Glutathione

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Glutathione (GSH) is a tripeptide.

It contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side chain. Glutathione, an antioxidant, protects cells from toxins such as free radicals.[1]

Thiol groups are kept in a reduced state at a concentration of approximately ~5 mM in animal cells.

In effect, glutathione reduces any disulfide bonds formed within cytoplasmic proteins to cysteines by acting as an electron donor. Glutathione is found almost exclusively in its reduced form, since the enzyme that reverts it from its oxidized form (GSSG), glutathione reductase, is constitutively active and inducible upon oxidative stress. In fact, the ratio of reduced glutathione to oxidized glutathione within cells is often used scientifically as a measure of cellular toxicity.

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Contents

Biosynthesis of glutathione

Glutathione is not an essential nutrient since it can be synthesized from the amino acids L-cysteine, L-glutamate and glycine.

It is synthesized in two adenosine triphosphate-dependent steps:

  • First, gamma-glutamylcysteine is synthesized from L-glutamate and cysteine via the enzyme gamma-glutamylcysteine synthetase (a.k.a. glutamate cysteine ligase, GCL). This reaction is the rate-limiting step in glutathione synthesis.
  • Second, glycine is added to the C-terminal of gamma-glutamylcysteine via the enzyme glutathione synthetase.

Glutamate cysteine ligase (GCL) is a heterodimeric enzyme composed of a catalytic (GCLC) and modulatory (GCLM) subunit. GCLC constitutes all the enzymatic activity, whereas GCLM increases the catalytic efficiency of GCLC. Mice lacking GCLC (i.e., all de novo GSH synthesis) die before birth.[2] Mice lacking GCLM demonstrate no outward phenotype, but exhibit marked decrease in GSH and increased sensitivity to toxic insults.[3][4][5]

While all cells in the human body are capable of synthesizing glutathione, liver glutathione synthesis has been shown to be essential. Following birth, mice with genetically-induced loss of GCLC (i.e., GSH synthesis) only in the liver die within 1 month of birth.[6]

The biosynthesis pathway for glutathione is found in some bacteria, like cyanobacteria and proteobacteria, but is missing in many other bacteria. Most eukaryotes synthesize glutathione, including humans, but some do not, such as Leguminosae, Entamoeba, and Giardia. The only archaea that make glutathione are halobacteria.[7][8]

 

Function of glutathione

Glutathione exists in reduced (GSH) and oxidized (GSSG) states. In the reduced state, the thiol group of cysteine is able to donate a reducing equivalent (H++ e-) to other unstable molecules, such as reactive oxygen species. In donating an electron, glutathione itself becomes reactive, but readily reacts with another reactive glutathione to form glutathione disulfide (GSSG). Such a reaction is possible due to the relatively high concentration of glutathione in cells (up to 5 mM in the liver). GSH can be regenerated from GSSG by the enzyme glutathione reductase.

In healthy cells and tissue, more than 90% of the total glutathione pool is in the reduced form (GSH) and less than 10% exists in the disulfide form (GSSG). An increased GSSG-to-GSH ratio is considered indicative of oxidative stress.

GSH is known as a substrate in both conjugation reactions and reduction reactions, catalyzed by glutathione S-transferase enzymes in cytosol, microsomes, and mitochondria. However, it is also capable of participating in non-enzymatic conjugation with some chemicals, as in the case of n-acetyl-p-benzoquinone imine (NAPQI), the reactive cytochrome P450-reactive metabolite formed by paracetamol (or acetaminophen as it is known in the US), that becomes toxic when GSH is depleted by an overdose of acetaminophen.

Glutathione in this capacity binds to NAPQI as a suicide inhibitor and in the process detoxifies it, taking the place of cellular protein thiol groups, which would otherwise be covalently modified; when all GSH has been spent, NAPQI begins to react with the cellular proteins, killing the cells in the process. The preferred treatment for an overdose of this painkiller is the administration (usually in atomized form) of N-acetyl-L-cysteine, which is processed by cells to L-cysteine and used in the de novo synthesis of GSH.

