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Glutathione is made up of three amino acids which are connected by peptide bonds. The amino acids are cysteine, glycine and glutamic acid. The peptide is usually observed between the carboxyl group of glutamic acid and amino group of cysteine. Glutathione is a compound with low molecular weight and has two forms; reduced glutathione (GSH) with a monomeric form and oxidized glutathione (GSSG or GSSH) with a dimeric form. Glutathione is the most important antioxidant found in cells and function to protect cells from deleterious effects of foreign substances such as reactive oxygen species. The cell cycle is also regulated with the help of glutathione (Meister 1992).
Foods rich in proteins, amino acids and vitamins are all sources of glutathione. Examples of foods include fish, fruits, milk and vegetables. When glutathione is administered orally, it is digested and broken down into constituents of amino acids. In the intestine, the amino acid constituent undergoes hydroxylation reaction catalyzed by the enzyme Ñƒ-glutamyltransferase found in the intestine and undergoes metabolism rapidly in the portal circulation by hepatic Ñƒ-glutamyltransferase. The amount of glutathione in a cell will increase when glutathione precursors are taken which helps to avoid glutathione depletion in the body. Glutathione depletion in the body is caused as a result of air and water pollution, injuries, exhaust from motor vehicles, acetaminophen poisoning, household chemicals, cigarette smoke and presence of heavy metals.
SYNTHESIS OF GLUTATHIONE
Glutathione is a de novo process which can be divided into two reactions. The first reaction involves joining cysteine to glutamate which results in Ñƒ-glutamyl cysteine. The enzyme involved in the first reaction is glutamate cysteine ligase (GCL). An amide bond is required between the amino group of cysteine and Ñƒ-carboxyl group of glutamate which is formed as a result of coupled ATP hydrolysis by the enzyme glutamate cysteine ligase (GCL) (Huang et al., 1993). The second reaction also involves coupled ATP hydrolysis. It is a process involving addition of glycine to Ñƒ-glutamyl cysteine. Glutathione synthetase is the enzyme required to catalyze this reaction to produce Ñƒ-glutamyl cysteine glycine (GSH). It is possible to transport GSH out of cells because the process is physiologically important due to the fact that the GSH in the plasma are supplied by the hepatocytes, which generates or produces cysteine required for the synthesis of GSH in other cells (Forman et al., 2009).
FIG 2:- Glutathione synthesis. The sequential ATP dependent formation of amide bonds between cysteine and the Î³-carboxyl group of glutamate and then between glycine and cysteines are shown.
Adapted from Forman et al (2009) pg 8
PROTECTIVE ROLES OF GLUTATHIONE
As an antioxidant
An antioxidant is a compound which slows or does not allow the oxidation of other compounds. The most important antioxidant produced in cells is glutathione (GSH). Vitamins such as vitamin C and vitamin E are also known as sources which generate small molecular weight antioxidants. Lipid peroxides and lipid hydroxyl radicals generated from polyunsaturated fatty acids can undergo the process of reduction with the help of vitamin E. Vitamin then reduces oxidized vitamin E in a rapid but non-enzymatic reaction. Enzymatic reactions are therefore required to convert the oxidized vitamin C to the reduced form (Forman et al., 2009). During this enzymatic conversion, GSH is used as a substrate. It is involved in protecting cells from the toxic effects generated by anticancer drugs and is also considered as an anti-tumour agent which is therefore required in the treatment of cancer. Neutralisation of free radicals and oxidative stress can induce cell damage by donating an electron from cysteine residue (Forman et al., 2009). Therefore, glutathione is involved in preventing these processes from occurring.
Glutathione is very important and more effective in the brain because the sensitivity of certain receptors to dopamine is increased. Therefore, the presence of glutathione in the brain prevent disorders such as brain injury and neurodegenerative diseases which may be caused due to the presence of high level of oxidative stress.
As a detoxifying agent
Glutathione is regarded as a detoxifying agent. It is involved in eliminating foreign compounds from the body. This can be achieved by conjugation of the xenobiotic compound with GSH. The adduct formed is then secreted from the cell with the help of membrane transporters (Boyland and Chasseand 1969). Electrophiles such as 4-hydroxynonenal (HNE) are also eliminated by GSH and majority of these processes are catalyzed by GSTs (Forman et al., 2009). The process is a Michael addition therefore a conjugate termed "Michael adduct" is formed. A cyclic hemiacetal then result due to the re-arrangement of the Michael adduct (Alary et al., 2003). Both the conjugate and the cyclic hemiacetal can then be excreted from cells in the body and this is considered as the main route to eliminate HNE and other compounds that conjugate with GSH (Forman et al., 2009).
FIG 3:- Glutathione conjugation with 4-hydroxynonental. Glutathione S-transferases catalyze the conjugation of GSH with HNE. This is a Michael addition that can slowly occur non-enzymatically.
Adapted from Forman et al., (2009) pg 5
Glutathione also protects mammalian organism from potentially toxic compounds by multiplication of lymphocytes. Antibodies are produced when lymphocytes are multiplied which then fight against diseases in the body. The level of glutathione in the body must be high because oxygen radicals are produced vastly by the immune system. For cellular metabolism to take place oxygen is highly required and therefore free radicals could be produced if there is overconsumption of oxygen, otherwise known as reactive oxygen species (Forman et al., 2009). There are enzymes in the body such as catalase, superoxide dismutase and glutathione peroxidise which possess antioxidant properties and function to protect cells from the harmful effects of ROS. Synthesis of important agents such as leukotriene in inflammatory response also requires high level of glutathione. Roum et al., 1993 reported that patients with cystic fibrosis and smokers whose lungs are exposed to oxidants have lower GSH compared with normal individual (Roum et al., 1993 cited in Forman et al., 2009).
FIG 4:- The various protective roles of reduced GSH and the relationship with GSSG. The NADPH maybe regenerated by the pentose phosphate shunt. Abbreviations: GSH, glutathione; GSSG, oxidized glutathione.
Adapted from Timbrell J.A (2009) pg 231
DEFICIENCY OF GLUTATHIONE
The important functions of glutathione (GSH) are metabolically and physiologically regulated in mammalian cells. Oxidative stress and free radical damage could result when there is deficiency of glutathione in the body which ultimately damage red blood cells. Deficiency of glutathione could result in neurological disorders and could be inherited genetically. Inhibition of glutathione synthesis and amino acids by diseases such as arthritis, illness, asthma and rheumatoid could lead to glutathione deficiency in the human body. Low levels of glutathione are usually observed in HIV and AIDS patient and tend to decrease with age. It has also been reported that lower amounts of NADPH could result due to glucose-6-phosphate dehydrogenase deficiency and NADPH is a required cofactor in glutathione synthesis (Franklin et al., 2009).
The protective roles of glutathione in the mammalian cell cannot be over-emphasised. It is also very important to note at this point that the body's master antioxidant is glutathione. Its absence in the body could make other antioxidants to malfunction. Glutathione depletion could be caused by diseases, oxidative stress and so on. Eating diets rich in vitamins, proteins make the body capable of manufacturing glutathione. The three major functions of glutathione in the body include; as an antioxidant which helps to prevent oxidation of other molecules in the body. It also functions as a detoxifier where it undergoes conjugation reaction with the foreign substance detected, eliminates the compound and its metabolites. Finally, it is involved in lymphocytes multiplication in the immune system.
The cysteinyl moiety has a reactive thiol group and is regarded as the most important element of the GSH molecule. The protective roles of GSH are also carried out by the cysteinyl moiety.