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Glutathione
Identifiers
CAS number 70-18-8
PubChem 745
MeSH Glutathione
SMILES NC(CCC(=O)NC(CS)C(=O)NCC(O)=O)C(O)=O
Properties
Molecular formula C10H17N3O6S
Molar mass 307.325
Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)
Infobox disclaimer and references
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 within ~5 mmol 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 which reverts it from its oxidized form (GSSG), glutathione reductase, is constitutively active and inducible upon oxidative stress. In fact, the ratio of reduced to oxidized glutathione within cells is often used scientifically as a measure of cellular toxicity.
Contents
[hide]
* 1 Biosynthesis
* 2 Function
* 3 Supplementation
* 4 Pathology
* 5 See also
* 6 References
* 7 Related research
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 comprised of a catalytic (GCLC) and modulatory (GCLM) subunit. GCLC constitutes all the enzymatic activity, while GCLM increases the catalytic efficiency of GCLC. Mice lacking GCLC (ie 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]
The liver is the principal site of glutathione synthesis. Following birth, mice with genetically-induced loss of GCLC (ie GSH synthesis) only in the liver die within 1 month of birth.[6]
In healthy tissue, more than 90% of the total glutathione pool is in the reduced form and less than 10% exists in the disulfide form (GSSG). An increased GSSG/GSH ratio is considered indicative of oxidative stress.
Glutathione 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.
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 substrate 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-acetylcysteine, which is used by cells to replace spent GSSG and renew the usable GSH pool.
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."[7][8] However glutathione precursors such as undenatured whey protein [9], [10], [11], [12], [13], [14], [15], [16] and N-acetyl-cysteine [17] 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. [18] 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%. [19]
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