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)

Thioredoxin, thioredoxin reductase and NADPH form the thioredoxin system and are the major cellular protein disulphide reductase. We report here that Escherichia coli thioredoxin and thioredoxin reductase interact with unfolded and denatured proteins, in a manner similar to that of molecular chaperones that are involved in protein folding and protein renaturation after stress. Thioredoxin and/or thioredoxin reductase promote the functional folding of citrate synthase and alpha-glucosidase after urea denaturation. They also promote the functional folding of the bacterial galactose receptor, a protein without any cysteines. Furthermore, redox cycling of thioredoxin/thioredoxin reductase in the presence of NADPH and cystine stimulates the renaturation of the galactose receptor, suggesting that the thioredoxin system functions like a redox-powered chaperone machine. Thioredoxin reductase prevents the aggregation of citrate synthase under heat-shock conditions. It forms complexes that are more stable than those formed by thioredoxin with several unfolded proteins such as reduced carboxymethyl alpha-lactalbumin and unfolded bovine pancreatic trypsin inhibitor. These results suggest that the thioredoxin system, in addition to its protein disulphide isomerase activity possesses chaperone-like properties, and that its thioredoxin reductase component plays a major role in this function.
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PMID:Chaperone properties of Escherichia coli thioredoxin and thioredoxin reductase. 1254 77

Heat shock may increase oxidative stress due to increased production of reactive oxygen species and/or the promotion of cellular oxidation events. NADP(+)-dependent isocitrate dehydrogenase (ICDH) in Escherichia coli produces NADPH, an essential reducing equivalent for the antioxidant system. The protective role of ICDH against heat shock in E. coli was investigated in wild-type and ICDH-deficient strains. Upon exposure to heat shock, the viability was lower and the protein oxidation was higher in mutant cells as compared to wild-type cells. Induction and inactivation of antioxidant enzymes were observed after their exposure to heat shock both in wild-type and in mutant cells. However, wild-type cells maintained significantly higher activities of antioxidant enzymes than did mutant cells. These results suggest that ICDH plays an important role as an antioxidant enzyme in cellular defense against heat shock through the removal of reactive oxygen species as well as in the protection of other antioxidant enzymes.
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PMID:Thermosensitive phenotype of Escherichia coli mutant lacking NADP+-dependent isocitrate dehydrogenase. 1263 45

We have characterized the thioredoxin reductase (trr1) genes from Pneumocystis carinii and Pneumocystis jiroveci, and have demonstrated that multiple copies of an approximately 500 base pair fragment of the trr1 gene are present in P. carinii, but not in P. jiroveci. Thioredoxin reductases encoded by the full-length genes have predicted molecular weights of approximately 35,000 and show high homology to yeast Trr1. An NADPH-binding domain with a putative redox active site CAVC as well as an flavin-adenine dinucleotide-binding domain are highly conserved in both proteins, which were 85% identical. The multicopy trr1 gene fragments in P. carinii are not transcribed or expressed. Duplication of the gene fragment likely occurred in conjunction with duplication of the kexin homologue, protease-1, which is located immediately upstream of the trr1 gene. Thioredoxin reductase, an enzyme implicated in the growth, survival and pathogenicity of certain microbes, could be a potential target for therapeutic intervention in Pneumocystis infection.
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PMID:Characterization of thioredoxin reductase genes (trr1) from Pneumocystis carinii and Pneumocystis jiroveci. 1280 45

