Glutamyl cysteine synthetase

The inhibition of membrane Ca2+/Mg2+ ATPase leads to a derangement of Ca2+ levels, which will damage the mitochondria and hence also indirectly contribute to ATP depletion. Inhibition of y-glutamyl cysteine synthetase reduces the ability of the liver cell to synthesize new GSH, so reducing its ability to protect itself. Overall, some 17 enzymes have been shown to be inhibited ex vivo after treatment of animals and another 14 are known to have bound paracetamol and may or may not be inhibited. 

Kang Y, Viswanath V, Jha N, Qiao X, Mo JQ, Andersen JK (1999) Brain gamma-glutamyl cysteine synthetase (GCS) mRNA expression patterns coirelate with regional-specific enzyme activities and glutathione levels. J Neurosci Res 58 436 441. 

Erythrocyte GSH concentration is diminished in many people who have defects in the hexose monophosphate or GSH synthesis pathways. The GSH stability test, originally devised to permit identification of people susceptible to hemolysis from primaquine (later shown to be the result of G6PD deficiency), still remains a useful "stress test of the intactness of these closely hnked pathways. Because deficiencies of GSH synthetase and y-glutamyl cysteine synthetase are rare disorders, it is not practical for clinical laboratories to contemplate assays for these enzymes unless results of the easily performed GSH stability test are abnormal. 

Glutathione (8.20) y-glutamylcysteinylglycine, is biosynthesised in a stepwise manner from the A -terminus but not by the ribosomal route. Instead, each peptide bond is formed under the control of a specific enzyme, glutamyl-cysteine synthetase and glutathione synthetase, respectively, with ATP as a substrate to form an acyl phosphate as an unsymmetrical anhydride. Reduced glutathione (GSH) with a thiol... 

Huang C, Anderson ME, Meister A (1993) Amino acid sequence and function of the light subunit of rat kidneyy-glutamyl cysteine synthetase. J Biol Chem 268 20578-2058330... 

AvUa MA, Berasain C, Torres L, Martfn-Duce A, Corrales FJ, Yang H, Prieto J (2000) Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. J Hepatol 33 907-914 Serviddio G, Pereda J, Pailardo FV, Carretero J, Borras C, Cutrin J, Vendemiale G, Poli G, Vina J, Sastre J (2004) Ursodeoxycholic acid protects against secondary biliary cirrhosis via up-regulation of y-glutamyl cysteine synthetase and prevention of mitochondrial oxidative stress. Hepatology (in press)... 

GSH-peroxidase because of detoxification of putatively increased amounts of hydroperoxides. Therefore, it seems crucial to protect cells from loss of antioxidants and potent reducing substances, such as NADPH or NADH. In turn, depletion of cells from ATP by inhibition of oxidative phosphorylation could result in decreased activity of 5-oxoprolinase, glutamyl-cysteine-synthetase and GSH synthetase, all known to be dependent on ATP (Meister, 1991), resulting in impaired detoxification mechanisms and subsequent cell damage because of oxidative stress. 

MTF-1 has recently been linked to the transcriptional regulation of the y-glutamyl cysteine synthetase gene which encodes an enzyme needed for GSH synthesis [45], strengthening the role of this transcription factor in oxidative stress which, depending on the stimulus, can lead to GSH depletion. Since heme-hemopexin increases oxi-... 

Rathbun, W. B. y-Glutamyl-cysteine synthetase from bovine lens. II. Cysteine analog studies. Arch. Biochem. Biophys. 122, 73 (1967). 

Reaction (a) is catalyzed by y-glutamyl-cysteine synthetase, reaction (b) by glutathione synthetase. Possibly amino acid phosphates are the activated intermediates. 

Meister, A., Inhibition of Glutamine Synthetase and Y"Glutamyl-cysteine Synthetase by Methionine Sulfoximine and Related Compounds, Enzyme-Activated Irreversible Inhibitors (N. Seiler, M.J. Jung and J. Koch-Weser, eds.), Elsevier-North Holland Biomedical Press, Amsterdam pp. 187-211 (1978). 

Richman, P., and Meister, A., 1975, Regulation of y-glutamyl-cysteine synthetase by non-allosteric feedback inhibition by glutathione, J. Biol. Chem. 250 1422. 

GSH is synthesized by two enzymes, y-glutamyl cysteine is formed from cysteine and glutamate by y-glutamyl synthetase. GSH is formed from y-glutamyl cysteine and glycine by glutathione synthetase. Both enzymes are found in the brain (Figure 13.7). 

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