Reduced glutathione (GSH) is the most prevalent non-protein thiol in animal cells. Its de novo and salvage synthesis serves to maintain a reduced cellular environment and the tripeptide is a co-factor for many cytoplasmic enzymes and may also act as an important posttranslational modification in a number of cellular proteins. The cysteine thiol acts as a nucleophile in reactions with both exogenous and endogenous electrophilic species. As a consequence, reactive oxygen species (ROS) are frequently targeted by GSH in both spontaneous and catalytic reactions. Since ROS have defined roles in cell signaling events as well as in human disease pathologies, an imbalance in expression of GSH and associated enzymes has been implicated in a variety of circumstances. Cause and effect links between GSH metabolism and diseases such as cancer, neurodegenerative diseases, cystic fibrosis (CF), HIV, and aging have been shown. Polymorphic expression of enzymes involved in GSH homeostasis influences susceptibility and progression of these conditions. This review provides an overview of the biological importance of GSH at the level of the cell and organism.
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Glutathione (GSH) is a water-soluble tripeptide composed of the amino acids glutamine, cysteine, and glycine. The thiol group is a potent reducing agent, rendering GSH the most abundant intracellular small molecule thiol, reaching millimolar concentrations in some tissues. As an important antioxidant, GSH plays a role in the detoxification of a variety of electrophilic compounds and peroxides via catalysis by glutathione S-transferases (GST) and glutathione peroxidases (GPx). The importance of GSH is evident by the widespread utility in plants, mammals, fungi and some prokaryotic organisms. In addition to detoxification, GSH plays a role in other cellular reactions, including, the glyoxalase system, reduction of ribonucleotides to deoxyribonucleotides, regulation of protein and gene expression via thiol:disulfide exchange reactions. The tripeptide can exist intracellularly in either an oxidized (GSSG) or reduced (GSH) state. Maintaining optimal GSH:GSSG ratios in the cell is critical to survival, hence, tight regulation of the system is imperative. A deficiency of GSH puts the cell at risk for oxidative damage. It is not surprising that an imbalance of GSH is observed in a wide range of pathologies, including, cancer, neurodegenerative disorders, cystic fibrosis (CF), HIV and aging. The role of GSH in these disorders will be discussed in this review.
GSH is synthesized de novo from the amino acids glycine, cysteine and glutamic acid. Synthesis of GSH requires the consecutive action of two enzymes, c-glutamylcysteine synthetase (c-GCS) and GSH synthetase, (Fig. 1). c-GCS is a heterodimer composed of a catalytically active heavy subunit c-GCS-HS (73 kDa) and a regulatory subunit, c-GCS-LS (30 kDa) [4,5]. The regulation of c-GCS is complex. Induction of c-GCS expression has been demonstrated in response to diverse stimuli in a cell specific manner. The bioavailability of cysteine is rate limiting for the synthesis of GSH. Cysteine and the oxidized form of the amino acid, cystine, are transported into the cell via sodium dependent and independent transporters, respectively. Oxidants (including hyperoxide, H2O2 and electrophilic compounds) promote cystine uptake and a concomitant increase in expression of c-GCS. The c-GCS promotor region contains a putative AP-1 binding site, an antioxidant response element (ARE), and an electrophile responsive element. The AP-1 site is critical to constitutive expression of the c-GCS-HS subunit. Post-translational modifications of c-GCS also influence GSH synthesis [10,11]. Specifically, phosphorylation of c-GCS leads to the inhibition of GSH synthesis. GSH itself regulates the activity of c-GCS via a negative feedback mechanism. Hence, GSH depletion increases the rate of GSH synthesis.
GSH redox cycle
The formation of excessive amounts of reactiveO2 species (ROS), including peroxide (H2O2) and superoxide anions (O2) is toxic to the cell. Hence, metabolizing and scavenging systems to remove them are functionally critical and tightly controlled in the cell. GSH peroxidase (GPx) in concert with catalase and superoxide dismutase (SOD) function to protect the cell from damage due to ROS. GPx detoxifies peroxides with GSH acting as an electron donor in the reduction reaction, producing GSSG as an end product. The reduction of GSSG is catalyzed by GSH reductase (GR) in a process that requires NADPH. GR is a member of the flavoprotein disulfide oxidoreductase family and exists as a dimer. Under conditions of oxidative stress, GR is regulated at the level of transcription as well as by posttranslational modifications. Alterations in GR expression and activity have been implicated in cancer and aging. GPx is an 80 kDa protein that is composed of four identical subunits. Five distinct GPx isozymes have been characterized in mammals, (Table 1). While GPx's are ubiquitously expressed, individual isoforms are tissue specific. GPx expression is induced by oxidative stress and aberrant expression of GPx's has been associated with a wide variety of pathologies, including hepatitis, HIV, and a wide variety of cancers, including skin, kidney, bowel and breast.