Biosynthesis, Metabolism, and Utilization

Biosynthesis, Metabolism, and UtilizationDifferent ways glutathi iodine acts to protect mammalian organisms from potentially venomous exogenous and endogenetic compounds.Glutathione (GSH or gamma-glutamylcysteinylglycine) is a tripeptide and a sulfhydryl (thiol or -SH) antioxidant, enzyme cofactor and antitoxin that is made up of three amino supermans namely L-glutamine, L-cysteine and glycine. The wet solubility nature make it to be found in the cell cytosol and within aqueous phases of financial backing system, although is constantly encountered in animals, plants and microorganisms (Kosower NS et al 1978 , Meister A et al 1976, Kidd PM et al 1991 and Lomaestro BM et al, 1995). Glutathione exists intracellularly in dickens versions in either reduced form or oxidized form which feces be an antioxidant in reduced form (GSH) and sulphur-sulphur bond compound called glutathione disulphide (GSSG) in the oxidized form. Sensitive indicator of oxidative mark is the ratio of the reduced form (GSH)/ oxidized form (GSSG) which is to a fault important in cell surgical process in the organisms.Biosynthesis, Metabolism, and UtilizationThe homeostatical control status of glutathione by continuous self adjusting to equilibrate GSH production, its reprocessing from GSSG and its usage is a function of enzymes such as GSH synthetase, GSH reductase, peroxidises, transferases, transhydrogenases and transpeptidases. Cysteinyl moiety is the functional element of glutathione that provides the thiol reactive group which is liable for the reinforcement of protein structure and functions through proteins disulfide linkages reduction, controlling of production and breakdown of protein, sustenance of immune function, defence against oxidative injury, remotion of reactive chemicals. The metabolism and function of glutathione is directly decided by structural elements of glutathione which ar -carboxyl peptide linkages of glutamate and C-terminal glycine presence. exclusively mammalian cells produces GSH (Meister and Tate, 1976) and major site of biosynthesis is the liver ( Deleve and Kaplowitz, 1991). The production of GSH occurs in the cytosol of cell and its breakdown takes do outside the cell production involves a two phase reaction catalyzed by GSH synthetase and -glutamylcysteine synthetase that uses two moles of adenosine triphosphate(ATP) per one mole of GSH while the breakdown argon catalyzed by -glutamyl transpeptidase and dipeptidases gravel on the top surface of epithelial tissues. The first phase is under the influence negative feedback from its end product, GSH (Richman and Meister, 1975). The blockage of the regulatory site of the enzymes by excess glutamate fire partially prevent feedback inhibition (Meister, 1984 Meister and Anderson, 1983 Richman and Meister, 1975). The limiting factor after the utilization of GSH and dismission of feedback inhibition is the availability of cysteine. The breakdown products of GSH S-conjugates and G SH argon the same (glutamate, glycine, and cysteine) and are also metabolized by same degradative enzymes which metabolized GSH and the products potful be reabsorbed into the cell for GSH production. Intracellular N-acetyltransferases can acetylate cysteine S-conjugates on the amino group of residue of cysteinyl to form mercapturic acids (N-acetylcysteine S-conjugates) which are released into the circulation or bile (Hinchman et al., 1991). -glutamyl cyclotransferase is responsible for the change of excess -glutamylcysteine accumulation, in the absence of its change to GSH which can result to 5-oxoproline and 5-oxoproline accumulation has harmful effect because of metabolic acidosis.REDOX AND CELLULAR REGULATORY ROLE OF GSHGSH Peroxidases and phospholipid hydroperoxide GSH peroxidases are antioxidant enzymes which uses glutathione has an important cofactor although GSH peroxidases exist in both selenium-dependent and non-dependent forms ( Zhang L., 1989). GSH peroxidases acts by re acting hydrogen peroxide and other peroxides with GSH in water phase to detoxify them while peroxides produced in cell membranes and lipophilic cell phase are detoxified by phospholipid hydroperoxide GSH peroxidases using GSH (Cathcart RF III., 1985). GSH can also be used by GSH transhydrogenases as a cofactor in the reconversion of dehydroascorbate to ascorbate, ribonucleotides to deoxyribonucleotides and interconversion occurring among disulphide and thiol group. GSH reducing power source is the nicotinamide adenine dinucleotide phosphate(NADPH) in reduced form which is from the pentose phosphate shunt that glutathione reductase uses as a source of electron in the reprocessing of GSSG to GSH (Cathcart RF III., 1985) and indicative of increased risk of oxidative injury in subjects unable to produce enough NADPH due to GSH insufficiency. Vitamin E and carotenoids which are lipid-phase antioxidant can be conserved by GSH reducing power ability (Meister A et al, 1994). in that resp ect are two pools of GSH in liver which are the cytosolic GSH and mitochondrial GSH the first has a half-life of 2-4 hours and the second half-life is about 30hours (Meister A et al, 1995). There are various disorders associated with two enzymes involved in the two phase synthesis of GSH which include encircling(prenominal) neuropathy, haemolytic anaemia, aminoaciduria, CNS function defects, myopathy, spinocerebellar degeneration in inherited deficiency individuals (Meister A, Larsson A., 1995). Kosower NS. et al,. 