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Glutathione
Glutathione
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Infobox disclaimer and references


Glutathione (GSH) is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine (which is attached by normal peptide linkage to a glycine) and the carboxyl group of the glutamate side-chain. It is an antioxidant, preventing damage to important cellular components caused by reactive oxygen species such as free radicals and peroxides.[1]

Thiol groups are reducing agents, existing at a concentration of approximately 5 mM in animal cells. Glutathione reduces disulfide bonds formed within cytoplasmic proteins to cysteines by serving as an electron donor. In the process, glutathione is converted to its oxidized form glutathione disulfide (GSSG), also called L(-)-Glutathione.

Glutathione is found almost exclusively in its reduced form, since the enzyme that reverts it from its oxidized form, 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 as a measure of cellular toxicity.[2]

Glutathione synthetase deficiency is a rare autosomal recessive[3] metabolic disorder that prevents the production of glutathione. Individuals affected by the severe form of this disorder may experience neurological symptoms. These problems may include seizures; a generalized slowing down of physical reactions, movements, and speech (psychomotor retardation); mental retardation; and a loss of coordination (ataxia).

BiosynthesisEdit

Glutathione is not an essential nutrient (meaning it does not have to be obtained via food), since it can be synthesized in the body from the amino acids L-cysteine, L-glutamic acid, and glycine. The sulfhydryl (thiol) group (SH) of cysteine serves as a proton donor and is responsible for the biological activity of glutathione. Provision of this amino acid is the rate-limiting factor in glutathione synthesis by the cells, since cysteine is relatively rare in foodstuffs. Furthermore, if released as the free amino acid, cysteine is toxic and spontaneously catabolized in the gastrointestinal tract and blood plasma.[4]

Glutathione 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.[5]
  • Second, glycine is added to the C-terminal of gamma-glutamylcysteine via the enzyme glutathione synthetase.

Animal 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.[6] Mice lacking GCLM demonstrate no outward phenotype, but exhibit marked decrease in GSH and increased sensitivity to toxic insults.[7][8][9]

While all cells in the human body are capable of synthesizing glutathione, liver glutathione synthesis has been shown to be essential. Mice with genetically-induced loss of GCLC (i.e., GSH synthesis) only in the liver die within 1 month of birth.[10]

The plant glutamate cysteine ligase (GCL) is a redox-sensitive homodimeric enzyme, conserved in the plant kingdom.[11] In an oxidizing environment, intermolecular disulfide bridges are formed and the enzyme switches to the dimeric active state. The mid-point potential of the critical cysteine pair is -318 mV. In addition to the redox-dependent control is the plant GCL enzyme feedback inhibited by GSH.[12] GCL is exclusively located in plastids, and glutathione synthetase is dual-targeted to plastids and cytosol, thus are GSH and gamma-glutamylcysteine exported from the plastids.[13] Both glutathione biosynthesis enzymes are essential in plants; knock-outs of GCL and GS are lethal to embryo and seedling.[14]

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.[15][16]

FunctionEdit

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.

Glutathione has multiple functions:

  • It is the major endogenous antioxidant produced by the cells, participating directly in the neutralization of free radicals and reactive oxygen compounds, as well as maintaining exogenous antioxidants such as vitamins C and E in their reduced (active) forms.[17]
  • Regulation of the nitric oxide cycle, which is critical for life but can be problematic if unregulated[18]
  • It is used in metabolic and biochemical reactions such as DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport, and enzyme activation. Thus, every system in the body can be affected by the state of the glutathione system, especially the immune system, the nervous system, the gastrointestinal system and the lungs.[4]

Function in animalsEdit

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.

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 is an essential antidote to overdose. Glutathione conjugates to NAPQI and helps to detoxify it. In this capacity, it protects cellular protein thiol groups, which would otherwise become 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 (often as a trademarked preparation called Mucomyst® [1]), 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-lactic acid.

