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 reductase catalyzes the NADPH-dependent reduction of the catalytic disulfide bond of thioredoxin. In mammals and other higher eukaryotes, thioredoxin reductases contain the rare amino acid selenocysteine at the active site. The mitochondrial enzyme from Caenorhabditis elegans, however, contains a cysteine residue in place of selenocysteine. The mitochondrial C. elegans thioredoxin reductase was cloned from an expressed sequence tag and then produced in Escherichia coli as an intein-fusion protein. The purified recombinant enzyme has a kcat of 610 min(-1) and a Km of 610 microM using E. coli thioredoxin as substrate. The reported kcat is 25% of the kcat of the mammalian enzyme and is 43-fold higher than a cysteine mutant of mammalian thioredoxin reductase. The enzyme would reduce selenocysteine, but not hydrogen peroxide or insulin. The flanking glycine residues of the GCCG motif were mutated to serine. The mutants improved substrate binding, but decreased the catalytic rate.
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PMID:Characterization of mitochondrial thioredoxin reductase from C. elegans. 1678 Jul 99

Exposure of human umbilical endothelial cells (ECs) to cigarette smoke extract (CSE) activated the NADPH-oxidase enzyme and increased the production of superoxide (O-2) as well as reactive oxygen species (ROS). CSE also inhibited the prostacyclin (PGI2) formation by ECs. Preincubation of ECs with diphenylene iodonium (DPI), the inhibitor of NADPH oxidase, blocked the increase of O-2 production, but neither lowered the ROS level nor prevented the inhibition of PGI2 formation in CSE-treated cells. Preincubation of ECs with a medium supplemented with 1 mM vitamin C did not decrease, but rather increased the O-2 production in CSE-treated cells. However, adding 1 mM glutathione (GSH) to vitamin C decreased the O-2 production, indicating that vitamin C was overwhelmed by the prooxidant in CS, and GSH enhanced the recycling process and spared vitamin C. The ROS level remained high in CSE-treated cells even after preincubation with vitamin C or vitamin C + GSH compared to the control cells. These results are discussed in light of the possible decrease of antioxidant enzyme activities in CSE-treated cells and the increase of cellular hydrogen peroxide (H2O2) generated from the CSE, which cause an imbalance between oxidizing species and the antioxidants producing oxidative stress in CSE-treated cells. These results demonstrate that CSE has a direct inhibitory effect on PGI2 formation and enhances the level of ROS in CSE-treated ECs, regardless of the activation of NADPH-oxidase.
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PMID:Inhibition of prostacyclin release by cigarette smoke extract in endothelial cells is not related to enhanced superoxide generation and NADPH-oxidase activation. 1707 61

This study was carried to investigate neutrophil function in the presence of Prototheca zopfii. For this purpose, bovine milk neutrophils were incubated in the absence (control) of and presence of P. zopfii, and then they were examined hydrogen peroxide (H(2)O(2)) production, antioxidant enzyme activities, and phagocytic capacity. Milk was collected from negative "California Mastitis Test" (CMT) quarter from three lactating Holstein cows after induction of leukocytosis with an intramammary infusion of oyster glycogen. H(2)O(2) production was measured using the phenol red method. Catalase activity was measured following H(2)O(2) reduction at 240 nm and the activity of glutathione reductase was determined by measuring the rate of NADPH oxidation at 340 nm. P. zopfii death was assessed by fluorescent microscopy using acridine orange assay and by colony forming units (CFUs). Comparisons between the groups were initially performed by analysis of variance (ANOVA). Significant differences were then compared using Tukey's test with a significance coefficient of 0.05. Hydrogen peroxide production, catalase and glutathione reductase activities by neutrophils incubated in presence of P. zopfii were stimulated five times, 21% and 27% respectively, compared to the unstimulated-neutrophils. Neutrophils did not affect P. zopfii death as shown by microscopy and CFUs. These observations led to the conclusion that the P. zopfii promote a high increase of H(2)O(2) production by neutrophils from bovine milk during algae exposition accompanied by increase of antioxidant enzyme activities; however, this process did not affect P. zopfii death.
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PMID:Effect of Prototheca zopfii on neutrophil function from bovine milk. 1714 86

