Y-Glutamyl cysteines

In the second step, GSH-S catalyzes the synthesis of GSH from y-glutamyl-cysteine and glycine in the presence of ATP. A cDNA encoding human GSH-S has been cloned, and the deduced protein consists 474 amino acids with a subunit molecular weight of 52,352 (Gl). Active enzyme is considered to be a homodimer. 

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. 

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). 

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. 

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)... 

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-... 

S-alkyl cysteines, such as S-allyl cysteine (SAC), S-methyl cysteine (SMC), and S-propyl cysteines are slowly formed during sprouting from the action of y-glutamyl transpeptidase on y-glutamyl cysteines. S-allyl cysteine is also rapidly formed in the body by hydrolysis of y-glutamyl cysteine particularly in the kidney which contains an abundant amount of Y-glutamyl transpeptidase activity [2]. 

Figure 5 Comparison of thioredoxin coupled arsenate reductase (pI258 family) and glutaredoxin coupled arsenate reductase (R773 family). GSH reduced glutathione, the tripeptide consisting of y-glutamyl-cysteine-glycine. GSSG S-S bridged oxidized dimer of glutathionine.

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. 

It has been purified from wheat flour in which its activity is relatively high (Table 15.22). The enzyme is specific for the H-donor (Table 15.23) because it oxidizes only GSH, and with a much lower velocity also y-glutamyl cysteine, but neither cysteinyl glycine nor cysteine, which also occur in wheat flour (Table 15.24). The specificity for the H-acceptor is not so pronounced. As shown in Table 15.23, all four diastereomeric forms of dehydroascorbic acid are converted, but with different velocities. The substrate specificity corresponds to the varying activity of... 

Figure 2.17 Formation of S-alk(en)ylcysteine sulfoxides from y-glutamyl cysteine peptides in Allium vegetables.

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