Glutathione

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 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.

Additional recommended knowledge

Safe Weighing Range Ensures Accurate Results

Daily Visual Balance Check

Daily Sensitivity Test

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 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]}

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 (ie GSH synthesis) only in the liver die within 1 month of birth.^[6]

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.^[7][8]

Function

Glutathione exists in a reduced (GSH) and oxidized (GSSG) state. In the reduced state, the thiol group of cysteine is able to donate an electron (H+) 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 gluathione in cells (up to 5mM 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/GSH ratio is considered indicative of oxidative stress.

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 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 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 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.

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, it was found that it is not possible to increase circulating glutathione in a clinically relevant way.^[9] However, glutathione concentrations can be raised by increased intake of the precursor cysteine.

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.^[10]

See also

• Glutathione synthetase deficiency

References

1. ^ 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.
2. ^ Dalton, TP & et al. (2000), Biochem Biophys Res Commun. 279 (2): 324
3. ^ Yang Y, et al. (2002) J Biol Chem. 277(51):4944.
4. ^ Giordano G, et al. (2007) Toxicol Appl Pharmacol. 219(2-3):181.
5. ^ McConnachie LA, et al. (2007) Tox Sci Epub 21 June.
6. ^ Chen Y, et al. (2007) Hepatology 45:1118.
7. ^ (2002) "Lateral gene transfer and parallel evolution in the history of glutathione biosynthesis genes". Genome biology 3.
8. ^ Grill D, Tausz T, De Kok LJ (2001). Significance of glutathione in plant adaptation to the environment. Springer. ISBN 1402001789. 
9. ^ Witschi A, et. al. The systemic availability of oral glutathione. Eur J Clin Pharmacol. 1992;43(6):667-9
10. ^ 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.

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
• Ophthalmic acid