Glutathione peroxidase reductase

Thiols are also important protection against lipid peroxidation. Glutathione (7-Glu-Cys-Gly) is used by several glutathione-dependent enzymes such as free-radical reductase (converts vitamin E radical to vitamin E), glutathione peroxidase (reduces hydrogen peroxide and lipid hydroperoxides to water and to the lipid alcohol, respectively), and others. In addition, the thiol group of many proteins is essential for function. Oxidation of the thiol of calcium ATPases impairs function and leads to increased intracellular calcium. Thiol derivatives such as the ovothiols (l-methyl-4-mercaptohistidines) (Shapiro, 1991) have been explored as therapeutics. 

Garlic s proven mechanisms of action include (a) inhibition of platelet function, (b) increased levels of two antioxidant enzymes, catalase and glutathione peroxidase, and (c) inhibition of thiol enzymes such as coenzyme A and HMG coenzyme A reductase. Garlic s anti-hyperlipidemic effects are believed to be in part due to the HMG coenzyme A reductase inhibition since prescription medications for hyperlipidemia have that mechanism of action (statins). It is unknown whether garlic would have the same drug interactions, side effects, and need for precautions as the statins. 

The present chapter reviews applications in biocatalysis of the ONIOM method. The focus is on studies performed in our research group, in most cases using the two-layer ONIOM(QM MM) approach as implemented in Gaussian [23], The studied systems include methane monooxygenase (MMO), ribonucleotide reductase (RNR) [24, 25], isopenicillin N synthase (IPNS) [26], mammalian Glutathione peroxidase (GPx) [27,28], Bi2-dependent methylmalonyl-CoA mutase [29] and PLP-dependent P-lyase [30], These systems will be described in more detail in the following sections. ONIOM applications to enzymatic systems performed by other research groups will be only briefly described. 

The importance of having adequate supplies of NADPH for the regeneration of these various enzymes cannot be over emphasized. In normal situations this cofactor can be adequately provided by the reductive pentose phosphate pathway. Monitoring the activity of the pentose phosphate pathway has been proposed as a unique way to study the metabolic response to oxidative stress, since the glutathione peroxidase activity is coupled via glutathione reductase to the enzyme glucose-6-phosphate dehydrogenase (Ben Yoseph et ah, 1994). 

O Donnell et al. [70] found that LOX and not cyclooxygenase, cytochrome P-450, NO synthase, NADPH oxidase, xanthine oxidase, ribonucleotide reductase, or mitochondrial respiratory chain is responsible for TNF-a-mediated apoptosis of murine fibrosarcoma cells. 15-LOX activity was found to increase sharply in heart, lung, and vascular tissues of rabbits by hypercholesterolemia [71], Schnurr et al. [72] demonstrated that there is an inverse regulation of 12/15-LOXs and phospholipid hydroperoxide glutathione peroxidases in cells, which balanced the intracellular concentration of oxidized lipids. 

Glutathione redox cycle consists of NADPH, reduced glutathione GSH, glutathione reductase (GR), and glutathione peroxidase (GP) (Reactions (7) and (8)) ... 

In contrast, antioxidant enzymes can efficiently counteract all UV-induced ROS (Aguilera et al. 2002). These enzymes are represented by superoxide dismutase (SOD), catalase and glutathione peroxidase as well as those involved in the ascorbate-glutathione cycle, such as ascorbate peroxidase, mono-dehydroascorbate reductase, dehydroascorbate reductase and glutathione reductase. One of the most important classes of antioxidant enzymes is the SOD family, which eliminate noxious superoxide radical anions. Different metalloforms of SOD exist (Fe, Mn, CuZn and Ni), which due to their intracellular localisation protect different cellular proteins (Lesser and Stochaj 1990). 

Figure 5.3. The glutathione cycle. Abbreviations HMP, hexose monophosphate shunt GSH, reduced glutathione GSSH, oxidised glutathione GR, glutathione reductase GPO, glutathione peroxidase. In the system shown, H2O2 is converted into H20, but the system is also effective in breaking down organic peroxides.

Glutathione peroxidase 6 Thioredoxin reductase 1 Thioredoxin reductase 2 Thioredoxin reductase 3... 

Dose-related increased activity of lung glutathione peroxidase and glutathione reductase (gjucose-6-phosphate dehydrogenase activity significantly increased at 0.5 ppm)... 

Selenium Organ meats, seafood, muscle meats, cereals and grains Component of glutathione peroxidase lodothyronine deiodinase, thioredoxin reductase... 

A major class of enzymes that catalyze oxidation-reduction reactions. This class includes dehydrogenases, reductases, oxygenases, peroxidases, and a few synthases. Examples include alcohol dehydrogenase (EC 1.1.1.1), aldehyde oxidase (EC 1.2.3.1), orotate reductase (EC 1.3.1.14), glutamate synthase (EC 1.4.1.14), NAD(P) transhydrogenase (EC 1.6.1.1), and glutathione peroxidase (EC 1.11.1.9). 

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