Drosophila melanogaster thioredoxin reductase-1 (DmTrxR-1) is a key flavoenzyme in dipteran insects, where it substitutes for glutathione reductase. DmTrxR-1 belongs to the family of dimeric, high Mr thioredoxin reductases, which catalyze reduction of thioredoxin by NADPH. Thioredoxin reductase has an N-terminal redox-active disulfide (Cys57-Cys62) adjacent to the flavin and a redox-active C-terminal cysteine pair (Cys489'-Cys490' in the other subunit) that transfer electrons from Cys57-Cys62 to the substrate thioredoxin. Cys489'-Cys490' functions similarly to Cys495-Sec496 (Sec = selenocysteine) and Cys535-XXXX-Cys540 in human and parasite Plasmodium falciparum enzymes, but a catalytic redox center formed by adjacent Cys residues, as observed in DmTrxR-1, is unprecedented. Our data show, for the first time in a high Mr TrxR, that DmTrxR-1 oscillates between the 2-electron reduced state, EH2, and the 4-electron state, EH4, in catalysis, after the initial priming reduction of the oxidized enzyme (Eox) to EH2. The reductive half-reaction consumes 2 eq of NADPH in two observable steps to produce EH4. The first equivalent yields a FADH--NADP+ charge-transfer complex that reduces the adjacent disulfide to form a thiolate-flavin charge-transfer complex. EH4 reacts with thioredoxin rapidly to produce EH2. In contrast, Eox formation is slow and incomplete; thus, EH2 of wild-type cannot reduce thioredoxin at catalytically competent rates. Mutants lacking the C-terminal redox center, C489S, C490S, and C489S/C490S, are incapable of reducing thioredoxin and can only be reduced to EH2 forms. Additional data suggest that Cys57 attacks Cys490' in the interchange reaction between the N-terminal dithiol and the C-terminal disulfide.
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PMID:The mechanism of high Mr thioredoxin reductase from Drosophila melanogaster. 1281 54

Reactive oxygen species (ROS)-mediated cell injury contributes to the pathophysiology of cardiovascular disease and myocardial dysfunction. Protection against ROS requires maintenance of endogenous thiol pools, most importantly, reduced glutathione (GSH), by NADPH. In cardiomyocytes, GSH resides in two separate cellular compartments: the mitochondria and cytosol. Although mitochondrial GSH is maintained largely by transhydrogenase and isocitrate dehydrogenase, the mechanisms responsible for sustaining cytosolic GSH remain unclear. Glucose-6-phosphate dehydrogenase (G6PD) functions as the first and rate-limiting enzyme in the pentose phosphate pathway, responsible for the generation of NADPH in a reaction coupled to the de novo production of cellular ribose. We hypothesized that G6PD is required to maintain cytosolic GSH levels and protect against ROS injury in cardiomyocytes. We found that in adult cardiomyocytes, G6PD activity is rapidly increased in response to cellular oxidative stress, with translocation of G6PD to the cell membrane. Furthermore, inhibition of G6PD depletes cytosolic GSH levels and subsequently results in cardiomyocyte contractile dysfunction through dysregulation of calcium homeostasis. Cardiomyocyte dysfunction was reversed through treatment with either a thiol-repleting agent (L-2-oxothiazolidine-4-carboxylic acid) or antioxidant treatment (Eukarion-134), but not with exogenous ribose. Finally, in a murine model of G6PD deficiency, we demonstrate the development of in vivo adverse structural remodeling and impaired contractile function over time. We, therefore, conclude that G6PD is a critical cytosolic antioxidant enzyme, essential for maintenance of cytosolic redox status in adult cardiomyocytes. Deficiency of G6PD may contribute to cardiac dysfunction through increased susceptibility to free radical injury and impairment of intracellular calcium transport. The full text of this article is available online at http://www.circresaha.org.
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PMID:Glucose-6-phosphate dehydrogenase modulates cytosolic redox status and contractile phenotype in adult cardiomyocytes. 1456 10