Glutathione (GSH) participates in leukotriene synthesis and is a cofactor for the enzyme glutathione peroxidase. It is also important as a hydrophilic molecule that is added to lipophilic toxins and waste in the liver during biotransformation before they can become part of the bile. Glutathione is also needed for the detoxification of methylglyoxal, a toxin produced as a by-product of metabolism.

This detoxification reaction is carried out by the glyoxalase system. Glyoxalase I (EC 4.4.1.5) catalyzes the conversion of methylglyoxal and reduced glutathione to S-D-Lactoyl-glutathione. Glyoxalase II (EC 3.1.2.6) catalyzes the hydrolysis of S-D-Lactoyl-glutathione to glutathione and D-lactate.

 

Supplementation of glutathione

Supplementing has been difficult, as research suggests that glutathione taken orally is not well absorbed across the GI tract. In a study of acute oral administration of a very large dose (3 grams) of oral glutathione, Witschi and coworkers found that "it is not possible to increase circulating glutathione to a clinically beneficial extent by the oral administration of a single dose of 3 g of glutathione."[9][10]. However, tissue and serum glutathione concentrations can be raised by increased intake of the precursor cysteine. Glutathione precursors rich in cysteine include N-acetylcysteine (NAC),[11], [12] and undenatured whey protein [13][14][15][16][17][18][19][20], and these supplements have been shown to increase glutathione content within the cell. N-acetylcysteine is a generically available supplement which has been demonstrated to increase intracellular reduced and total glutathione by 92% and 58% respectively. [21] All of the published clinical studies using bioactive whey proteins mentioned in the references above used a form of a bioactive whey protein and bonded cystine dietary supplement derived from lactose-free organic milk (whey protein) called Immunocal. This whey protein is clinically proven to increase glutathione levels within the lymphocytes of the immune system by 35.5% while increasing peak power and muscular performance by 13%. [22]

 

Pathology associated with glutatione

Excess glutamate at synapses, which may be released in conditions such as traumatic brain injury, can prevent the uptake of cysteine, a necessary building block of glutathione. Without the protection from oxidative injury afforded by glutathione, cells may be damaged or killed.[23]

 

See also for glutatione

  • Glutathione synthetase deficiency

 

