MINORITY PREDOCTORAL FELLOWSHIP PROGRAM

描述（由申请方提供）：谷胱甘肽S-转移酶（GST）在异生物质解毒中非常重要，催化谷胱甘肽巯基对异生物质底物的亲核攻击。Pl类在GST中引起注意有两个主要原因：第一，因为其在肿瘤组织中的显著增加以及文献中的证据表明其是对某些化疗剂的耐药性发展的重要贡献者。其次，因为它是具有最广泛的组织分布的GST，在肝脏中明显缺乏，这表明这种酶可能在生命系统中除了解毒之外还具有其他生物学作用。该提案的总体目标是为这种酶的多种功能提供结构见解。第一个目的是确定详细的机制，占谷胱甘肽S-转移酶PI使用蛋白质-蛋白质复合物的形成和定点诱变谷胱甘肽化和激活1-半胱氨酸过氧化物酶。第二个目的是使用亲和标记和定点诱变来表征生育酚衍生物与谷胱甘肽S-转移酶pi结合的结合位点。这些研究将提供深入了解谷胱甘肽S-转移酶pi的几个功能。

DESCRIPTION (provided by applicant): Glutathione S-transferases (GST) are important in the detoxification of xenobiotics, catalyzing the nucleophilic attack by the thiol group of glutathione on the xenobiotic substrate. The pi class has attracted attention among the GSTs for two major reasons: First, because of its marked increase in tumor tissues and the evidence in the literature that it is an important contributor to the development of resistance to certain chemotherapeutic agents. Secondly, because it is the GST with the broadest tissue distribution, with a notable absence in the liver, suggesting this enzyme may engage in other biological roles aside from detoxification in living systems. The overall goal of this proposal is to provide structural insights into the multiple functions of this enzyme. The first aim is to determine the detailed mechanism that accounts for glutathionylation and activation of 1-Cys Peroxiredoxin by glutathione S-transferase pi using protein-protein complex formation and site-directed mutagenesis. The second aim is to characterize the binding site where tocopherol derivatives bind to glutathione S- transferase pi using affinity labeling and site-directed mutagenesis. These studies will provide insight into the several functions of glutathione S-transferase pi.