Glutathione
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Glutathione (GSH), whose IUPAC name is 2-amino-5-{[2-[(carboxymethyl)amino]- 1-(mercaptomethyl)-2-oxoethyl]amino}-5-oxopentanoic acid, is γ-glutamylcysteinylglycine, 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 mM 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.
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[edit] Function
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 acetaminophen (or paracetamol as it is known in the UK), 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.
Phorone efficiently reacts to the GSH thiol groups which makes phorone a GSH depletor. It is used to study the effects of GSH as a hydrogen peroxide scavenger in asthma.[2] The health food industry promotes glutathione as a very efficient antioxidant to be used against a whole range of diseases. This runs counter to research, which suggests that glutathione is not orally bioactive. Nutritional supplement companies also offer N-acetylcysteine, which has been shown to increase glutathione in vivo.
[edit] 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.[3]
[edit] References
- ^ Strużńka L, Chalimoniuk M, Sulkowski G. (September 2005). "The role of astroglia in Pb-exposed adult rat brain with respect to glutamate toxicity". Toxicology 212 (2-3): 185-194. PMID 15955607. Retrieved on 2006-05-05.
- ^ Thesis Joris Kloek 2001
- ^ Pereira C.F, de Oliveira C.R. (July 2000). "Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis". Neuroscience Research 37 (3): 227-236. DOI:doi:10.1016/S0168-0102(00)00124-3. Retrieved on 2006-05-05.
[edit] Related research
- The antioxidant glutathione peroxidase family and spermatozoa: A complex story. PMID 16427183
- 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
