Dossier : Oxidative stress pathologies and antioxidantsThe importance of glutathione in human disease
Introduction
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 [1]. 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 [2].
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.
Section snippets
Glutathione synthesis
GSH is synthesized de novo from the amino acids glycine, cysteine and glutamic acid. Synthesis of GSH requires the consecutive action of two enzymes, γ-glutamylcysteine synthetase (γ-GCS) and GSH synthetase [3], (Fig. 1). γ-GCS is a heterodimer composed of a catalytically active heavy subunit γ-GCS-HS (73 kDa) and a regulatory subunit, γ-GCS-LS (30 kDa) [4], [5]. The regulation of γ-GCS is complex. Induction of γ-GCS expression has been demonstrated in response to diverse stimuli in a cell
GSH redox cycle
The formation of excessive amounts of reactive O2 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
Redox balance and glutathionylation in regulation pathways
Many drugs and chemicals can produce ROS as direct or indirect by-products. An interpretation of data from some cell survival assays suggests that low levels of ROS can have growth stimulatory effects. For example, Adriamycin undergoes redox cycling to produce quinone intermediates that provide a potent source of ROS. Using standard colony formation assays, low concentrations of Adriamycin (low nM) can actually stimulate proliferation resulting in survival above 100%. As concentrations
Polymorphism of γ-GCS
Alterations in GSH levels are associated with a wide variety of pathologies, including cancer, HIV, lung disease and Parkinson’s disease (PD). Hence polymorphisms in the genes governing GSH levels may contribute to the etiology of these disorders. Polymorphisms within the γ-GCS gene have been identified within the heavy subunit, (Table 3) [37]. The gene, located on chromosome 1, encompasses 22 kb and contains seven exons and six introns. Three alleles of the γ-GCS-HS subunit have been
Defects in enzymes of the γ-glutamyl cycle
To date, hereditary defects have been described in four of the major enzymes that mediate GSH metabolism through the γ-glutamyl cycle [66]. As mentioned previously, polymorphic variants of γ-GCS have been linked to specific diseases. However, where mutant enzyme expression occurs, the most prevalent syndromes include hemolytic anemia, either with or without hepatosplenomegaly. Hereditary defects in GSH synthetase are autosomal recessive and can lead to mental retardation and neuropsychiatric
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