Glutathione (Wikipedia)

Glutathione[1]

(2S)-2-amino-4-{[(1R)-1-[(carboxymethyl)carbamoyl]-2-

sulfanylethyl]carbamoyl}butanoic acid

γ-L-Glutamyl-L-cysteinylglycine(2S)-2-Amino-

5-[[(2R)-1-(carboxymethylamino)-1-oxo-3-sulfanylpropan-2-yl]amino]-5-oxopentanoic acid

Identifiers

Abbreviations GSH

CAS number 70-18-8

PubChem 124886

ChemSpider 111188

UNII GAN16C9B8O

DrugBank DB00143

KEGG C00051

MeSH Glutathione

ChEBI CHEBI:60836

ChEMBL CHEMBL1543

Jmol-3Dimages

Image 1 (http://chemapps.stolaf.edu/jmołjmol.php?model=C%28CC%28%3DO%29N%5BC%40%40H

GlutathioneFrom Wikipedia, the free encyclopedia

Glutathione (GSH) is a tripeptide with an unusualpeptide linkage between the amine group of cysteine(which is attached by normal peptide linkage to aglycine) and the carboxyl group of the glutamateside-chain. It is an antioxidant, preventing damage toimportant cellular components caused by reactiveoxygen species such as free radicals and peroxides.[2]

Thiol groups are reducing agents, existing at aconcentration of approximately 5 mM in animal cells.Glutathione reduces disulfide bonds formed withincytoplasmic proteins to cysteines by serving as anelectron donor. In the process, glutathione isconverted to its oxidized form glutathione disulfide(GSSG), also called L(-)-Glutathione.

Once oxidized, glutathione can be reduced back byglutathione reductase, using NADPH as an electrondonor. The ratio of reduced glutathione to oxidizedglutathione within cells is often used as a measure ofcellular toxicity.[3]

Contents1 Biosynthesis2 Function

2.1 Function in animals2.2 Function in plants

3 Supplementation3.1 Cancer

4 Pathology5 Methods to determine glutathione6 Importance in winemaking7 See also8 References9 Related research10 External links

IUPAC name

Other names

Glutathione - Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Glutathione

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%5D%28CS%29C%28%3DO%29NCC%28%3DO%29O%29%5BC%40%40H%5D%28C%28%3DO%29O%29N)

Properties

Molecularformula

C10H17N3O6S

Molar mass 307.32 g/mol

Melting point195 °C, 468 K, 383 °F

Solubility inwater

Freely soluble[1]

Solubility inmethanol,diethyl ether

Insoluble

(verify) (what is: / ?)Except where noted otherwise, data are given for

materials in their standard state (at 25 °C, 100 kPa)

Infobox references

BiosynthesisGlutathione is not an essential nutrient (meaning itdoes not have to be obtained via food), since it can besynthesized in the body from the amino acidsL-cysteine, L-glutamic acid, and glycine. Thesulfhydryl (thiol) group (SH) of cysteine serves as aproton donor and is responsible for the biologicalactivity of glutathione. Cysteine is the rate-limitingfactor in cellular glutathione synthesis, since thisamino acid is relatively rare in foodstuffs.

Glutathione is synthesized in two adenosinetriphosphate-dependent steps:

First, gamma-glutamylcysteine is synthesizedfrom L-glutamate and cysteine via the enzymegamma-glutamylcysteine synthetase (a.k.a.glutamate cysteine ligase, GCL). This reactionis the rate-limiting step in glutathionesynthesis.[4]Second, glycine is added to the C-terminal ofgamma-glutamylcysteine via the enzymeglutathione synthetase.

Animal glutamate cysteine ligase (GCL) is aheterodimeric enzyme composed of a catalytic(GCLC) and modulatory (GCLM) subunit. GCLC constitutes all the enzymatic activity, whereas GCLMincreases the catalytic efficiency of GCLC. Mice lacking GCLC (i.e., all de novo GSH synthesis) diebefore birth.[5] Mice lacking GCLM demonstrate no outward phenotype, but exhibit marked decrease inGSH and increased sensitivity to toxic insults.[6][7][8]

While all cells in the human body are capable of synthesizing glutathione, liver glutathione synthesis hasbeen shown to be essential. Mice with genetically-induced loss of GCLC (i.e., GSH synthesis) only inthe liver die within 1 month of birth.[9]

