Glutathione

Glutathione (GSH) is a tripeptide. It contains an unusual free radicals.^[1]

oxidative stress. In fact, the ratio of reduced to oxidized glutathione within cells is often used scientifically as a measure of cellular toxicity.

Biosynthesis

Glutathione is not an essential nutrient since it can be synthesized from the amino acids 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 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 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 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 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