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 i s 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 i s 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31GM075387-01
Application #
6984224
Study Section
Special Emphasis Panel (ZRG1-F08 (29))
Program Officer
Gaillard, Shawn R
Project Start
2005-08-15
Project End
2008-08-14
Budget Start
2005-08-15
Budget End
2006-08-14
Support Year
1
Fiscal Year
2005
Total Cost
$35,244
Indirect Cost
Name
University of Delaware
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
Ralat, Luis A; Misquitta, Stephanie A; Manevich, Yefim et al. (2008) Characterization of the complex of glutathione S-transferase pi and 1-cysteine peroxiredoxin. Arch Biochem Biophys 474:109-18
Ralat, Luis A; Manevich, Yefim; Fisher, Aron B et al. (2006) Direct evidence for the formation of a complex between 1-cysteine peroxiredoxin and glutathione S-transferase pi with activity changes in both enzymes. Biochemistry 45:360-72
Ralat, Luis A; Colman, Roberta F (2006) Identification of tyrosine 79 in the tocopherol binding site of glutathione S-transferase pi. Biochemistry 45:12491-9