The plant glutamate cysteine ligase (GCL) is a redox-sensitive homodimeric enzyme, conserved in theplant kingdom.[10] In an oxidizing environment, intermolecular disulfide bridges are formed and theenzyme switches to the dimeric active state. The mid-point potential of the critical cysteine pair is -318mV. In addition to the redox-dependent control is the plant GCL enzyme feedback inhibited by GSH.[11]GCL is exclusively located in plastids, and glutathione synthetase is dual-targeted to plastids andcytosol, thus are GSH and gamma-glutamylcysteine exported from the plastids.[12] Both glutathionebiosynthesis enzymes are essential in plants; knock-outs of GCL and GS are lethal to embryo andseedling.[13]

SMILES

InChI


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The biosynthesis pathway for glutathione is found in some bacteria, like cyanobacteria andproteobacteria, but is missing in many other bacteria. Most eukaryotes synthesize glutathione, includinghumans, but some do not, such as Leguminosae, Entamoeba, and Giardia. The only archaea that makeglutathione are halobacteria.[14][15]

FunctionGlutathione exists in reduced (GSH) and oxidized (GSSG) states. In the reduced state, the thiol group ofcysteine is able to donate a reducing equivalent (H++ e-) to other unstable molecules, such as reactiveoxygen species. In donating an electron, glutathione itself becomes reactive, but readily reacts withanother reactive glutathione to form glutathione disulfide (GSSG). Such a reaction is possible due to therelatively high concentration of glutathione in cells (up to 5 mM in the liver). GSH can be regeneratedfrom 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) andless than 10% exists in the disulfide form (GSSG). An increased GSSG-to-GSH ratio is consideredindicative of oxidative stress.

Glutathione has multiple functions:

It is the major endogenous antioxidant produced by the cells, participating directly in theneutralization of free radicals and reactive oxygen compounds, as well as maintaining exogenousantioxidants such as vitamins C and E in their reduced (active) forms.[16]Regulation of the nitric oxide cycle, which is critical for life but can be problematic ifunregulated[17]It is used in metabolic and biochemical reactions such as DNA synthesis and repair, proteinsynthesis, prostaglandin synthesis, amino acid transport, and enzyme activation. Thus, everysystem in the body can be affected by the state of the glutathione system, especially the immunesystem, the nervous system, the gastrointestinal system and the lungs.[18]It has a vital function in iron metabolism. Yeast cells depleted of or containing toxic levels of GSHshow an intense iron starvation-like response and impairment of the activity of extra-mitochondrial ISC enzymes, followed by death.[19]

Reaction mechanism of human glutathione reductase

NADPH reduces FAD present in GSR to produce a transient FADH- anion. This anion then quicklybreaks a disulfide bond (Cys58 - Cys63) and leads to Cys63’s nucleophilically attacking the nearestsulfide unit in the GSSG molecule (promoted by His467), which creates a mixed disulfide bond(GS-Cys58) and a GS- anion. His467 of GSR then protonates the GS- anion to form the first GSH. Next,Cys63 nucleophilically attacks the sulfide of Cys58, releasing a GS- anion, which, in turn, picks up asolvent proton and is released from the enzyme, thereby creating the second GSH. So, for every GSSGand NADPH, two reduced GSH molecules are gained, which can again act as antioxidants scavengingreactive oxygen species in the cell.

Function in animals


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GSH is known as a substrate in both conjugation reactions and reduction reactions, catalyzed byglutathione S-transferase enzymes in cytosol, microsomes, and mitochondria. However, it is also capableof participating in non-enzymatic conjugation with some chemicals.

In the case of N-acetyl-p-benzoquinone imine (NAPQI), the reactive cytochrome P450-reactivemetabolite formed by paracetamol (or acetaminophen as it is known in the US), which becomes toxicwhen GSH is depleted by an overdose of acetaminophen, glutathione is an essential antidote tooverdose. Glutathione conjugates to NAPQI and helps to detoxify it. In this capacity, it protects cellularprotein 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 treatmentfor 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] (http://www.rxmed.com/b.main/b2.pharmaceuticałb2.1.monographs/CPS-%20Monographs/CPS-%20%28General%20Monographs-%20M%29/MUCOMYST.html) ), which is processed by cells toL-cysteine and used in the de novo synthesis of GSH.