1978 discovered the essential habit of GSH in cellular homeostasis and various cellular functions biological processes such as cell maturation, protein synthesis, transmembrane transport, intermediary metabolism, enzyme contact action and receptor action. Ondarza RN. , 1989 also observed that redox uniqueness are essential to life process with some vital enzymes and about eight taking part in glucose metabolism organism regulated by redox balance (2 thiol group and di sulphide). Intracellular sulfhydryl (-SH) groups of proteins are mainly pro-homeostatically regulated by GSH (Crane FL. et al,. 1988). The whole set out of biomolecules are protected by combination of the reducing power of glutathione with other antioxidants and ascorbate, which also helps in regulate their function, and to assist the survival and maximum functioning of the cell as a living unit. Metallothioneins are proteins which can bind with heavy metals and potential sulfhydryl poisons due to glutathiones reducing power and its -SH character that set the redox story and also speed up their removal from the body later (Hidalgo J. et al,. 1990). The redox state of many cellular environments are fine- tune homeostatically by glutathione reducing power. GSH plays a central role in the antioxidant defending team system that protects against various free radicals and oxidative stressors which its candid to regularly (Cross CE, Halliwell B, Borish ET, et al. 1987). The exogenous oxidative insults tends to be much easily controlled by GSH.SYSTEMIC ANTITOXIN ROLE OF GSHOrgans like lungs, intestines, kidneys and liver which are directly exposed to exogenous toxins are often important to GSH, although high concentration of GSH in lower section of lungs helps pine away inhaled toxins (cigarette smoke) and free radicals made by activated lung phagocytes (Lomaestro BM et al, 1995 Cross CE, Halliwell B, Borish ET, et al, 1987). The detoxification of substances foreign to body is mainly by the liver and also carries GSH to other organs. The bodily function of GSH transferase enzymes (GSTs) drains GSH in normal functioning liver while malnutrition or starvation depletes liver GSH stores (Deleve LD, Kaplowitz N. 1990 Mandl J, et al,. 1995). The electron-donating co-factor of GSTs is GSH due to definite specificity its has for it, although GSTs have fairly wide specificity for their substrates. GSH plays a fair sizable role in liver P450 conjugation activity which is responsible for about 60% of liver metabolites present in bile but GSH conjugation is certainly of full advantage to organism though it is not positive in every circumstance. There are different classes of xenobiotics that induce P450 enzymes which produce more toxic GSH conjugates than the parent xenobiotics ( Monks TJ, et al,. 1994). Depletion of liver pool of GSH can decrease conjugation and increase xenobiotics toxicity for example are Tylenol (experimental acetaminophen) and bromobenzene toxicity (Kidd PM. 1985). Glutathione and also glutathione S-transferase plays important role in the regulation of both acute and chronic chemical toxicity in the lung (west et al., 2003). Detoxification function of glutathione is dependent on the ability of its synthesis in the lungs and the cellular localization (plopper et al., 2001b, West et al., 2000). In human liver, the pulmonary glutathione S-transferase activity is about 30% while in the rodents liver, it is 5-15% (Buckpitt and Cru ikshank, 1997). The distribution of isoforms of glutathione S-transferase varies in the lungs. The result of polymorphisms expression in humans and potential for similarity of this with cancer of the lungs, curiously in smokers, makes glutathione transferase a focus point of acute interest. There are equilibrium systems working between enzymes, that is a decrease in one enzymes can cause an increase in another enzymes at the same time the location and balance of all the enzymes determines toxicity.CONCLUSIONGlutathione functions in the body are legion(predicate) which include neutralization of free radicals and reactive oxygen compounds, sustaining exogenous antioxidant in their reduced forms (Vitamins E and C). It also plays important role in diverse metabolic and biochemical reactions for example enzymes activation, DNA synthesis and repair, amino acid transport, protein synthesis, prostaglandin synthesis etc. In the immune system, glutathione manifest full potential by adjustin g antigen being presented to lymphocytes which might influence formation of cytokine, resulting in formation of cellular or humoral responses, magnitude of responses are increased by promoting lymphocytes production, thereby causing promotion of killing activity of cytotoxic T cells and NK cells and adjust apoptosis thus sustaining control of immune system.REFERENCESBuckpitt AR, Cruikshank MK Biochemical function of the respiratory tract Metabolism of Xenobiotics, in Sipes IG, Mc Queen CA, Gandolfi JA (eds.) Comprehensive Toxicology, Vol 8, Toxicology of the respiratory system. Oxford Elsevier Science, 1997, pp 159-186.Plopper CG, Buckpitt A, Evans M, et al. Factors modulating the epithelial response to toxicants in tracheobronchial airways.Toxicology. 