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| Abbreviations=GSH
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| ChemSpiderID = 111188
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| PubChem=124886
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Revision as of 21:11, 8 September 2009

{{chembox | verifiedrevid = 268444898 |Reference=[1] |ImageFile=Glutathion.svg |ImageSize= 200px |ImageFile2=Glutathione-from-xtal-3D-balls.png |ImageSize2= 200px |IUPACName=(2S)-2-amino-4-{[(1R)-1-[(carboxymethyl)carbamoyl]-2-sulfanylethyl]carbamoyl}butanoic acid |OtherNames=γ-L-Glutamyl-L-cysteinylglycine
(2S)-2-Amino-5-[[(2R)-1-(carboxymethylamino)-1-oxo- 3-sulfanylpropan-2-yl]amino]-5-oxopentanoic acid |Section1= ! colspan=2 style="background: #f8eaba; text-align: center;" |Identifiers

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3D model (JSmol)

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| Abbreviations | GSH |-


| ChemSpider

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| ECHA InfoCard | 100.000.660 Edit this at Wikidata |-



| MeSH | Glutathione |-

|

|

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| colspan="2" |

  • C(CC(=O)N[C@@H](CS)C(=O)NCC(=O)O)[C@@H](C(=O)O)N

|- |Section2= ! colspan=2 style="background: #f8eaba; text-align: center;" |Properties

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| C10H17N3O6S

|- | Molar mass

| 307.32 g/mol

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| Melting point | 195 °C (383 °F; 468 K)

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|

| Miscible |- |Section3= }} 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, helps protect cells from reactive oxygen species such as free radicals and peroxides.[2]

Thiol groups are kept in a reduced state at a concentration of approximately ~5 mM in animal cells. In effect, glutathione reduces any disulfide bond formed within cytoplasmic proteins to cysteines by acting as an electron donor. In the process, glutathione is converted to its oxidized form glutathione disulfide (GSSG). 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 scientifically as a measure of cellular toxicity.[3]

Biosynthesis

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

Animal and insect 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.[4] Mice lacking GCLM demonstrate no outward phenotype, but exhibit marked decrease in GSH and increased sensitivity to toxic insults.[5][6][7]

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.[8]

The plant glutamate cysteine ligase (GCL) is a redox sensitive homodimeric enzyme, conserved in the plant kingdom.[9]. 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 paire is - 318 mV. In addition to the redox dependent control is the plant GCL enzyme feedback inhibited by GSH.[10] 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.[11] Both glutathione biosynthesis enzymes are essential in plants, knock-outs of GCL and GS are embryo and seedling lethal.[12]

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.[13][14]

Function

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.

Function in animals

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 conjugates to NAPQI and helps to detoxify it, in this capacity 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, 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 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. "[15]

Function in plants

In plants glutathione is crucial for biotic and abiotic stress management. It is a pivotal component of the glutathione-ascorbate cycle, a system that reduces poisonous hydrogen peroxide. [16] It is the precursor of phytochelatins, glutathione oligomeres which chelates heavy metals such as cadmium. [17] Glutathione is required for efficient defence against plant pathogens such as Pseudomonas syringae and Phytophthora brassicae. [18] APS reductase, an enzyme of the sulfur assimilation pathway uses glutathione as electron donor. Other enzymes using glutathione as substrate are glutaredoxin, these small oxidoreductases are involved in flower development, salicylic acid and plant defence signalling. [19]

Supplementation

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."[20][21]

However, tissue and sperm glutathione concentrations can be raised by increased intake of the precursor cysteine, or in chronic conditions, by S-adenosylmethionine (SAMe).[22][23] Glutathione precursors rich in cysteine include N-acetylcysteine (NAC)[24][25] and undenatured whey protein,[26][27][28][29][30][31][32][33] and these supplements have been shown to increase glutathione content within the cell. N-Acetylcysteine is available both as a drug and as a generic supplement.