Glutathione (GSH) participates in leukotriene synthesis and is a cofactor for the enzyme glutathioneperoxidase. It is also important as a hydrophilic molecule that is added to lipophilic toxins and waste inthe liver during biotransformation before they can become part of the bile. Glutathione is also needed forthe 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)(http://us.expasy.org/enzyme/4.4.1.5) catalyzes the conversion of methylglyoxal and reduced glutathioneto S-D-lactoyl-glutathione. Glyoxalase II (EC 3.1.2.6) (http://us.expasy.org/enzyme/3.1.2.6) catalyzes thehydrolysis 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 likeJapan and the Philippines, this product is sold as a whitening soap. Glutathione competitively inhibitsmelanin synthesis in the reaction of tyrosinase and L-DOPA by interrupting L-DOPA’s ability to bind totyrosinase during melanin synthesis. The inhibition of melanin synthesis was reversed by increasing theconcentration of L-DOPA, but not by increasing tyrosinase. Although the synthesized melanin wasaggregated within 1 h, the aggregation was inhibited by the addition of glutathione. These resultsindicate that glutathione inhibits the synthesis and agglutination of melanin by interrupting the functionof L-DOPA.”[20]

Function in plants

In plants, glutathione is crucial for biotic and abiotic stress management. It is a pivotal component of theglutathione-ascorbate cycle, a system that reduces poisonous hydrogen peroxide.[21] It is the precursorof phytochelatins, glutathione oligomeres that chelate heavy metals such as cadmium.[22] Glutathione isrequired for efficient defence against plant pathogens such as Pseudomonas syringae and Phytophthorabrassicae.[23] APS reductase, an enzyme of the sulfur assimilation pathway uses glutathione as electrondonor. Other enzymes using glutathione as substrate are glutaredoxin, these small oxidoreductases areinvolved in flower development, salicylic acid and plant defence signalling.[24]


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SupplementationRaising GSH levels through direct supplementation of glutathione is difficult. Research suggests thatglutathione taken orally is not well absorbed across the gastrointestinal tract. In a study of acute oraladministration of a very large dose (3 grams) of oral glutathione, Witschi and coworkers found “it is notpossible to increase circulating glutathione to a clinically beneficial extent by the oral administration of asingle dose of 3 g of glutathione.”[25][26]

Calcitriol, the active metabolite of vitamin D synthesized in the kidney, increases glutathione levels inthe brain and appears to be a catalyst for glutathione production.[27]

In addition, plasma and liver GSH concentrations can be raised by administration of certain supplementsthat serve as GSH precursors. N-acetylcysteine, commonly referred to as NAC, is the most bioavailableprecursor of glutathione.[28] Other supplements, including S-adenosylmethionine (SAMe)[29][30][31] andwhey protein[32][33][34][35][36][37] 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 torestore intracellular glutathione.[38][39] Melatonin has been shown to stimulate a related enzyme,glutathione peroxidase,[40] and silymarin, an extract of the seeds of the milk thistle plant (Silybummarianum), has also demonstrated an ability to replenish glutathione levels in lab rats.[41][42]

Glutathione is a tightly regulated intracellular constituent, and is limited in its production by negativefeedback inhibition of its own synthesis through the enzyme gamma-glutamylcysteine synthetase, thusgreatly minimizing any possibility of overdosage. Glutathione augmentation using precursors ofglutathione synthesis or intravenous glutathione is a strategy developed to address states of glutathionedeficiency, high oxidative stress, immune deficiency, and xenobiotic overload in which glutathione playsa 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 infectioushepatitis, myalgic encephalomyelitis chronic fatigue syndrome ME / CFS,[43][44][45] prostate and othercancers, cataracts, Alzheimer’s disease, Parkinson’s disease, chronic obstructive pulmonary disease,asthma, radiation poisoning, malnutritive states, arduous physical stress, and aging, and has beenassociated with suboptimal immune response. Many clinical pathologies are associated with oxidativestress and are elaborated upon in numerous medical references.[18][46][47]

Low glutathione is also strongly implicated in wasting and negative nitrogen balance,[48] as seen incancer, AIDS, sepsis, trauma, burns and even athletic overtraining. Glutathione supplementation canoppose this process, and in AIDS, for example, result in improved survival rates.[49] However, studies inmany of these conditions have not been able to differentiate between low glutathione as a result ofacutely (as in septic patients) or chronically (as in HIV) increased oxidative stress, and increasedpathology as a result of preexisting deficiencies.

