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(2S)-2-Amino-5-[[(2R)-1-(carboxymethylamino)-1-oxo- 3-sulfanylpropan-2-yl]amino]-5-oxopentanoic acid
|Molar mass||307.32 g/mol|
195 °C, 468 K, 383 °F
|Solubility in water||Miscible|
|Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)
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.
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.
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. Mice lacking GCLM demonstrate no outward phenotype, but exhibit marked decrease in GSH and increased sensitivity to toxic insults.
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.
The plant glutamate cysteine ligase (GCL) is a redox sensitive homodimeric enzyme, conserved in the plant kingdom.. 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. 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. Both glutathione biosynthesis enzymes are essential in plants, knock-outs of GCL and GS are embryo and seedling lethal.
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.
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 184.108.40.206) catalyzes the conversion of methylglyoxal and reduced glutathione to S-D-lactoyl-glutathione. Glyoxalase II (EC 220.127.116.11) 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 dose dependently inhibit melanin synthesis in the reaction of tyrosinase and L-DOPA. The inhibition of melanin synthesis was recovered by increasing the concentration of L-DOPA, but not recovered by increasing tyrosinase. Glutathione inhibited the binding between tyrosinase and L-DOPA. 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. "
 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.  It is the precursor of phytochelatins, glutathione oligomeres which chelates heavy metals such as cadmium.  Glutathione is required for efficient defence against plant pathogens such as Pseudomonas syringae and Phytophthora brassicae.  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. 
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."
However, tissue and sperm glutathione concentrations can be raised by increased intake of the precursor cysteine, or in chronic conditions, by S-adenosylmethionine (SAMe). Glutathione precursors rich in cysteine include N-acetylcysteine (NAC) and undenatured whey protein, 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.
Glutathione has shown positive preliminary results in several studies of glutathione's ability to affect levels of reactive oxygen species,  which may have implications in the reduction of cancer rates. 
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. 
 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. 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). 
 See also
- Glutathione synthetase deficiency
- Ophthalmic acid
- roGFP, a tool to measure the cellular glutathione redox potential
- Glutathione-ascorbate cycle
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