Membrane lipid peroxidation processes yield products that may react with DNA and proteins to cause oxidative modifications. Cytosolic NADP+-dependent isocitrate dehydrogenase (ICDH) in U937 cells produces NADPH, an essential reducing equivalent for the antioxidant system. The protective role of ICDH against lipid peroxidation-mediated oxidative damage in U937 cells was investigated in control cells pre-treated with oxalomalate, a competitive inhibitor of ICDH. Upon exposure to 2,2'-azobis(2-amidinopropane) hydrochloride (AAPH) to U937 cells, which induces lipid peroxidation in membranes, the viability was lower and the protein oxidation, lipid peroxidation, and oxidative DNA damage, reflected by an increase in 8-hydroxy-2'-deoxyguanosine, were higher in oxalomalate-treated cells as compared to control cells. We also observed the significant increase in the endogenous production of reactive oxygen species, as measured by the oxidation of 2',7'-dichlorodihydrofluorescin, as well as the significant decrease in the intracellular GSH level in oxalomalate-treated U937 cells upon exposure to AAPH. These results suggest that ICDH plays an important role as an antioxidant enzyme in cellular defense against lipid peroxidation-mediated oxidative damage through the removal of reactive oxygen species.
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PMID:Oxalomalate, a competitive inhibitor of NADP+-dependent isocitrate dehydrogenase, enhances lipid peroxidation-mediated oxidative damage in U937 cells. 1285 79

Recently, we reported that male accessory sex gland (ASG) secretions protect sperm genomic integrity by demonstrating that DNA damage was more extensive in sperm not exposed to the secretions. The present study was conducted to find out if ASGs secrete the main antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx or GSH-Px), and catalase (CAT) and if the most abundant one, SOD, can protect those sperm that were not exposed to ASG secretions against NADPH-induced oxidative stress. Four experimental groups of male golden hamsters were used: intact animals with proven fertility, animals with all major ASGs removed (TX), animals that were bilaterally vasectomized, and sham-operated controls. SOD, CAT, and GPx activities were measured in secretions from all 5 ASGs and sperm-free uterine flushing from virgin females and those mated with the experimental males. The alkaline comet assay was used to analyze DNA integrity of the TX group sperm after incubation in a medium containing 50 U/mL of SOD along with 0 to 20 mmol/L NADPH. The main antioxidant enzyme in ASGs was SOD from coagulating glands (P <.05) and GPx together with CAT from ampullary glands (P <.05). Uterine flushing of ejaculates that contained ASG secretions had more SOD and CAT activities than those with epididymal secretions alone (P <.05 and P <.001, respectively), whereas activity of GPx was the same (P >.05). Addition of SOD in vitro dose dependently decreased the incidence of single-strand DNA damage in sperm not exposed to ASG secretions incubated in the presence of 0 to 20 mmol/L NADPH (P <.001). These results indicated that, in terms of abundance, SOD was the main antioxidant enzyme secreted by male ASGs, whereas CAT was the second one. The GPx activity came from both epididymis and ASGs. We conclude that ASG secretions play a significant role in protecting sperm against oxidative stress.
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PMID:Male genital tract antioxidant enzymes: their source, function in the female, and ability to preserve sperm DNA integrity in the golden hamster. 1295 61

The metabolic functions of NADP(+)-specific isocitrate dehydrogenase (ID2), which may participate in the production of NADPH and biosynthesis of fatty acids, are not yet clearly understood. Accordingly, the current study investigated the effect of oxalomalate, known as a competitive inhibitor of ID2 in vitro, on lipid metabolism and the cellular defense system in vivo. Male Sprague Dawley rats (3 weeks old) were divided into two groups, fed a pelletized AIN-76 semisynthetic diet for 8 weeks, and injected intraperioneally with either saline or oxalomalate (25 mg/kg BW) dissolved in saline every 2 days. Oxalomalate did not lower the body weight and adipose tissue weight significantly; however, it significantly lower the plasma leptin concentration (p < 0.000), plasma and hepatic triglyceride levels (p < 0.01, p < 0.05), and adipocyte lipoprotein lipase activity (p < 0.01) compared to the control group. Meanwhile, hepatic antioxidant enzyme activities, except for superoxide dismutase activity (p < 0.01), glutathione content, and thiobarbituric acid reactive substances levels were not significantly different between the groups. Therefore, the current data suggests that oxalomalate produces a triglyceride-lowering activity and play a possible inhibitory role in fat accumulation. Furthermore, it was not found to affect the most antioxidative enzyme activities, glutathione content, and thiobarbituric acid reactive substances levels in rats fed normal diet.
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PMID:Effect of oxalomalate on lipid metabolism and antioxidant defense system in rats. 1459 52