160173-80, 2001b.West JA, caravan Winkle LS, Morin D, et al. Repeated inhalation exposures of the bioactivated cytotoxicant naphthalene (NA) produce airway specific clara cell tolerance in mice. Toxicol sci one hundred ninety286-29 3, 2003.West JA, Chichester CH, Buckpitt AR, et al. Heterogeneity of clara cell glutathione. A possible basis for differences in cellular responses to pulmonary cytotoxicants. Am J Respir cell Mol Biol 2327-36, 2000.Kosower NS, Kosower EM. The glutathione status of cells. Intl rev up Cytology 197854109-160.Meister A. Glutathione metabolism and transport. In Nygaard OF. Simic MG, ed. Radioprotectors and Anticarcinogens. smart York, NY Academic Press 1976.Kidd PM. Natural antioxidants-first line of defense. In Kidd PM, Huber W. Living with the AIDS Virus A outline for Long-Term Survival. Albany. California PMK Biomedical-Nutritional Consulting PMK Biomedical-Nutritional Consulting 1991115-142.Lomaestro BM, Malone M. Glutathione in health and disease pharmacotherapeutic issues. Annals Pharmacother 1995291263-73.Meister A. Minireview Glutathione-ascorbic acid antioxidant system in animals. J Biol Chem 1994(April1)269(13)9397-9400.Meister A, Larsson A. Glutathione synthetase deficienc y and other disorders of the gamma-glutamyl cycle. In Scriver CR, et al eds. The Meatbolic and Molecular Bases of Inherited Disease (volume 1). New York McGraw-Hill19951461-1495 (chapter 43).Meister A. Glutathione, ascorbate, and cellular protection. Cancer Res (Suppl) 1994(Apr 1)541969S-1975SMeister A. Mitochondrial changes associated with glutathione deficiency. Biochim Biophys Acta 1995127135-42.Meister A (1984) New aspects of glutathione biochemistry and transport-selective alteration of glutathione metabolism. Nutr Rev 42397-410.Meister A and Anderson ME (1983) Glutathione. Annu Rev Biochem 52711-760.Meister and Tate SS (1976) Glutathione and related gamma-glutamyl compounds Biosynthesis and utilization. Annu Rev Biochem 45559-604.Hinchman CA, Matsumoto H, Simmons Tw and Ballatori n (1991) Intrahepatic conversion of a glutathione conjugate to its mercapturic acid Metabolism of 1-chloro-2,4-dinitrobenzene in isolated perfused rat and guinea pig livers. J Biol Chem 26622179-22185 .Richman PG and Meister A (1975) Regulation of gamma-glutamylcysteine synthetase by nonallosteric feedback inhibition by glutathione. J Biol Chem 2501422-1426.Wei wang and Nazzareno Ballatori (1998) Endogenous glutathione conjugates Occurrence and biological functions. Pharmacological reviews Vol. 50, No 3.Zhang L. Phospholipid hydroperoxide glutathione peroxidise specific activity in rats of different ages. Biochim Biophys Acta 19891006140-143.Cathcart RF III. Vitamin C the nontoxic, nonrated-limited, antioxidant free radical scavenger. Med Hypotheses 19851861-77.Crane FL. Morre DJ. Low H (eds). Plasma Membrane Oxidoreductases in Control of Animal and plant Growth. New York Plenum Press 1988.Ondarza RN. Enzymes regulation by biological disulfides. Bioscience Reps 19899593-604.Hildalgo J. Garvey JS. Armario A. On the metallothionein. Glutathione and cysteine relationship in rat liver. J Pharmacol Exptl Ther 1990225554-564.Cross CE. Halliwell B. Borish ET. Et al. atomic number 8 rad icals and human disease (proceedings of a conference). Ann Intern Med 1987107526-545.Kidd PM. Liver biotransformation of xenobiotics, foods, and drugs to free radicals oxidants. In Levine SA. Kidd PM Antioxidant Adaptation- Its Role in Free Radical Pathology. San Leandro. CA Biocurrents 1985222-281.Deleve LD, Kaplowitz N. Importance and regulation of hepatic glutathione. Seminars Liver Dis 199010251-266.Mandl J, Banhegyi G, Kalapos MP, et al. Increased oxidation and decreased conjugation of drugs in the liver caused by starvation. Altered metabolism of certain aromatic compounds and acetone. Chem Biol move 19959687-101.Monks TJ, Lau SS. Glutathione conjugation as a mechanism for the transport of reactive metabolites. Adv Pharmacol 199427183-206.Kidd PM et al. (1997) Glutathione general protectant against oxidative and free radicals damage. Alternative medicine review vol.2 No 3, pp 155-176.Stryer L. Biochemistry (3rd ed) New York NY WH Freeman1988.Hinchman CA and Ballatori N (1994 ) Glutathione conjugation and conversion to mercapturic acids can occur as an intrahepatic process. J Toxicol Environ Health 41387-409.