Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P30044 (antioxidant enzyme)
8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The flavoprotein thioredoxin reductase catalyzes the reduction of the small redox protein thioredoxin by NADPH. Thioredoxin reductase contains a redox active disulfide and is a member of the pyridine nucleotide-disulfide oxidoreductase family of flavoenzymes that includes lipoamide dehydrogenase, glutathione reductase, trypanothione reductase, mercuric reductase, and NADH peroxidase. The structure of thioredoxin reductase has recently been determined from X-ray crystallographic data. In this paper, we attempt to correlate the structure with a considerable body of mechanistic data and to arrive at a mechanism consistent with both. The path of reducing equivalents in catalysis by glutathione reductase and lipoamide dehydrogenase is clear. To envisage the path of reducing equivalents in catalysis by thioredoxin reductase, a conformational change is required in which the NADPH domain rotates relative to the FAD domain. The rotation moves the nascent dithiol from its observed position adjacent to the re surface of the flavin ring system toward the protein surface for dithiol-disulfide interchange with the protein substrate thioredoxin and moves the nicotinamide ring of NADPH adjacent to the flavin ring for efficient hydride transfer. Reverse rotation allows reduction of the redox active disulfide by the reduced flavin. This requires that the enzyme pass through a ternary complex; the kinetic evidence for such a complex is discussed.
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PMID:Mechanism and structure of thioredoxin reductase from Escherichia coli. 755 16

The crystal structures of three forms of Escherichia coli thioredoxin reductase have been refined: the oxidized form of the wild-type enzyme at 2.1 A resolution, a variant containing a cysteine to serine mutation at the active site (Cys138Ser) at 2.0 A resolution, and a complex of this variant with nicotinamide adenine dinucleotide phosphate (NADP+) at 2.3 A resolution. The enzyme mechanism involves the transfer of reducing equivalents from reduced nicotinamide adenine dinucleotide phosphate (NADPH) to a disulfide bond in the enzyme, via a flavin adenine dinucleotide (FAD). Thioredoxin reductase contains FAD and NADPH binding domains that are structurally similar to the corresponding domains of the related enzyme glutathione reductase. The relative orientation of these domains is, however, very different in the two enzymes: when the FAD domains of thioredoxin and glutathione reductases are superimposed, the NADPH domain of one is rotated by 66 degrees with respect to the other. The observed binding mode of NADP+ in thioredoxin reductase is non-productive in that the nicotinamide ring is more than 17 A from the flavin ring system. While in glutathione reductase the redox active disulfide is located in the FAD domain, in thioredoxin reductase it is in the NADPH domain and is part of a four-residue sequence (Cys-Ala-Thr-Cys) that is close in structure to the corresponding region of thioredoxin (Cys-Gly-Pro-Cys), with a root-mean-square deviation of 0.22 A for atoms in the disulfide bonded ring. There are no significant conformational differences between the structure of the wild-type enzyme and that of the Cys138Ser mutant, except that a disulfide bond is not present in the latter. The disulfide bond is positioned productively in this conformation of the enzyme, i.e. it stacks against the flavin ring system in a position that would facilitate its reduction by the flavin. However, the cysteine residues are relatively inaccessible for interaction with the substrate, thioredoxin. These results suggest that thioredoxin reductase must undergo conformational changes during enzyme catalysis. All three structures reported here are for the same conformation of the enzyme and no direct evidence is available as yet for such conformational changes. The simplest possibility is that the NADPH domain rotates between the conformation observed here and an orientation similar to that seen in glutathione reductase. This would alternately place the nicotinamide ring and the disulfide bond near the flavin ring, and expose the cysteine residues for reaction with thioredoxin in the hypothetical conformation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Crystal structure of Escherichia coli thioredoxin reductase refined at 2 A resolution. Implications for a large conformational change during catalysis. 811 95

The authors studied the effect of alpha-tocopherol acetate and nicotinamide on lipid peroxidation and antioxidant enzyme defense (AED) in red cell membranes of 61 patients with new-onset insulin-dependent diabetes mellitus. Lipid peroxidation products were found in excessive quantities, whereas enzymes of the cell antioxidant defense were on the decrease. Combination of tocopherol with nicotinamide as adjuvants to conventional insulin therapy promoted normalization of lipid peroxidation and AED, improving beta-cell function. It is believed justified to introduce antioxidant treatment early in the disease onset to prevent toxic damage to beta-cells and vascular endothelium induced by lipid peroxidation products.
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PMID:[Treatment with thymogen and myelopid of patients with bronchial asthma]. 869 81

