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 normally observed between the carboxyl group of glutamic acid and amino group of cysteine. Glutathione is a compound with low molecular weight and has two signifiers ; reduced glutathione ( GSH ) with a monomeric signifier and oxidized glutathione ( GSSG or GSSH ) with a dimeric signifier. Glutathione is the most of import antioxidant found in cells and map to protect cells from hurtful effects of foreign substances such as reactive O species.
Foods rich in proteins, aminic acids and vitamins are all beginnings of glutathione. Examples of nutrients include fish, fruits, milk and veggies. When glutathione is administered orally, it is digested and broken down into components of aminic acids. In the bowel, the amino acerb component undergoes hydroxylation reaction catalyzed by the enzyme N?-glutamyltransferase found in the bowel and undergoes metamorphosis quickly in the portal circulation by hepatic N?-glutamyltransferase. The sum of glutathione in a cell will increase when glutathione precursors are taken which helps to avoid glutathione depletion in the organic structure. Glutathione depletion in the organic structure is caused as a consequence of air and H2O pollution, hurts, exhaust from motor vehicles, Datril toxic condition, family chemicals, coffin nail fume and presence of heavy metals.
SYNTHESIS OF GLUTATHIONE
Glutathione is a de novo procedure which can be divided into two reactions. The first reaction involves fall ining cysteine to glutamate which consequences in N?-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 N?-carboxyl group of glutamate which is formed as a consequence of coupled ATP hydrolysis by the enzyme glutamate cysteine ligase ( GCL ) ( Huang et al. , 1993 ) . The 2nd reaction besides involves coupled ATP hydrolysis. It is a procedure affecting add-on of glycine to N?-glutamyl cysteine. Glutathione synthetase is the enzyme required to catalyse this reaction to bring forth N?-glutamyl cysteine glycine ( GSH ) . It is possible to transport GSH out of cells because the procedure is physiologically of import 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 consecutive ATP dependant formation of amide bonds between cysteine and the I?-carboxyl group of glutamate and so 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 non let the oxidization of other compounds. The most of import antioxidant produced in cells is glutathione ( GSH ) . Vitamins such as vitamin C and vitamin Tocopherol are besides known as beginnings which generate little molecular weight antioxidants. Lipid peroxides and lipid hydroxyl groups generated from polyunsaturated fatty acids can undergo the procedure of decrease with the aid of vitamin E. Vitamin so reduces oxidized vitamin E in a rapid but non-enzymatic reaction. Enzymatic reactions are hence required to change over the oxidised vitamin C to the reduced signifier ( Forman et al. , 2009 ) . During this enzymatic transition, GSH is used as a substrate. It is involved in protecting cells from the toxic effects generated by anticancer drugs and is besides considered as an anti-tumour agent which is hence required in the intervention of malignant neoplastic disease. Neutralization of free groups and oxidative emphasis can bring on cell harm by donating an negatron from cysteine residue ( Forman et al. , 2009 ) . Therefore, glutathione is involved in forestalling these procedures from happening.
Glutathione is really of import and more effectual in the encephalon because the sensitiveness of certain receptors to dopamine is increased. Therefore, the presence of glutathione in the encephalon prevent upsets such as encephalon hurt and neurodegenerative diseases which may be caused due to the presence of high degree of oxidative emphasis.
As a detoxifying agent
Glutathione is regarded as a detoxifying agent. It is involved in extinguishing foreign compounds from the organic structure. This can be achieved by junction of the xenobiotic compound with GSH. The adduct formed is so secreted from the cell with the aid of membrane transporters ( Boyland and Chasseand 1969 ) . Electrophiles such as 4-hydroxynonenal ( HNE ) are besides eliminated by GSH and bulk of these procedures are catalyzed by GSTs ( Forman et al. , 2009 ) . The procedure is a Michael add-on hence a conjugate termed “ Michael adduct ” is formed. A cyclic hemiacetal so ensue due to the re-arrangement of the Michael adduct ( Alary et al. , 2003 ) . Both the conjugate and the cyclic hemiacetal can so be excreted from cells in the organic structure and this is considered as the chief path to extinguish HNE and other compounds that conjugate with GSH ( Forman et al. , 2009 ) .
FIG 3: – Glutathione junction with 4-hydroxynonental. Glutathione S-transferases catalyze the junction of GSH with HNE. This is a Michael add-on that can slowly occur non-enzymatically.
Adapted from Forman et al. , ( 2009 ) pg 5
Glutathione besides protects mammalian being from potentially toxic compounds by generation of lymph cells. Antibodies are produced when lymph cells are multiplied which so fight against diseases in the organic structure. The degree of glutathione in the organic structure must be high because O groups are produced immensely by the immune system. For cellular metamorphosis to take topographic point O is extremely required and hence free groups could be produced if there is overconsumption of O, otherwise known as reactive O species ( Forman et al. , 2009 ) . There are enzymes in the organic structure such as catalase, superoxide dismutase and glutathione peroxidise which possess antioxidant belongingss and map to protect cells from the harmful effects of ROS. Synthesis of of import agents such as leukotriene in inflammatory response besides requires high degree of glutathione.
FIG 4: – The assorted protective functions of decreased GSH and the relationship with GSSG. The NADPH possibly regenerated by the pentose phosphate shunt. Abbreviations: GSH, glutathione ; GSSG, oxidized glutathione.
Adapted from Timbrell J.A ( 2009 ) pg 231
DEFICIENCY OF GLUTATHIONE
The of import maps of glutathione ( GSH ) are metabolically and physiologically regulated in mammalian cells. Oxidative emphasis and free extremist harm could ensue when there is lack of glutathione in the organic structure which finally damage ruddy blood cells. Lack of glutathione could ensue in neurological upsets and could be inherited genetically. Inhibition of glutathione synthesis and amino acids by diseases such as arthritis, unwellness, asthma and rheumatoid could take to glutathione lack in the human organic structure. Low degrees of glutathione are normally observed in HIV and AIDS patient and tend to diminish with age. It has besides been reported that lower sums of NADPH could ensue due to glucose-6-phosphate dehydrogenase lack and NADPH is a needed cofactor in glutathione synthesis ( Franklin et al. , 2009 ) .
The protective functions of glutathione in the mammalian cell can non be over-emphasised. It is besides really of import to observe at this point that the organic structure ‘s maestro antioxidant is glutathione. Its absence in the organic structure could do other antioxidants to malfunction. Glutathione depletion could be caused by diseases, oxidative emphasis and so on. Eating diets rich in vitamins, proteins make the organic structure capable of fabricating glutathione. The three major maps of glutathione in the organic structure include ; as an antioxidant which helps to forestall oxidization of other molecules in the organic structure. It besides 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 lymph cells generation in the immune system.
The cysteinyl mediety has a reactive thiol group and is regarded as the most of import component of the GSH molecule. The protective functions of GSH are besides carried out by the cysteinyl mediety.