Glutathione has recently been used as an inhibitor of melanin in the cosmetics industry. In countries like Japan and the Philippines, this product is sold as a whitening soap. Glutathione competitively inhibits melanin synthesis in the reaction of tyrosinase and L-DOPA by interrupting L-DOPA's ability to bind to tyrosinase during melanin synthesis. The inhibition of melanin synthesis was reversed by increasing the concentration of L-DOPA, but not by increasing tyrosinase. Although the synthesized melanin was aggregated within 1 h, the aggregation was inhibited by the addition of glutathione. These results indicate that glutathione inhibits the synthesis and agglutination of melanin by interrupting the function of L-DOPA."[19]

SupplementationEdit

Raising GSH levels through direct supplementation of glutathione is difficult. Research suggests that glutathione taken orally is not well absorbed across the gastrointestinal tract. In a study of acute oral administration of a very large dose (3 grams) of oral glutathione, Witschi and coworkers found "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."[20][21]

Calcitriol, the active metabolite of vitamin D synthesized in the kidney, increases glutathione levels in the brain and appears to be a catalyst for glutathione production.[22]

In addition, plasma and liver GSH concentrations can be raised by administration of certain supplements that serve as GSH precursors. N-acetylcysteine, commonly referred to as NAC, is the most bioavailable precursor of glutathione.[23] Other supplements, including S-adenosylmethionine (SAMe)[24][25][26] and whey protein[27][28][29][30][31][32] have also been shown to increase glutathione content within the cell.

NAC is available both as a drug and as a generic supplement. Alpha lipoic acid has also been shown to restore intracellular glutathione.[33][34] Melatonin has been shown to stimulate a related enzyme, glutathione peroxidase,[35] and silymarin, an extract of the seeds of the milk thistle plant (Silybum marianum) has also demonstrated an ability to replenish glutathione levels.[36][37]

Glutathione is a tightly regulated intracellular constituent, and is limited in its production by negative feedback inhibition of its own synthesis through the enzyme gamma-glutamylcysteine synthetase, thus greatly minimizing any possibility of overdosage. Glutathione augmentation using presursors of glutathione synthesis or intravenous glutathione is a strategy developed to address states of glutathione deficiency, high oxidative stress, immune deficiency, and xenobiotic overload in which glutathione plays a part in the detoxification of the xenobiotic in question (especially through the hepatic route). Glutathione deficiency states include, but are not limited to, HIV/AIDS, chemical and infectious hepatitis, myalgic encephalomyelitis chronic fatigue syndrome ME / CFS,[38][39][40] prostate and other cancers, cataracts, Alzheimer's disease, Parkinson's disease, chronic obstructive pulmonary disease, asthma, radiation poisoning, malnutritive states, arduous physical stress, and aging, and has been associated with suboptimal immune response. Many clinical pathologies are associated with oxidative stress and are elaborated upon in numerous medical references.,[4][41][42]

Low glutathione is also strongly implicated in wasting and negative nitrogen balance,[43] as seen in cancer, AIDS, sepsis, trauma, burns and even athletic overtraining. Glutathione supplementation can oppose this process, and in AIDS, for example, result in improved survival rates.[44] However, studies in many of these conditions have not been able to differentiate between low glutathione as a result of acutely (as in septic patients) or chronically (as in HIV) increased oxidative stress, and increased pathology as a result of preexisting deficiencies.

Schizophrenia and bipolar disorder are associated with lowered glutathione. Accruing data suggest that oxidative stress may be a factor underlying the pathophysiology of bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Glutathione (GSH) is the major free radical scavenger in the brain.[45] Diminished GSH levels elevate cellular vulnerability towards oxidative stress; characterized by accumulating reactive oxygen species. Replenishment of glutathione using N-acetyl cysteine has been shown to reduce symptoms of both disorders.[citation needed]

CancerEdit

Preliminary results indicate glutathione changes the level of reactive oxygen species in isolated cells grown in a laboratory,[46][47] which may reduce cancer development.[48] [49] None of these tests were performed in humans.

However, once a cancer has already developed, by conferring resistance to a number of chemotherapeutic drugs, elevated levels of glutathione in tumour cells are able to protect cancerous cells in bone marrow, breast, colon, larynx, and lung cancers.[50]

PathologyEdit

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.[51]

Methods to determine glutathioneEdit

Reduced glutathione may be visualized using Ellman's reagent or bimane derivates such as monobromobimane. The monobromobimane method is more sensitive. In this procedure, cells are lysed and thiols extracted using a HCl buffer. The thiols are then reduced with dithiothreitol (DTT) and labelled by monobromobimane. Monobromobimane becomes fluorescent after binding to GSH. The thiols are then separated by HPLC and the fluorescence quantified with a fluorescence detector. Bimane may also be used to quantify glutathione in vivo. The quantification is done by confocal laser scanning microscopy after application of the dye to living cells.[52] Another approach, which allows to measure the glutathione redox potential at a high spatial and temporal resolution in living cells is based on redox imaging using the redox-sensitive green fluorescent protein (roGFP)[53] or redox sensitive yellow fluorescent protein (rxYFP) [54]