Schizophrenia and bipolar disorder are associated with lowered glutathione. Accruing data suggest thatoxidative stress may be a factor underlying the pathophysiology of bipolar disorder (BD), majordepressive disorder (MDD), and schizophrenia (SCZ). Glutathione (GSH) is the major free radical


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scavenger in the brain.[50] Diminished GSH levels elevate cellular vulnerability towards oxidative stress;characterized by accumulating reactive oxygen species. Replenishment of glutathione using N-acetylcysteine has been shown to reduce symptoms of both disorders.[51]

Cancer

Preliminary results indicate glutathione changes the level of reactive oxygen species in isolated cellsgrown in a laboratory,[52][53] which may reduce cancer development.[54] [55] None of these tests wereperformed in humans.

However, once a cancer has already developed, by conferring resistance to a number ofchemotherapeutic drugs, elevated levels of glutathione in tumour cells are able to protect cancerous cellsin bone marrow, breast, colon, larynx, and lung cancers.[56]

PathologyExcess glutamate at synapses, which may be released in conditions such as traumatic brain injury, canprevent the uptake of cysteine, a necessary building-block of glutathione. Without the protection fromoxidative injury afforded by glutathione, cells may be damaged or killed.[57]

Methods to determine glutathioneReduced glutathione may be visualized using Ellman’s reagent or bimane derivates such asmonobromobimane. The monobromobimane method is more sensitive. In this procedure, cells are lysedand thiols extracted using a HCl buffer. The thiols are then reduced with dithiothreitol (DTT) andlabelled by monobromobimane. Monobromobimane becomes fluorescent after binding to GSH. Thethiols are then separated by HPLC and the fluorescence quantified with a fluorescence detector. Bimanemay also be used to quantify glutathione in vivo. The quantification is done by confocal laser scanningmicroscopy after application of the dye to living cells.[58] Another approach, which allows to measurethe glutathione redox potential at a high spatial and temporal resolution in living cells is based on redoximaging using the redox-sensitive green fluorescent protein (roGFP)[59] or redox sensitive yellowfluorescent protein (rxYFP) [60]

Importance in winemakingThe content in glutathione of must determines the browning effect during the production of white wineby trapping the caffeoyltartaric acid quinones generated by enzymic oxidation as grape reaction product(GRP).[61]

See alsoGlutathione synthetase deficiency


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Ophthalmic acidroGFP, a tool to measure the cellular glutathione redox potentialGlutathione-ascorbate cycleBacterial glutathione transferaseThioredoxin, a cysteine-containing small proteins with very similar functions as reducing agentsGlutaredoxin, an antioxidant protein that uses reduced glutathione as a cofactor and is reducednonenzymatically by it

References

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Related research


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Drevet, J (2006). “The antioxidant glutathione peroxidase family and spermatozoa: A complexstory”. Molecular and Cellular Endocrinology 250 (1–2): 70–9. doi:10.1016/j.mce.2005.12.027(http://dx.doi.org/10.1016%2Fj.mce.2005.12.027) . PMID 16427183 (//www.ncbi.nlm.nih.gov/pubmed/16427183) .The Role of Glutathione in Cell Defense. (http://www.fda.gov/ohrms/dockets/ac/00/slides/3652s1_05/)Wu, Guoyao; Fang, Yun-Zhong; Yang, Sheng; Lupton, Joanne R.; Turner, Nancy D. (2004).“Glutathione metabolism and its implications for health” (http://jn.nutrition.org/cgi/content/fulł134/3/489) . The Journal of nutrition 134 (3): 489–92. PMID 14988435(//www.ncbi.nlm.nih.gov/pubmed/14988435) . http://jn.nutrition.org/cgi/content/fulł134/3/489.

External linksGlutathione bound to proteins (http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=GSH)in the PDBGlutathione bound to proteins (http://www.immunolifestyle.com) in the PDB

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