What is Glutathione and How is it Synthesized in our Body?
Glutathione (GSH) is a tripeptide of glutamate, cysteine, and glycine. However, the peptide bond between glutamate and cysteine is not a normal peptide bond but is a pseudo-peptide bond (peptide bond formed not by the α-carbonyl group, but with a γ-carbonyl group of glutamate and α-amino group of cysteine). The second peptide bond (between cysteine and glycine) is a normal one.
It is an important natural antioxidant that is found in all living organisms including some bacteria. As it contains a thiol (-SH) group on its cysteine residue, it acts as a reducing agent and reduces the disulfide bond of some cytoplasmic proteins, being itself oxidized into the glutathione disulfide (GSSG). The oxidized form, GSSG is also called as L (-) glutathione.
GSH is synthesized in all tissues and cells, but the major site of biosynthesis is the liver. There are two enzymes responsible for its synthesis. These are as follows:
- γ-glutamylcysteine Synthetase catalyzes the condensation of glutamate and cysteine to give rise to a product, γ-glutamylcysteine. This enzyme is dependent on ATP and the reaction uses energy from ATP hydrolysis.
- Glutathione Synthetase, an ATP-dependent enzyme catalyzes the condensation of γ-glutamylcysteine with glycine to produce glutathione using the energy from ATP hydrolysis.
It is a potent scavenger of free radicals and reactive oxygen species and thus prevents cellular damage. It is a major endogenous (synthesized in the cell) antioxidant and it also maintains the exogenous (externally taken) antioxidants like vitamin C, vitamin E, etc. It also regulates the nitric oxide (NO signaling) cycle. It is used in different biochemical processes like DNA synthesis, repair, and protein synthesis. In prostaglandin and leukotriene biosynthesis.
Regeneration of GSH from GSSG
Once, GSH reduces Reactive Oxygen Species and or free radicals, itself is converted into oxidized form GSSG. This reaction is catalyzed by Glutathione Peroxidase and GSSG needs to be reduced again to the GSH, to continue the deactivation of free radicals and reactive oxygen species. This is accomplished by the NADPH-dependent enzyme Glutathione Reductase. Therefore, NADPH is extremely important in the biological system not only in other biosynthetic pathways but also in the regeneration of GSH from its oxidized form.
However, the body’s ability to produce GSH and its recycling decreases with aging. Therefore, people with older age have high oxidative stress because there is less antioxidant to scavenge ‘Reactive Oxygen Species’ and free radicals.
Therefore, an antioxidant supplement like vitamin C and E rich fruits and vegetables and some medicinal supplements are recommended for these people. However, as a diet, glutathione is not fruitful because it can be digested by digestive enzymes present in the stomach/intestine and the amount reaching the cell after absorption will be in less amount.
Thus, supplement GSH needs to be acetylated (acetyl-GSH) to prevent from being degraded by digestive enzymes in the GI tract. GSH can be found in the form of pills (acetyl-GSH), which can be taken through the mouth and it is also available in the injection form (not acetylated) that is given intravenously.
It is used to treat different diseases like glaucoma, cataract, and high cholesterol level and to reduce the side effect of chemotherapy treatment for cancer. However, an excess of glutathione can have side effects and may prevent the action of chemotherapy agents by deactivating them and thus may prevent the cancerous cells from been killed by chemotherapeutic agents. However, the GSH supplement is not recommended for pregnant women and the person with asthma.