Experiments on rats with experimental streptosotocin-induced diabetes have shown intensification of the lipid peroxidation processes and reduction of activity of antioxidant defensive enzymes. The content of G-SH and glutathione peroxidase activity has decreased in comparison with the normal rate by 69% and 28%, respectively. Glutathione reductase activity has risen by 20%. Activity of the antioxidant enzymes (superoxide dismutase, catalase) has reduced and the amount of the final product of lipid peroxidation, MDA has increased. Injection of nicotinamide to diabetic rats (200 mg/1 kg of weight) for 14 days normalized activity of the antioxidant enzyme system and the content of the lipid peroxidation products.
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PMID:[The effect of nicotinamide on the enzymatic activity of the antioxidant defense in experimental diabetes]. 900 53

Thioredoxin reductase is a homodimeric flavoenzyme containing a flavin adenine dinucleotide (FAD) and a redox-active disulfide in each subunit. Structural work on the enzyme from Escherichia coli suggests that thioredoxin reductase exists in two conformations, both of which are necessary for catalysis [Waksman, G., Krishna, T. S. R., Williams, C. H., Jr., & Kuriyan, J. (1994) J. Mol. Biol. 236, 800-816]. These factors make it likely that the mechanism of this enzyme is complex. The rapid reaction of enzyme with nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) (the reductive half-reaction), proceeds in three phases. The first phase represents the formation of an NADPH-FAD charge transfer complex. The second phase involves FAD reduction, with loss of the NADPH-FAD charge transfer band. The third phase shows a slower decrease in absorbance at 456 nm and the formation of a reduced flavin-NADP+ charge transfer band. These and other results indicate that NADP+ and NADPH compete for the single binding site on oxidized and fully reduced enzyme and that NADP+ release does not limit the third phase of reduction. Experiments that include examination of the reductive half-reactions of active-site mutants, having the active-site disulfide removed by mutating one or both of the active-site cysteines, indicate that the third phase does not represent reduction by a second equivalent of NADPH. Comparison of the rate constants and temperature dependence of the reductive half-reaction with those of turnover show that the reductive half-reaction is not solely rate-limiting in catalysis. The results suggest that wild type and each altered enzyme exists in a unique equilibrium of conformers. It is proposed that the third phase of the reductive half-reaction represents a flavin reduction event largely limited by the conformational change proposed in the structural work.
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PMID:Reductive half-reaction of thioredoxin reductase from Escherichia coli. 923 91

Lipid peroxidation was intensified by streptozotocin induced diabetes mellitus in erythrocytes and liver. Activity of antioxidant enzyme superoxide-dismutase was decreased, activity of catalase was increased. Concentration of lipid peroxidation products was decreased after nicotinamide injections. It was investigated liver- and erythrocyte catalase inhibition in the presence of 3-amino-1,2,4-triazole. Effective inhibitor concentration for liver catalase by streptozotocin induced diabetes mellitus was 10 mM, by control-20 mM. Ascorbic acid induced catalase inhibition in the erythrocytes by diabetes mellitus increased by ascorbic acid concentration from 25 to 150 mM. [DHAA]/[AA]-ratio increased from 0.26 by control to 1.6 by diabetes mellitus and decreased to 0.44 after nicotinamide injections.
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PMID:[Features of the inhibition of catalase activity by 3-amino-1,2,4-triazole in erythrocytes and liver of rats with streptozotocin diabetes]. 1045 96

Concentration of lipid peroxidation products and antioxidant enzyme activities in rat brain and erythrocytes and the effects of nicotinamide and nicotinoyl-GABA administration on these parameters were estimated on 21st day of streptozotocin-induced diabetes. It was demonstrated more then two-fold diabetes-induced accumulation of conjugated dienes and malondialdehyde in tissues studied. Superoxide dismutase and glutathione reductase activities of both brain homogenate and erythrocytes as well as catalase and glutathione peroxidase activities of brain homogenate were shown to decrease significantly in diabetic rats, meanwhile, catalase activity of erythrocytes was increased and glutathione peroxidase unchanged. So the correlation between changes in enzymatic antioxidant system in brain and erythocytes failed to be found. Alterations observed were virtually prevented by the course of nicotinamide and nicotinoyl-GABA treatment. The results suggested that the suppression of antioxidant system could be primary biochemical disturbance in diabetic neuropathy progression. It was shown that the antioxidant efficacy of nicotinoyl-GABA is lower than that of nicotinamide. It was suggested that the mechanism of antioxidant action of nicotinamide and its structural analogue consists of both scavenging of lipid peroxides and NAD biosynthesis that leads to activation and normalization of altered energy and lipid metabolism.
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PMID:[Oxidative stress correction by nicotinamide and nicotynol-GABA in diabetic neuropathy]. 1291 62

