关节炎药物抑制的降解是远非清晰。通过检查分子物种和硒的相互作用及其直接环境谷胱甘肽过氧化物酶，均具有底物和抑制剂，A 更好地理解两者的功能需求硒（参见硫）和金色药物和其他人应在关节炎治疗方面有效。这种理解是该项目的长期目标。这是建议的： 1。使用77-SE NMR作为遵循的非常敏感的手段谷胱甘肽过氧化物酶中硒氧化状态的变化在催化周期中并确定所涉及的物种。 2。表征酶上的结合位点以减少并通过1-H NMR差异光谱法氧化了谷胱甘肽。 3。获得有关亚基相互作用的证据 77-SE共振和1小时差异光谱的等效性。 4。在模型系统和谷胱甘肽过氧化物酶中进行研究黄金与其他关节炎药物之间的相互作用以及使用77-SE和199-HG NMR。 5。将牛酶与人，卵子和大鼠进行比较通过1-H NMR差异光谱法进行肝酶。 6。比较合成低的作用机理分子量谷胱甘肽过氧化物酶模仿（PZ-51）使用1-H和77-SE NMR的酶的酶。