Glutatione References

  1. ^ Strużńka L, Chalimoniuk M, Sulkowski G. (September 2005). "The role of astroglia in Pb-exposed adult rat brain with respect to glutamate toxicity". Toxicology 212 (2-3): 185–194. doi:10.1016/j.tox.2005.04.013. PMID 15955607. 
  2. ^ Dalton, TP (2000). "Knockout of the Mouse Glutamate Cysteine Ligase Catalytic Subunit (Gclc) Gene: Embryonic Lethal When Homozygous, and Proposed Model for Moderate Glutathione Deficiency When Heterozygous". Biochem Biophys Res Commun. 279 (2): 324. doi:10.1006/bbrc.2000.3930. 
  3. ^ Yang Y, et al. (2002). "Initial Characterization of the Glutamate-Cysteine Ligase Modifier Subunit Gclm(-/-) Knockout Mouse. NOVEL MODEL SYSTEM FOR A SEVERELY COMPROMISED OXIDATIVE STRESS RESPONSE". J Biol Chem 277 (51): 49446. doi:10.1074/jbc.M209372200. PMID 12384496. 
  4. ^ Giordano G, et al. (2007). "Organophosphorus insecticides chlorpyrifos and diazinon and oxidative stress in neuronal cells in a genetic model of glutathione deficiency". Toxicol Appl Pharmacol 219 (2-3): 181. doi:10.1016/j.taap.2006.09.016. 
  5. ^ McConnachie LA, et al. (2007) Tox Sci Epub 21 June.
  6. ^ Chen Y, et al. (2007). "Hepatocyte-specificGclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure". Hepatology 45: 1118. doi:10.1002/hep.21635. 
  7. ^ Shelley D. Copley and Jasvinder K. Dhillon (2002). "Lateral gene transfer and parallel evolution in the history of glutathione biosynthesis genes" (free full text). Genome biology 3: research0025.1. doi:10.1186/gb-2002-3-5-research0025. 
  8. ^ Grill D, Tausz T, De Kok LJ (2001). Significance of glutathione in plant adaptation to the environment. Springer. ISBN 1402001789. 
  9. ^ Witschi A, Reddy S, Stofer B, Lauterburg BH (1992). "The systemic availability of oral glutathione". Eur. J. Clin. Pharmacol. 43 (6): 667–9. PMID 1362956. 
  10. ^ AIDS Line Update
  11. ^ Acetylcysteine and glutathione, PubMed
  12. ^ Gross CL, Innace JK, Hovatter RC, Meier HL, Smith WJ (1993). "Biochemical manipulation of intracellular glutathione levels influences cytotoxicity to isolated human lymphocytes by sulfur mustard". Cell Biol. Toxicol. 9 (3): 259–67. PMID 8299004. 
  13. ^ Glutathione information for Physicians
  14. ^ Micke P, Beeh KM, Schlaak JF, Buhl R (February 2001). "Oral supplementation with whey proteins increases plasma glutathione levels of HIV-infected patients". Eur. J. Clin. Invest. 31 (2): 171–8. doi:10.1046/j.1365-2362.2001.00781.x. PMID 11168457. 
  15. ^ Moreno YF, Sgarbieri VC, da Silva MN, Toro AA, Vilela MM (February 2006). "Features of whey protein concentrate supplementation in children with rapidly progressive HIV infection". J. Trop. Pediatr. 52 (1): 34–8. doi:10.1093/tropej/fmi074. PMID 16014759. 
  16. ^ Grey V, Mohammed SR, Smountas AA, Bahlool R, Lands LC (December 2003). "Improved glutathione status in young adult patients with cystic fibrosis supplemented with whey protein". J. Cyst. Fibros. 2 (4): 195–8. doi:10.1016/S1569-1993(03)00097-3. PMID 15463873. 
  17. ^ Micke P, Beeh KM, Buhl R (February 2002). "Effects of long-term supplementation with whey proteins on plasma glutathione levels of HIV-infected patients". Eur J Nutr 41 (1): 12–8. PMID 11990003. 
  18. ^ Bounous G, Baruchel S, Falutz J, Gold P (June 1993). "Whey proteins as a food supplement in HIV-seropositive individuals". Clin Invest Med 16 (3): 204–9. PMID 8365048. 
  19. ^ Bounous G, Gold P (August 1991). "The biological activity of undenatured dietary whey proteins: role of glutathione". Clin Invest Med 14 (4): 296–309. PMID 1782728. 
  20. ^ Bounous et al. Multiple references on glutathione enhancement with bioactive whey protein in multiple disease states
  21. ^ Yim CY, Hibbs JB, McGregor JR, Galinsky RE, Samlowski WE (June 1994). "Use of N-acetyl cysteine to increase intracellular glutathione during the induction of antitumor responses by IL-2". J. Immunol. 152 (12): 5796–805. PMID 8207209. 
  22. ^ Lands LC, Grey VL, Smountas AA (October 1999). "Effect of supplementation with a cysteine donor on muscular performance". J. Appl. Physiol. 87 (4): 1381–5. PMID 10517767. 
  23. ^ Pereira C.F, de Oliveira C.R. (July 2000). "Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis". Neuroscience Research 37 (3): 227–236. doi:10.1016/S0168-0102(00)00124-3. 

 

Related research

  • The antioxidant glutathione peroxidase family and spermatozoa: A complex story. PMID 16427183
  • The Role of Glutathione in Cell Defense.
  • Glutathione metabolism and its implications for health. PMID 14988435
  • The changing faces of glutathione, a cellular protagonist. PMID 14555227
  • Ophthalmic acid

Web links

Glutathione effects]

Glutathione, the mother of all antioxidants

 

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