MINORITY PREDOCTORAL FELLOWSHIP PROGRAM

说明(申请人提供)：谷胱甘肽S转移酶(谷胱甘肽转移酶)在异物的解毒过程中起重要作用，它催化谷胱甘肽的硫醇基团对异物底物的亲核攻击。Pi类之所以受到GST的关注，主要有两个原因：第一，它在肿瘤组织中的显著增加，以及文献中的证据表明，它是导致某些化疗药物耐药的重要因素。其次，因为它是组织分布最广的GST，在肝脏中明显缺失，这表明这种酶可能参与了生命系统中除解毒之外的其他生物学作用。这项提案的总体目标是提供对这种酶的多种功能的结构性见解。第一个目的是通过蛋白质-蛋白质复合体的形成和定点突变来确定谷胱甘肽S转移酶pi激活1-半胱氨酸过氧化还蛋白和谷胱甘肽的详细机制。第二个目的是用亲和标记和定点突变的方法研究生育酚衍生物与谷胱甘肽S转移酶pi结合的结合部位。这些研究将为深入了解谷胱甘肽S转移酶pi的几个功能提供帮助。

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.