|Topic:||Glutathione Functions .|
|Details:|| Glutathione (abbreviated GSH) is a tripeptide composed of glutamate, cysteine and glycine that has numerous important functions within cells. Glutathione serves as a potent reductant eliminating hydroxy radicals, peroxynitrites, and hydroperoxides; it is conjugated to drugs to make them more water soluble; it is involved in amino acid transport across cell membranes (the γ-glutamyl cycle); it is a substrate for the peptidoleukotrienes; it serves as a cofactor for some enzymatic reactions; and it serves as an aid in the rearrangement of protein disulfide bonds.
GSH is synthesized in the cytosol of all mammalian cells via the two-step reaction shown in the Figure. The rate of GSH synthesis is dependent upon the availability of cysteine and the activity of the rate-limiting enzyme, γ-glutamylcysteine synthetase (also called glutamate-cysteine ligase, GCL). The second reaction of GSH synthesis involves the enzyme, glutathione synthetase, which condenses γ-glutamylcysteine with glycine. Both reactions of GSH synthesis require ATP. Functional GCL is a heterodimer composed of the catalytic subunit and a regulatory subunit called the modifier subunit. The GCL catalytic subunit is encoded by the GCLC gene and the modifier subunit is encoded by the GCLM gene. The GCLC gene is located on chromosome 6p12 and is composed of 16 exons that generate two alternatively spliced mRNA that encode GCL isoform a (637 amino acids) and GCL isoform b (599 amino acids). The GCLM gene is located on chromosome 1p22.1 and is composed of 8 exons that encode a protein of 274 amino acids. The glutathione synthetase gene (symbol: GSS) is located on chromosome 20q11.2 and is composed of 15 exons that encode a protein of 474 amino acids.
In the liver, major factors that determine the availability of cysteine are diet, membrane transport activities of the three sulfur amino acids cysteine, cystine and methionine, and the conversion of methionine to cysteine (see the Amino Acid Metabolism page). Numerous conditions can alter the level of GSH synthesis via changes in glutamate-cysteine ligase activity and expression of the GCLC gene such as oxidative stress, antioxidant levels, hormones, cell proliferation, and diabetes mellitus.
The role of GSH as a reductant is extremely important particularly in the highly oxidizing environment of the erythrocyte. The sulfhydryl of GSH can be used to reduce peroxides formed during oxygen transport. Endogenously produced hydrogen peroxide (H2O2) is reduced by GSH in the presence of selenium-dependent GSH peroxidase. Hydrogen peroxide can also be reduced by catalase, which is present only in the peroxisomes. In the mitochondria, GSH is particularly important because mitochondria lack catalase. The resulting oxidized form of GSH consists of two molecules disulfide bonded together (abbreviated GSSG). The enzyme glutathione reductase utilizes NADPH as a cofactor to reduce GSSG back to two moles of GSH. Hence, the pentose phosphate pathway is an extremely important pathway of erythrocytes for the continuing production of the NADPH needed by glutathione reductase. In fact as much as 10% of glucose consumption, by erythrocytes, may be mediated by the pentose phosphate pathway.
Detoxification of xenobiotics or their metabolites is another major function of GSH. These compounds form conjugates with GSH either spontaneously or enzymatically in reactions catalyzed by members of the glutathione S-transferase (GST) family. The conjugates formed are usually excreted from the cell and, in the case of the liver they are excreted in the bile. There are several GST enzymes that are divided into three major families that comprise cytosolic, mitochondrial, and microsomal family members. The cytosolic GST enzymes comprise the largest family and based upon amino acid sequences and substrate specificities this family has been divided into seven subclasses identified as alpha (α, A), mu (μ, M), omega (ω, O), pi (π, P), sigma (σ, S), theta (θ, T), and zeta (ζ, Z). The human genome contains five GST alpha genes, five mu genes, two omega genes, one pi gene, one sigma gene, two theta genes, and one zeta gene. The cytosolic enzymes are functional as dimers and since the alpha and mu proteins can form functional heterodimers, the complexity of functional enzymes is greater than the number of individual subunit genes. Another soluble GST enzyme that is not found in the cytosol is the human GST kappa (κ, K) enzyme (encoded by the GSTK1 gene) that is localized to the peroxisomes. The GST enzymes function not only in detoxification and antioxidant reactions but also in the biosynthesis and metabolism of eicosanoids and steroids as well as in the modulation of signal transduction processes.
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