Cancer

Glutathione has shown positive preliminary results in several studies of glutathione's ability to affect levels of reactive oxygen species,[34] [35] which may have implications in the reduction of cancer rates.[36] [37]

Pathology

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. [38]

Methods to determine glutathione

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. Subsequently are the thiols reduced with DTT and labelled by monobromobimane. Monobrombimane 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 CLSM after application of the dye to living cells.[39] An other 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). [40]

See also

References

  1. ^ Merck Index, 11th Edition, 4369.
  2. ^ Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF (2003). "The changing faces of glutathione, a cellular protagonist". Biochem Pharmacol. 66 (8): 1499–503. doi:10.1016/S0006-2952(03)00504-5. PMID 14555227. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Pastore A, Piemonte F, Locatelli M, Lo Russo A, Gaeta LM, Tozzi G, Federici G (2003). "Determination of blood total, reduced, and oxidized glutathione in pediatric subjects". Clin. Chem. 47: 1467–1469. PMID 11468240. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Dalton, TP; et al. (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. {{cite journal}}: Explicit use of et al. in: |last2= (help)
  5. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: unflagged free DOI (link)
  6. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)
  7. ^ McConnachie LA, Mohar I, Hudson FN; et al. (2007). "Glutamate cysteine ligase modifier subunit deficiency and gender as determinants of acetaminophen-induced hepatotoxicity in mice". Toxicol Sci. 99 (2): 628–36. doi:10.1093/toxsci/kfm165. PMID 17584759. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)
  9. ^ Hothorn M, Wachter A, Gromes R, Stuwe T, Rausch T, Scheffzek K (2006). "Structural basis for the redox control of plant glutamate cysteine ligase". J Biol Chem. 15: 27557–65. doi:10.1074/jbc.M602770200. PMID 16766527. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  10. ^ Hicks LM, Cahoon RE, Bonner ER, Rivard RS, Sheffield J, Jez JM (2007). "Thiol-based regulation of redox-active glutamate-cysteine ligase from Arabidopsis thaliana". Plant Cell. 19: 2653–61. doi:10.1105/tpc.107.052597. PMID 17766407. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Wachter A, Wolf S, Steininger H, Bogs J, Rausch T. (2005). "Differential targeting of GSH1 and GSH2 is achieved by multiple transcription initiation: implications for the compartmentation of glutathione biosynthesis in the Brassicaceae". Plant J. 41: 15–30. doi:10.1111/j.1365-313X.2004.02269.x. PMID 15610346. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Pasternak M, Lim B, Wirtz M, Hell R, Cobbett CS, Meyer AJ (2008). "Restricting glutathione biosynthesis to the cytosol is sufficient for normal plant development". Plant J. 53: 999–1012. doi:10.1111/j.1365-313X.2007.03389.x. PMID 18088327. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ 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. {{cite journal}}: Unknown parameter |nopp= ignored (|no-pp= suggested) (help)CS1 maint: unflagged free DOI (link)
  14. ^ Grill D, Tausz T, De Kok LJ (2001). Significance of glutathione in plant adaptation to the environment. Springer. ISBN 1402001789.{{cite book}}: CS1 maint: multiple names: authors list (link)
  15. ^ http://www.ncbi.nlm.nih.gov/pubmed/18670186
  16. ^ Noctor G, Foyer CH (1998). "ASCORBATE AND GLUTATHIONE: Keeping Active Oxygen Under Control". Annu Rev Plant Physiol Plant Mol Biol. 49: 249–279. PMID 15012235. {{cite journal}}: Text "doi:10.1146/annurev.arplant.49.1.249" ignored (help)