Thioredoxin reductase (TrxR) is the homodimeric flavoenzyme that catalyzes reduction of thioredoxin disulfide (Trx). For Plasmodium falciparum, a causative agent of tropical malaria, TrxR is an essential protein which has been validated as a drug target. The high-throughput screening of 350000 compounds has identified Mannich bases as a new class of TrxR mechanism-based inhibitors. During catalysis, TrxR conducts reducing equivalents from the NADPH-reduced flavin to Trx via the two redox-active cysteine pairs, Cys88-Cys93 and Cys535'-Cys540', referred to as N-terminal and C-terminal cysteine pairs. The structures of unsaturated Mannich bases suggested that they could act as bisalkylating agents leading to a macrocycle that involves both C-terminal cysteines of TrxR. To confirm this hypothesis, different Mannich bases possessing one or two electrophilic centers were synthesized and first studied in detail using glutathione as a model thiol. Michael addition of glutathione to the double bond of an unsaturated Mannich base (3a) occurs readily at physiological pH. Elimination of the amino group, promoted by base-catalyzed enolization of the ketone, is followed by addition of a second nucleophile. The intermediate formed in this reaction is an alpha,beta-unsaturated ketone that can react rapidly with a second thiol. When studying TrxR as a target of Mannich bases, we took advantage of the fact that the charge-transfer complex formed between the thiolate of Cys88 and the flavin in the reduced enzyme can be observed spectroscopically. The data show that it is the C-terminal Cys 535'-Cys540' pair rather than the N-terminal Cys88-Cys93 pair that is modified by the inhibitor. Although alkylated TrxR is unable to turn over its natural substrate Trx, it can reduce low M(r) electron acceptors such as methyl methanethiolsulfonate by using its unmodified N-terminal thiols. On the basis of results with chemically distinct Mannich bases, a detailed mechanism for the inactivation of TrxR is proposed.
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PMID:Mechanism-based inactivation of thioredoxin reductase from Plasmodium falciparum by Mannich bases. Implication for cytotoxicity. 1460 42

H(2)O(2) production was evaluated in liver microsomes prepared from Cyp1a1/1a2(+/+) wild-type and Cyp1a1(-/-) and Cyp1a2(-/-) knockout mice pretreated with 5 microg dioxin (TCDD)/kg body wt or vehicle alone. NADPH-dependent H(2)O(2) production in TCDD-induced microsomes from wild-type mice was about one-third of that in noninduced microsomes. In Cyp1a2(-/-) mice, H(2)O(2) production was the same for induced and noninduced microsomes, with levels significantly higher than those in wild-type mice. Cyp1a1(-/-) microsomes displayed markedly lower levels of H(2)O(2) production in both induced and noninduced microsomes, compared with those in wild-type and Cyp1a2(-/-) microsomes. The CYP1A2 inhibitor furafylline in vitro exacerbated microsomal H(2)O(2) production proportional to the degree of CYP1A2 inhibition, and the CYP2E1 inhibitor diethyldithiocarbamate decreased H(2)O(2) production proportional to the degree of CYP2E1 inhibition. Microsomal H(2)O(2) production was strongly correlated to NADPH-stimulated production of thiobarbituric acid-reactive substances, as well as to decreases in microsomal membrane polarization anisotropy, indicative of peroxidation of unsaturated membrane lipids. Our results suggest that possibly acting as an "electron sink," CYP1A2 might decrease CYP2E1-and CYP1A1-mediated H(2)O(2) production and oxidative stress. In this regard, CYP1A2 may be considered an antioxidant enzyme.
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PMID:Cyp1a2 protects against reactive oxygen production in mouse liver microsomes. 1498 Jul 4


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