Glutathione 81625 225473798 2008-07-13T21:50:03Z ToNToNi 5531086 [[ca:Glutatió]] {{Chembox new |ImageFile=Glutathione-skeletal.svg |ImageSize= 350px |ImageFile2=Glutathione-3D-vdW.png |ImageSize2= 300px |IUPACName= |OtherNames= |Section1= {{Chembox Identifiers | CASNo=70-18-8 | PubChem=745 | SMILES=NC(CCC(=O)NC(CS)C (=O)NCC(O)=O)C(O)=O | MeSHName=Glutathione }} |Section2= {{Chembox Properties | Formula=C<sub>10</sub>H<sub>17</sub>N<sub>3</sub>O<sub>6</sub>S | MolarMass=307.325 | Appearance= | Density= | MeltingPt= | BoilingPt= | Solubility= }} |Section3= {{Chembox Hazards | MainHazards= | FlashPt= | Autoignition= }} }} '''Glutathione''' ('''GSH''') is a [[tripeptide]]. It contains an unusual [[peptide]] linkage between the [[amino acid|amine group]] of [[cysteine]] and the [[carboxyl]] group of the [[glutamate]] [[side chain]]. Glutathione, an [[antioxidant]], protects cells from toxins such as [[free radical]]s.<ref>{{cite journal | author = Strużńka L, Chalimoniuk M, Sulkowski G. | year = 2005 | month = September | title = The role of astroglia in Pb-exposed adult rat brain with respect to glutamate toxicity | journal = Toxicology | volume = 212 | issue = 2-3 | pages = 185–194 | pmid = 15955607 | accessdate = | doi = 10.1016/j.tox.2005.04.013 }} </ref> [[Thiol]] groups are kept in a [[redox|reduced]] state at a concentration of approximately ~5 mM in [[animal]] [[cell (biology)|cell]]s. In effect, glutathione reduces any [[disulfide bond]]s formed within [[cytoplasm]]ic [[protein]]s to [[cysteine]]s 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. ==Biosynthesis== 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.<ref>{{Cite journal | last = Dalton | first = TP | last2 = et al. | year = 2000 | journal = Biochem Biophys Res Commun. | volume = 279 | issue = 2 | pages = 324 | doi = 10.1006/bbrc.2000.3930 | title = Knockout of the Mouse Glutamate Cysteine Ligase Catalytic Subunit (Gclc) Gene: Embryonic Lethal When Homozygous, and Proposed Model for Moderate Glutathione Deficiency When Heterozygous}}</ref> Mice lacking GCLM demonstrate no outward phenotype, but exhibit marked decrease in GSH and increased sensitivity to toxic insults.<ref>{{Cite journal | author = Yang Y, et al. | year = 2002 | journal = [[J Biol Chem]] | volume = 277 | issue = 51 | pages = 49446 | doi = 10.1074/jbc.M209372200}}</ref><ref>{{cite journal | author = Giordano G, et al. | year = 2007 | journal = Toxicol Appl Pharmacol | volume = 219 | issue = 2-3 | pages = 181 | doi = 10.1016/j.taap.2006.09.016 | title = Organophosphorus insecticides chlorpyrifos and diazinon and oxidative stress in neuronal cells in a genetic model of glutathione deficiency}}</ref><ref>McConnachie LA, et al. (2007) Tox Sci Epub 21 June.</ref> 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.<ref>{{Cite journal | author = Chen Y, et al. | year = 2007 | journal = Hepatology | volume = 45 | pages = 1118}}</ref> 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]].<ref>{{cite journal | author= Shelley D. Copley and Jasvinder K. Dhillon | format = free full text | title=Lateral gene transfer and parallel evolution in the history of glutathione biosynthesis genes| journal=Genome biology| year=2002| volume=3| url=http://genomebiology.com/2002/3/5/RESEARCH/0025| doi=10.1186/gb-2002-3-5-research0025| pages=research0025.1}}</ref><ref>{{cite book | title=Significance of glutathione in plant adaptation to the environment| url=http://books.google.com/books?hl=sv&lr=&id=aX2eJf1i67IC&oi=fnd&pg=PA13&ots=8feo-QOEPa&sig=XAMjZ0Wan17vmoUKg_FFNRl8g0I#PPP1,M1| author=Grill D, Tausz T, De Kok LJ| date=2001| publisher=Springer| isbn=1402001789}}</ref> ==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<sup>+</sup>+ e<sup>-</sup>) 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 (biochemistry)|substrate]] in both [[Conjugated system|conjugation]] reactions and [[Redox|reduction]] reactions, catalyzed by [[glutathione S-transferase]] enzymes in [[cytosol]], [[microsome]]s, 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 oxidase|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 [[protein]]s, killing the cells in the process. The preferred treatment for an overdose of this painkiller is the administration (usually in atomized form) of [[acetylcysteine|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 (biochemistry)|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 [http://us.expasy.org/enzyme/4.4.1.5 (EC 4.4.1.5)] catalyzes the conversion of methylglyoxal and reduced glutathione to S-D-Lactoyl-glutathione. Glyoxalase II [http://us.expasy.org/enzyme/3.1.2.6 (EC 3.1.2.6)] catalyzes the hydrolysis of S-D-Lactoyl-glutathione to glutathione and D-lactate. == 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."