  17. ^ Suk-Bong Ha, Aaron P. Smith, Ross Howden, Wendy M. Dietrich, Sarah Bugg, Matthew J. O'Connell, Peter B. Goldsbrough, and Christopher S. Cobbett (1999). "Phytochelatin Synthase Genes from Arabidopsis and the Yeast Schizosaccharomyces pombe". Plant Cell. 11: 1153–1164. doi:10.1105/tpc.11.6.1153. PMID 10368185.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Parisy V, Poinssot B, Owsianowski L, Buchala A, Glazebrook J, Mauch F (2007). "Identification of PAD2 as a gamma-glutamylcysteine synthetase highlights the importance of glutathione in disease resistance of Arabidopsis". Plant J. 49: 159–72. PMID 17144898. {{cite journal}}: Text "doi: 10.1111/j.1365-313X.2006.02938.x" ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ Rouhier N, Lemaire SD, Jacquot JP (2008). "The role of glutathione in photosynthetic organisms: emerging functions for glutaredoxins and glutathionylation". Annu Rev Plant Biol. 59: 143–66. doi:10.1146/annurev.arplant.59.032607.092811. PMID 18444899.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Witschi A, Reddy S, Stofer B, Lauterburg BH (1992). "The systemic availability of oral glutathione". Eur J Clin Pharmacol. 43 (6): 667–9. doi:10.1007/BF02284971. PMID 1362956.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ AIDS Line Update
  22. ^ Liber CS, Packer L (2002). "S-Adenosylmethionine: molecular, biological, and clinical aspects—an introduction". Am J Clin Nutr. 76 (5): 1148S–50S. PMID 12418492. {{cite journal}}: Unknown parameter |month= ignored (help)
  23. ^ Liber CS (2002). "S-Adenosyl-L-methionine: its role in the treatment of liver disorders". Am J Clin Nutr. 76 (5): 1183S–1187S. PMID 12418503. {{cite journal}}: Unknown parameter |month= ignored (help)
  24. ^ Acetylcysteine and glutathione, PubMed
  25. ^ 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. doi:10.1007/BF00755604. PMID 8299004.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ^ Glutathione information for Physicians
  27. ^ Micke P, Beeh KM, Schlaak JF, Buhl R (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  28. ^ Moreno YF, Sgarbieri VC, da Silva MN, Toro AA, Vilela MM (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  29. ^ Grey V, Mohammed SR, Smountas AA, Bahlool R, Lands LC (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  30. ^ Micke P, Beeh KM, Buhl R (2002). "Effects of long-term supplementation with whey proteins on plasma glutathione levels of HIV-infected patients". Eur J Nutr. 41 (1): 12–8. doi:10.1007/s003940200001. PMID 11990003. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  31. ^ Bounous G, Baruchel S, Falutz J, Gold P (1993). "Whey proteins as a food supplement in HIV-seropositive individuals". Clin Invest Med. 16 (3): 204–9. PMID 8365048. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  32. ^ Bounous G, Gold P (1991). "The biological activity of undenatured dietary whey proteins: role of glutathione". Clin Invest Med. 14 (4): 296–309. PMID 1782728. {{cite journal}}: Unknown parameter |month= ignored (help)
  33. ^ Bounous et al. Multiple references on glutathione enhancement with bioactive whey protein in multiple disease states
  34. ^ Han YH, Park WH (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". Oncol Rep. 22 (2): 385–91. PMID 19578781. {{cite journal}}: Unknown parameter |month= ignored (help)
  35. ^ Chow HH, Hakim IA (2007). "Modulation of human glutathione s-transferases by polyphenone intervention". Cancer Epidemiol Biomarkers Prev. 16 (8): 1662–6. PMID 17684143. {{cite journal}}: Unknown parameter |month= ignored (help)
  36. ^ WebMD: Whey Protein May Prevent Prostate Cancer
  37. ^ Glutathione Information on MedicineNet.com (a WebMD feature)
  38. ^ Pereira C.F, de Oliveira C.R. (2000). "Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis". Neuroscience Research. 37 (3): 227–36. doi:10.1016/S0168-0102(00)00124-3. {{cite journal}}: Unknown parameter |month= ignored (help)
  39. ^ Meyer AJ, May MJ, Fricker M (2001). "Quantitative in vivo measurement of glutathione in Arabidopsis cells". Plant J. 27 (1): 67–78. doi:10.1046/j.1365-313x.2001.01071.x. PMID 11489184.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  40. ^ Meyer, A.J., Brach, T., Marty, L., Kreye, S., Rouhier, N., Jacquot, J.P., and Hell, R. (2007). "Redox-sensitive GFP in Arabidopsis thaliana is a quantitative biosensor for the redox potential of the cellular glutathione redox buffer". Plant J. 52 (5): 973–86. doi:10.1111/j.1365-313X.2007.03280.x. PMID 17892447.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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