Glutathione catalytic subunit

Myhrstad, M.C.W. et ah, Flavonoids increase the intracellular glutathione level by transactivation of the y-glutamylcysteine synthetase catalytical subunit promoter. Free Radical Biol. Med., 32, 386, 2002. 

Either the catalytic subunit or both subunits are overexpressed in several drug-resistant human cancer cells such as cisplatin-resistant ovarian cancer cells and melphalan-resistant prostate cancer cells, suggesting that elevated production of glutathione may induce drug-resistance mechanisms in these cancer cells (Figure... 

Hamilton D, Wu JH, Alaoui-Jamali M, Batist G, A novel missense mutation in the gamma-glutamylcys-teine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production. Blood 2003 102 725-30. 

Apart from their catalytic function, at least one form of glutathione-5-trans-ferases has the function of simply binding xenobiotics and transporting them, without metabolism. In effect, this is an example of storage (see Section 2.3.3). The form in question is termed ligandin, and binding is associated with one particular subunit. Binding is not associated with catalytic activity. 

The Na/K ATPase has been extensively purified and characterized, and consists of a catalytic a subunit of around 95 kDa and a glycoprotein 0 subunit of approximately 45 kDa (Skou, 1992). The functional transporter exists as a dimer with each monomer consisting of an a and /3 subunit. Hiatt aal. (1984) have su ested that the non-catalytic jS subunit may be involved in the cottect insertion of the a subunit into the lipid bilayer and, therefore, it is conceivable that a modification of the 0 subunit structure may be reflected by changes in the catalytic activity of the a subunit. Therefore, in studies involving the manipulation of tissue glutathione levels, alterations of intracellular redox state may have an effect on substrate binding at an extracellular site on this ion-translocating protein. 

The OSR includes induction of genes encoding Phase II biotransformation enzymes (GSTA, NQOl), enzymes involved in glutathione synthesis (y-glutamylcysteine synthase catalytic and regulatory subunits (y-GCS-c and y-GCS-r, respectively)),... 

The hormonal regulation of GCS expression has special physiological relevance. Phenylephrine, glucagon or dibutyryl cAMP inhibit GCS activity, which decreases glutathione synthesis and leads to glutathione depletion in rat hepatocytes [26,27]. The loss of GCS activity induced by these stress hormones is mediated by phosphorylation of the catalytic GCS subunit due to activation of protein kinase A, protein kinase C or Ca -calmoduhn kinase [28]. Consequently, the stress response diminishes GSH synthesis, which may increase the availability of cysteine for the synthesis of stress proteins [14]. 

The normal catalytic process involves the sequence I- -II->-III->-IV- -I, while the steps IV- V- -VI- -III may also be part of the overall reaction. Thelander (131) has pointed out that the reaction mechanism of thioredoxin reductase differs from those of glutathione reductase and lipoyldehydrogenase because during the anaerobic titration of thioredoxin reductase no flavin semiquinone intermediate could be detected. Although thioredoxin reductase contains two subunits only one octapeptide... 

H19. Hayes, J. D., Judah, D. J., McLellan, L. I., Kerr, L. A., Peacock, S. D., and Neal, G. E., Ethoxyquin-induced resistance to aflatoxin Bj in the rat is associated with the expression of a novel Alpha-class glutathione S-transferase subunit, Yc2, which possesses high catalytic activity for aflatoxin 8,-8,9-epoxide. Biochem. J. 279, 385-398 (1991). 

The glutathione transferases are soluble dimeric proteins that are composed of identical subunits, although some forms are heterodimers. These enzymes are present in most tissues and are primarily cytosolic (approximately 95%), although a small percentage are found in the endoplasmic reticulum (approximately 5%). The cytosolic glutathione S-transferases (GSTs) are divided into six families or classes alpha, kappa, mu, pi, sigma, and theta. The alpha, mu, and pi GST classes are primarily responsible for most of the catalytic activity associated with liver detoxication of xenobiotics. 

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