MINORITY PREDOCTORAL FELLOWSHIP PROGRAM

描述（由申请人提供）：谷胱甘肽s -转移酶（GST）在异种生物解毒中很重要，催化谷胱甘肽的硫基对异种生物底物的亲核攻击。pi类在gst中引起关注主要有两个原因：第一，因为它在肿瘤组织中的显著增加，并且文献证据表明它是对某些化疗药物产生耐药性的重要贡献者。其次，由于GST是组织分布最广泛的GST，在肝脏中明显缺失，这表明该酶除了在生命系统中解毒外，还可能参与其他生物学作用。这项提议的总体目标是提供对这种酶的多种功能的结构见解。第一个目的是利用蛋白-蛋白复合物形成和定点诱变，确定谷胱甘肽s -转移酶pi对谷胱甘肽化和1-Cys过氧化物还蛋白活化的详细机制。第二个目的是利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。这些研究将深入了解谷胱甘肽s -转移酶pi的几种功能。

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.