<ref>{{cite journal |author=Witschi A, Reddy S, Stofer B, Lauterburg BH |title=The systemic availability of oral glutathione |journal=Eur. J. Clin. Pharmacol. |volume=43 |issue=6 |pages=667–9 |year=1992 |pmid=1362956 |doi= |}}</ref><ref>[http://www.aegis.com/aidsline/1993/may/M9350657.html AIDS Line Update]</ref>. However, tissue and serum glutathione concentrations can be raised by increased intake of the precursor [[cysteine]]. Glutathione precursors rich in cysteine include [[acetylcysteine|''N''-acetylcysteine]] (NAC),<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?dispmax=50&db=pubmed&pmfilter_EDatLimit=added%20to%20PubMed%20in%20the%20last%200%20i&cmd_current=Limits&orig_db=PubMed&cmd=Search&term=Acetylcysteine+glutathione%20&doptcmdl=DocSum Acetylcysteine and glutathione, PubMed]</ref> [[undenatured]] [[whey protein]] <ref>[http://www.nutritionadvisor.com/glutathione.html Glutathione information for Physicians]</ref><ref>{{cite journal |author=Micke P, Beeh KM, Schlaak JF, Buhl R |title=Oral supplementation with whey proteins increases plasma glutathione levels of HIV-infected patients |journal=Eur. J. Clin. Invest. |volume=31 |issue=2 |pages=171–8 |year=2001 |month=February |pmid=11168457}}</ref><ref>{{cite journal |author=Moreno YF, Sgarbieri VC, da Silva MN, Toro AA, Vilela MM |title=Features of whey protein concentrate supplementation in children with rapidly progressive HIV infection |journal=J. Trop. Pediatr. |volume=52 |issue=1 |pages=34–8 |year=2006 |month=February |pmid=16014759 |doi=10.1093/tropej/fmi074 |}}</ref><ref>{{cite journal |author=Grey V, Mohammed SR, Smountas AA, Bahlool R, Lands LC |title=Improved glutathione status in young adult patients with cystic fibrosis supplemented with whey protein |journal=J. Cyst. Fibros. |volume=2 |issue=4 |pages=195–8 |year=2003 |month=December |pmid=15463873 |doi=10.1016/S1569-1993(03)00097-3 |}}</ref><ref>{{cite journal |author=Micke P, Beeh KM, Buhl R |title=Effects of long-term supplementation with whey proteins on plasma glutathione levels of HIV-infected patients |journal=Eur J Nutr |volume=41 |issue=1 |pages=12–8 |year=2002 |month=February |pmid=11990003 |doi= |}}</ref><ref>{{cite journal |author=Bounous G, Baruchel S, Falutz J, Gold P |title=Whey proteins as a food supplement in HIV-seropositive individuals |journal=Clin Invest Med |volume=16 |issue=3 |pages=204–9 |year=1993 |month=June |pmid=8365048 |doi= |}}</ref><ref>{{cite journal |author=Bounous G, Gold P |title=The biological activity of undenatured dietary whey proteins: role of glutathione |journal=Clin Invest Med |volume=14 |issue=4 |pages=296–309 |year=1991 |month=August |pmid=1782728 |doi= |}}</ref><ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bounous%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus Bounous et al. Multiple references on glutathione enhancement with bioactive whey protein in multiple disease states]</ref>and [[acetylcysteine|N-acetyl-cysteine]] <ref>{{cite journal |author=Gross CL, Innace JK, Hovatter RC, Meier HL, Smith WJ |title=Biochemical manipulation of intracellular glutathione levels influences cytotoxicity to isolated human lymphocytes by sulfur mustard |journal=Cell Biol. Toxicol. |volume=9 |issue=3 |pages=259–67 |year=1993 |pmid=8299004 |doi= |}}</ref> 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. <ref>{{cite journal |author=Yim CY, Hibbs JB, McGregor JR, Galinsky RE, Samlowski WE |title=Use of N-acetyl cysteine to increase intracellular glutathione during the induction of antitumor responses by IL-2 |journal=J. Immunol. |volume=152 |issue=12 |pages=5796–805 |year=1994 |month=June |pmid=8207209 |doi= |url=http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=8207209}}</ref> 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 product|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%. <ref>{{cite journal |author=Lands LC, Grey VL, Smountas AA |title=Effect of supplementation with a cysteine donor on muscular performance |journal=J. Appl. Physiol. |volume=87 |issue=4 |pages=1381–5 |year=1999 |month=October |pmid=10517767 |doi= |url=http://jap.physiology.org/cgi/pmidlookup?view=long&pmid=10517767}}</ref> ==Pathology== Excess glutamate at [[synapse]]s, 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.<ref> {{cite journal | author = Pereira C.F, de Oliveira C.R. | year = 2000 | month = July | title = Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis | journal = Neuroscience Research | volume = 37 | issue = 3 | pages = 227–236 | doi = 10.1016/S0168-0102(00)00124-3 | accessdate = }}</ref> ==See also== *[[Glutathione synthetase deficiency]] == References == {{reflist|2}} == Related research == *The antioxidant glutathione peroxidase family and spermatozoa: A complex story. PMID 16427183 *[http://www.fda.gov/ohrms/dockets/ac/00/slides/3652s1_05/ 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]] *[http://www.rimkor7.com/index.html Which is Best? 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