See alsoEdit

ReferencesEdit

  1. (2003). The changing faces of glutathione, a cellular protagonist. Biochemical Pharmacology 66 (8): 1499–503.
  2. (2003). Determination of blood total, reduced, and oxidized glutathione in pediatric subjects. Clinical Chemistry 47 (8): 1467–9.
  3. Njålsson, R; Ristoff, E; Carlsson, K; Winkler, A; Larsson, A; Norgren, S (April 2005). Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency. Human genetics 116 (5): 384–9.
  4. 4.0 4.1 4.2 http://www.drugs.com/pdr/immunocal-powder-sachets.html
  5. http://www.sciencedirect.com/science/article/pii/S000326970300143X, someone please correct Wiki notation
  6. (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. Biochemical and Biophysical Research Communications 279 (2): 324–9.
  7. (2002). Initial characterization of the glutamate-cysteine ligase modifier subunit Gclm(-/-) knockout mouse. Novel model system for a severely compromised oxidative stress response. Journal of Biological Chemistry 277 (51): 49446–52.
  8. (2007). Organophosphorus insecticides chlorpyrifos and diazinon and oxidative stress in neuronal cells in a genetic model of glutathione deficiency. Toxicology and Applied Pharmacology 219 (2–3): 181–9.
  9. (2007). Glutamate Cysteine Ligase Modifier Subunit Deficiency and Gender as Determinants of Acetaminophen-Induced Hepatotoxicity in Mice. Toxicological Sciences 99 (2): 628–36.
  10. (2007). Hepatocyte-specificGclcdeletion leads to rapid onset of steatosis with mitochondrial injury and liver failure. Hepatology 45 (5): 1118–28.
  11. (2006). Structural Basis for the Redox Control of Plant Glutamate Cysteine Ligase. Journal of Biological Chemistry 281 (37): 27557–65.
  12. (2007). Thiol-Based Regulation of Redox-Active Glutamate-Cysteine Ligase from Arabidopsis thaliana. The Plant Cell Online 19 (8): 2653–61.
  13. (2004). Differential targeting of GSH1 and GSH2 is achieved by multiple transcription initiation: implications for the compartmentation of glutathione biosynthesis in the Brassicaceae. The Plant Journal 41 (1): 15–30.
  14. (2007). Restricting glutathione biosynthesis to the cytosol is sufficient for normal plant development. The Plant Journal 53 (6): 999–1012.
  15. (2002). {{{title}}}. Genome Biology 3 (5): research0025.1.
  16. Grill D, Tausz T, De Kok LJ (2001). Significance of glutathione in plant adaptation to the environment, Springer.
  17. Scholz RW. Graham KS. Gumpricht E. Reddy CC. Mechanism of interaction of vitamin E and glutathione in the protection against membrane lipid peroxidation. Ann NY Acad Sci 1989:570:514-7. Hughes RE. Reduction of dehydroascorbic acid by animal tissues.Nature 1964:203:1068-9.
  18. (1999). Phytochelatin synthase genes from Arabidopsis and the yeast Schizosaccharomyces pombe. The Plant cell 11 (6): 1153–64.
  19. (2008). Inhibitory Mechanism of Melanin Synthesis by Glutathione. Yakugaku Zasshi 128 (8): 1203–7.
  20. (1992). The systemic availability of oral glutathione. European Journal of Clinical Pharmacology 43 (6): 667–9.
  21. AIDS Line Update
  22. (2002). New clues about vitamin D functions in the nervous system. Trends in Endocrinology and Metabolism 13 (3): 100–5.
  23. (1993). Biochemical manipulation of intracellular glutathione levels influences cytotoxicity to isolated human lymphocytes by sulfur mustard. Cell Biology and Toxicology 9 (3): 259–67.
  24. (2002). S-adenosyl-L-methionine: its role in the treatment of liver disorders. The American journal of clinical nutrition 76 (5): 1183S–7S.
  25. (1989). Effects of Oral S-Adenosyl-l-Methionine on Hepatic Glutathione in Patients with Liver Disease. Scandinavian Journal of Gastroenterology 24 (4): 407–15.
  26. (1994). Effect of S-adenosyl-L-methionine administration on red blood cell cysteine and glutathione levels in alcoholic patients with and without liver disease. Alcohol and alcoholism (Oxford, Oxfordshire) 29 (5): 597–604.
