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.