Abstract Glutathione GSH is a tripeptide, which has many biological roles including protection against reactive oxygen and nitrogen species. Introduction Glutathione GSH is a tripeptide L- -glutamyl-L-cysteinyl-glycine with multiple functions in living organisms [ 1 — 4 ]. Figure 1. Glutathione is a tripeptide: L- -glutamyl-L-cysteinyl-glycine. In its reduced form a the N-terminal glutamate and cysteine are linked by the -carboxyl group of glutamate, preventing cleavage by common cellular peptidases and restricting cleavage to -glutamyltranspeptidase.
The cysteine residue is the key functional component of glutathione, providing a reactive thiol group that plays an essential role in its functions.
Furthermore, cysteine residues form the intermolecular dipeptide bond in the oxidized glutathione molecule b. Figure 2. Glutathione homeostasis involves both intra- and extracellular mechanisms. Glutathione is synthesized in both de novo and salvage synthesis pathways.
De novo synthesis requires the three amino acids and energy in the form of ATP. Glutamate may be provided in part from the conversion of a -glutamyl amino acid to 5-oxoproline, which is then converted to glutamate. Salvage synthesis involves either reduction of GSSG or uses precursors formed from the hydrolysis of GSH or its conjugates by -L-glutamyl transpeptidase at the external surface of the plasma membrane that are transported back into the cell as amino acids or dipeptides.
GSH is consumed in various processes. In addition to detoxification of reactive species and electrophiles such as methylglyoxal, GSH is involved in protein glutathionylation and several other processes, such as the biosynthesis of leukotrienes and prostaglandins, and reduction of ribonucleotides.
Modified from [ 27 ]. Figure 3. Involvement of glutathione in elimination of reactive oxygen and nitrogen species. Hydrogen peroxide may be removed by catalase or by glutathione peroxidase GPx. The latter requires GSH to reduce peroxide. Figure 4. The dynamics of reactive oxygen species in biological systems. Steady-state levels of reactive oxygen species fluctuate over a certain range under normal conditions.
However, under stress ROS levels may increase or decrease beyond the normal range resulting in acute or chronic oxidative or reductive stress. Under some conditions, ROS levels may not return to their initial range and stabilize at a new quasistationary level. Figure 5. Under nonstressed conditions the transcription factor Nrf2 binds to the Keap1 homodimer. The resulting protein complex can then further complex with Cullin 3 leading to ubiquitination of Nrf2 followed by proteasomal degradation.
Nrf2 migration into the nucleus is promoted by at least three different mechanisms: oxidation of Keap thiol groups to form disulfides, modification of Keap1 cysteine residues by electrophiles, or phosphorylation of Nrf2 by protein kinases that, in turn, may be activated by oxidants.
Figure 6. Oxidation of protein cysteine residues to sulfenic, sulfinic, or sulfonic derivatives and formation of glutathionylated proteins. In biological systems, sulfenic and sulfinic derivatives may be reduced by thioredoxin TR and sulfiredoxin Srx , respectively, whereas sulfonic moieties cannot be reduced. Glutathionylated proteins are formed by direct interaction of GSH with sulfenic acid derivatives, exchange between cysteine residues and GSSG, or interaction with oxidized glutathione forms.
Table 1. Figure 7. Involvement of glutathione in the detoxification of xenobiotics and reactive oxygen species, its relationship with pathological development and the potential role of different phytochemicals.
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The liver is the largest GSH reservoir. GSH is carried in the bile to the intestinal luminal compartment. Epithelial tissues of the kidney tubules, intestinal lining and lung have substantial P activity and modest capacity to export GSH.
GSH equivalents circulate in the blood predominantly as cystine, the oxidized and more stable form of cysteine. Cells import cystine from the blood, reconvert it to cysteine likely using ascorbate as cofactor , and from it synthesize GSH.
Conversely, inside the cell, GSH helps re-reduce oxidized forms of other antioxidants such as ascorbate and alpha-tocopherol. GSH is an extremely important cell protectant. It directly quenches reactive hydroxyl free radicals, other oxygen-centered free radicals, and radical centers on DNA and other biomolecules. GSH is a primary protectant of skin, lens, cornea, and retina against radiation damage and other biochemical foundations of P detoxification in the liver, kidneys, lungs, intestinal, epithelia and other organs.
GSH is the essential cofactor for many enzymes that require thiol-reducing equivalents, and helps keep redox-sensitive active sites on enzyme in the necessary reduced state. GSH and its metabolites also interface with energetics and neurotransmitter syntheses through several prominent metabolic pathways.
GSH availability down-regulates the pro-inflammatory potential of leukotrienes and other eicosanoids.
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