  27. (2001). Oral supplementation with whey proteins increases plasma glutathione levels of HIV-infected patients. European Journal of Clinical Investigation 31 (2): 171–8.
  28. (2006). Features of Whey Protein Concentrate Supplementation in Children with Rapidly Progressive HIV Infection. Journal of Tropical Pediatrics 52 (1): 34–8.
  29. (2003). Improved glutathione status in young adult patients with cystic fibrosis supplemented with whey protein. Journal of Cystic Fibrosis 2 (4): 195–8.
  30. (2002). Effects of long-term supplementation with whey proteins on plasma glutathione levels of HIV-infected patients. European Journal of Nutrition 41 (1): 12–8.
  31. (1993). Whey proteins as a food supplement in HIV-seropositive individuals. Clinical and investigative medicine. Medecine clinique et experimentale 16 (3): 204–9.
  32. (1991). The biological activity of undenatured dietary whey proteins: role of glutathione. Clinical and investigative medicine. Medecine clinique et experimentale 14 (4): 296–309.
  33. (2009). Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential. Biochimica et Biophysica Acta (BBA) - General Subjects 1790 (10): 1149–60.
  34. (1992). Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo. Arzneimittel-Forschung 42 (6): 829–31.
  35. (1995). Melatonin stimulates brain glutathione peroxidase activity. Neurochemistry International 26 (5): 497–502.
  36. (2007). Protective effect of silymarin on oxidative stress in rat brain. Phytomedicine 14 (2–3): 129–35.
  37. (2007). Selectivity of Silymarin on the Increase of the Glutathione Content in Different Tissues of the Rat. Planta Medica 55 (5): 420–2.
  38. (2002). CFS Treatment using Glutathione in Immunoprop. The CFS HandBook: 58–62.
  39. (1999). Competition for glutathione precursors between the immune system and the skeletal muscle: Pathogenesis of chronic fatigue syndrome. Med Hypotheses. 53(4) (oct): 347–9.
  40. (2000). Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome. Redox Rep. 1 (5): 35–41.
  41. Glutathione: Information for Physicians: http://www.nutritionadvisor.com/glutathione.html
  42. Benefits of Glutathione Enhancement in Disease or Stress: Pulmonary Disease http://www.fda.gov/ohrms/dockets/ac/00/slides/3652s1_05/tsld018.htm
  43. (1997). Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 11 (13): 1077–89.
  44. (1997). Glutathione deficiency is associated with impaired survival in HIV disease. Proceedings of the National Academy of Sciences 94 (5): 1967–72.
  45. (2011). Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) 14 (1): 123–30.
  46. (2009). The effects of N-acetyl cysteine, buthionine sulfoximine, diethyldithiocarbamate or 3-amino-1,2,4-triazole on antimycin A-treated Calu-6 lung cells in relation to cell growth, reactive oxygen species and glutathione. Oncology Reports: 385–91.
  47. (2007). Modulation of Human Glutathione S-Transferases by Polyphenon E Intervention. Cancer Epidemiology Biomarkers & Prevention 16 (8): 1662–6.
  48. WebMD: Whey Protein May Prevent Prostate Cancer
  49. Glutathione Information on MedicineNet.com (a WebMD feature)
  50. (2004). The role of glutathione in cancer. Cell Biochemistry and Function 22 (6): 343–52.
  51. (2000). Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis. Neuroscience Research 37 (3): 227–36.
  52. (2001). Quantitative in vivo measurement of glutathione in Arabidopsis cells. The Plant Journal 27 (1): 67–78.
  53. (2007). Redox-sensitive GFP inArabidopsis thalianais a quantitative biosensor for the redox potential of the cellular glutathione redox buffer. The Plant Journal 52 (5): 973–86.
  54. (2008). High-resolution imaging of redox signaling in live cells through an oxidation-sensitive yellow fluorescent protein. Science Signaling 1 (43): pl3.

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