Thioredoxin reductase (TrxR) is an essential enzyme required for the efficient maintenance of the cellular redox homeostasis, particularly in cancer cells that are sensitive to reactive oxygen species. In mammals, distinct isozymes function in the cytosol and mitochondria. Through an intricate mechanism, these enzymes transfer reducing equivalents from NADPH to bound FAD and subsequently to an active-site disulfide. In mammalian TrxRs, the dithiol then reduces a mobile C-terminal selenocysteine-containing tetrapeptide of the opposing subunit of the dimer. Once activated, the C-terminal redox center reduces a disulfide bond within thioredoxin. In this report, we present the structural data on a mitochondrial TrxR, TrxR2 (also known as TR3 and TxnRd2). Mouse TrxR2, in which the essential selenocysteine residue had been replaced with cysteine, was isolated as a FAD-containing holoenzyme and crystallized (2.6 A; R = 22.2%; R(free) = 27.6%). The addition of NADPH to the TrxR2 crystals resulted in a color change, indicating reduction of the active-site disulfide and formation of a species presumed to be the flavin-thiolate charge transfer complex. Examination of the NADP(H)-bound model (3.0 A; R = 24.1%; R(free) = 31.2%) indicates that an active-site tyrosine residue must rotate from its initial position to stack against the nicotinamide ring of NADPH, which is juxtaposed to the isoalloxazine ring of FAD to facilitate hydride transfer. Detailed analysis of the structural data in conjunction with a model of the unusual C-terminal selenenylsulfide suggests molecular details of the reaction mechanism and highlights evolutionary adaptations among reductases.
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PMID:Crystal structures of oxidized and reduced mitochondrial thioredoxin reductase provide molecular details of the reaction mechanism. 1621 27

Dysfunction of D2-like receptors has been reported in essential hypertension. Disruption of D2R in mice (D2-/-) results in high blood pressure, and several D2R polymorphisms are associated with decreased D2R expression. Because D2R agonists have antioxidant activity, we hypothesized that increased blood pressure in D2-/- is related to increased oxidative stress. D2-/- mice had increased urinary excretion of 8-isoprostane, a parameter of oxidative stress; increased activity of reduced nicotinamide-adenine dinucleotide phosphate oxidase in renal cortex; increased expression of the reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits Nox1, Nox2, and Nox4; and decreased expression of the antioxidant enzyme heme-oxygenase-2 in the kidneys, suggesting that regulation of reactive oxygen species (ROS) production by D2R involves both pro-oxidant and antioxidant systems. Apocynin, a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, or hemin, an inducer of heme oxigenase-1, normalized the blood pressure in D2-/- mice. Because D2Rs in the adrenal gland are implicated in aldosterone regulation, we evaluated whether alterations in aldosterone secretion contribute to ROS production in this model. Urinary aldosterone was increased in D2-/- mice and its response to a high-sodium diet was impaired. Spirolactone normalized the blood pressure in D2-/- mice and the renal expression of Nox1 and Nox4, indicating that the increased blood pressure and ROS production are, in part, mediated by impaired aldosterone regulation. However, spironolactone did not normalize the excretion of 8-isoprostane and had no effect on expression of Nox2 or heme-oxygenase-2. Our results show that the D2R is involved in the regulation of ROS production and that, by direct and indirect mechanisms, altered D2R function may result in ROS-dependent hypertension.
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PMID:Reactive oxygen species-dependent hypertension in dopamine D2 receptor-deficient mice. 1719 Aug 75

Low ethanol intake is known to have a beneficial effect on cardiovascular disease. In cardiovascular disease, insulin resistance leads to altered glucose and lipid metabolism resulting in an increased production of aldehydes, including methylglyoxal. Aldehydes react non-enzymatically with sulfhydryl and amino groups of proteins forming advanced glycation end products (AGEs), altering protein structure and function. These alterations cause endothelial dysfunction with increased cytosolic free calcium, peripheral vascular resistance, and blood pressure. AGEs produce atherogenic effects including oxidative stress, platelet adhesion, inflammation, smooth muscle cell proliferation and modification of lipoproteins. Low ethanol intake attenuates hypertension and atherosclerosis but the mechanism of this effect is not clear. Ethanol at low concentrations is metabolized by low Km alcohol dehydrogenase and aldehyde dehydrogenase, both reactions resulting in the production of reduced nicotinamide adenine dinucleotide (NADH). This creates a reductive environment, decreasing oxidative stress and secondary production of aldehydes through lipid peroxidation. NADH may also increase the tissue levels of the antioxidants cysteine and glutathione, which bind aldehydes and stimulate methylglyoxal catabolism. Low ethanol improves insulin resistance, increases high-density lipoprotein and stimulates activity of the antioxidant enzyme, paraoxonase. In conclusion, we suggest that chronic low ethanol intake confers its beneficial effect mainly through its ability to increase antioxidant capacity and lower AGEs.
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PMID:Beneficial effect of low ethanol intake on the cardiovascular system: possible biochemical mechanisms. 1732 32


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