Redox in redux: Emergent roles for glutathione S-transferase P (GSTP) in regulation of cell signaling and S-glutathionylation.
Glutathione (GSH) provides a major source of thiol homeostasis critical to the maintenance of a reduced cellular environment that is conducive to cell survival. Mammals have accumulated a significant cadre of sulfur containing proteins, the interactive significance of which has become clear in recent times. Glutathione transferases (GST) are prevalent in eukaryotes and have been ascribed catalytic functions that involve detoxification of electrophiles through thioether bond formation with the cysteine thiol of GSH. The neutralizing impact of these reactions on products of reactive oxygen has contributed to the significant evolutionary conservation and adaptive functional redundancy of the multifaceted GSH system. Amongst the GSTs, GSTP has been implicated in tumorigenesis and in anticancer drug resistance. Emerging studies indicate that GSTP has ligand binding properties and contributes in the regulation of signaling kinases through direct protein:protein interactions. Furthermore, S-glutathionylation is a post-translational modification of low pK(a) cysteine residues in target proteins. The forward rate of the S-glutathionylation reaction can be influenced by GSTP, whereas the reverse rate is affected by a number of redox sensitive proteins including glutaredoxin, thioredoxin and sulfiredoxin. The functional importance of these reactions in governing how cells respond to oxidative or nitrosative stress exemplifies the broad importance of GSH/GST homeostasis in conditions such as cancer, ageing and neurodegenerative diseases. GSTP has also provided a platform for therapeutic drug development where some agents have completed preclinical testing and are in clinical trial for the management of cancer.
Tew
Kenneth D
KD
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, P.O. Box 250505, Charleston, SC 29425, United States. tewk@musc.edu
D000818:Animals; D005057:Eukaryotic Cells / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000502:physiology*; D006801:Humans; D010084:Oxidation-Reduction; D010770:Phosphotransferases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000502:physiology*
D005982:Glutathione Transferase; D010770:Phosphotransferases; D005978:Glutathione