Glutathione reductase mechanism

Glutathione reductase (GR) catalyzes the reduction of oxidized glutathione (GSSG) to reduced glutathione (GSH) using NADPH provided from the hexose monophosphate pathway. GR, a ubiquitous flavoenzyme, maintains a high value of two for the GSH/GSSG ratio in the red blood cells. l,3-Bis(2-chloroethyl)-nitrosourea (BCNU) selectively inhibits cellular GR. GR is composed of two identical subunits, each of molecular mass 50 kDa (S8). The three-dimensional structure and mechanism of catalysis have been established for human GR (K17). 

Since glutathione reductase is a cornerstone of the malaria parasite antioxidant defence and repair mechanism, it is a potential target for antimalarial and cytostatic agents. 

Reaction Mechanism and Kinetic Constants for a Reaction Catalyzed by Glutathione Reductase... 

Experimental evidence supports a 4a adduct mechanism for glutathione reductase and related enzymes191/258/258a (Fig. 15-12). In this figure the reac-... 

Mechanism of the flavin-dependent glutathione reductase reaction. 

In this section on mechanism and in the section to follow on structure, the comparisons will show that the relationship between lipoamide dehydrogenase and glutathione reductase is more marked than is the relationship of either to thioredoxin reductase. Thus, in catalysis, lipoamide dehydrogenase and glutathione reductase cycle between the oxidized state and a spectrally characteristic state in which the enzyme has accepted two electrons and these are shared between the FAD and the active center disulfide. This intermediate does not seem to be operative in thioredoxin reductase, and in this enzyme the FAD and disulfide interact in a different way. The oxidized forms of these enzsrmes can then be represented as... 

The early kinetic studies on glutathione reductase did not include investigation of product inhibition, so vital to a proper interpretation of kinetic data in the elucidation of the mechanism 247, 248). In the one case where product inhibition patterns were observed, they were not interpreted by more recent kinetic theory 40). Subsequent kinetic analyses see below), in which product inhibition patterns have been obtained, were either completed prior to the discovery of the EH2-NADPH complex... 

Kinetic parameters are given in Table VI. Plots of 1/v against 1/(S) ve parallel lines both at 4° and 25° on this basis the assumption has been made that a binary complex mechanism is operative. As with lipo-amide dehydrogenase and glutathione reductase, this assumption is com-... 

Glutathione reductase amino acid composition, 102,104,105 cystine residues, 104 kinetic studies, 138-141 mechanism, 94, 97-98,134 metabolic functions, 129-133 reaction catalyzed, 92 reduction of, 112, 113 specificity of, 92-93 coenzymes and, 94 thiol groups, 141-142 two-electron-reduced enzyme, properties, 133-138... 

Like glutathione reductase, pyridoxine oxidase is sensitive to riboflavin depletion. In normal subjects and in experimental animals, the EGR and pyridoxine oxidase activation coefficients are correlated, and both reflect riboflavin nutritional status. In subjects with glucose 6-phosphate dehydrogenase deficiency, there is an apparent protection of EGR, so that even in riboflavin deficiency it does not lose its cofactor, and the EGR activation coefficient remains within the normal range. The mechanism of this protection is unknown. In such subjects, the erythrocyte pyridoxine oxidase activation coefficient gives a response that mirrors riboflavin nutritional status (Clements and Anderson, 1980). 

Experimental evidence supports a 4a adduct mechanism for glutathione reductase and related... 

Figure 15-12 Probable reaction mechanism for lipo-amide dehydrogenase and glutathione reductase. See C63 Pai and Schulz.

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