Cyclophosphamide (CTX) is in the nitrogen mustard group of alkylating antineoplastic chemotherapeutic agents. It is one of the most frequently used antitumor agents for the treatment of a broad spectrum of human cancers. Thioredoxin reductase (TrxR) catalyze the NADPH-dependent reduction of thioredoxin and play an important role in multiple cellular events related to carcinogenesis including cell proliferation, apoptosis, and cell signaling. This enzyme represents a promising target for the development of cytostatic agents. The purpose of this study is to determine whether CTX could target TrxR in vivo. Lewis lung carcinoma and solid H22 hepatoma treated with 50-250 mg/kg CTX for 3 h lost TrxR activity in a dose-dependent fashion. Over 75% and 95% of TrxR activity was lost at the dose of 250 mg/kg. There was, however, a recovery of TrxR activity such that it attained normal levels by 120 h after a dose of 250 mg/kg. In addition, we found that CTX caused a preferential TrxR inhibition over other antioxidant enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase. We also used ascites H22 cells to investigate cancer cells response after TrxR was inhibited by CTX in vivo since CTX is needed to be activated by liver cytochrome P450 enzymes. The time course and dose-dependent changes of cellular TrxR activity were similar with those in tumor tissue. CTX caused a dose-dependent cellular proliferation inhibition which was positively correlated with TrxR inhibition at 3 h. Furthermore, when 3 h CTX-treated cells with various TrxR backgrounds, harvested from ascites-bearing mice, were implanted into mice, the proliferations of these cells were again proportionally dependent on TrxR activity. The TrxR inhibition could thereby be considered as a crucial mechanism contributing to anticancer effect seen upon clinical use of CTX.
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PMID:Cyclophosphamide as a potent inhibitor of tumor thioredoxin reductase in vivo. 1715 7

Ionizing radiation induces the production of reactive oxygen species, which play an important causative role in apoptotic cell death. Recently, we demonstrated that the control of mitochondrial redox balance and the cellular defense against oxidative damage are primary functions of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDPm) by supplying NADPH for antioxidant systems. In this paper, we demonstrate that modulation of IDPm activity in the kidneys of mice regulates ionizing radiation-induced apoptosis. When oxalomalate, a competitive inhibitor of IDPm, was administered to mice, inhibition of IDPm and enhanced susceptibility of apoptosis reflected by DNA fragmentation, the changes in mitochondria function, and the modulation of apoptotic marker proteins were observed upon exposure to 2 Gy of gamma-irradiation. We also observed a significant difference in the mitochondrial redox status between the kidneys of the control and the oxalomalate-administered mice. This study indicates that IDPm may play an important role in regulating the apoptosis induced by ionizing radiation, presumably, through acting as an antioxidant enzyme.
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PMID:Oxalomalate regulates ionizing radiation-induced apoptosis in mice. 1715 92

Thioredoxin reductase from Drosophila melanogaster (DmTrxR) catalyzes the reversible transfer of reducing equivalents between NADPH and thioredoxin (Trx), a small protein that is involved in a wide variety of biological redox processes. The catalysis involves three essential redox states of the enzyme: the oxidized form of DmTrxR (Eox), the 2-electron-reduced forms (EH2), and the 4-electron-reduced forms (EH4). In the present work, the macroscopic redox potentials of Eox/EH2 and EH2/EH4 couples were determined to be -272 +/- 5 mV for Em(Eox/EH2) and -298 +/- 11 mV for Em(EH2/EH4) on the basis of redox equilibria between DmTrxR and NADH. The value for Em(EH2/EH4) obtained from the steady-state kinetics of the TrxR-catalyzed reaction between NADPH and D. melanogaster Trx-2 (DmTrx-2) was reasonably consistent with that based on redox equilibria. The redox potential of the Trx-(S)2/Trx-(SH)2 couple from D. melanogaster Trx-2 (DmTrx-2) was calculated to be -275.4 +/- 0.3 mV by using the Nernst equation and the Keq for the equilibrium of the reaction involving NADP/NADPH and Trx-(S)2/Trx-(SH)2. For the accurate determination of the Keq, an improved protocol has been developed to minimize errors that can be introduced by using starting concentrations far from equilibrium of the TrxR-catalyzed reaction between NADPH and Trx. This improved approach gives an Em of -284.2 +/- 1.0 mV for Escherichia coli Trx and -271.9 +/- 0.4 mV for Plasmodium falciparum Trx, which agree well with published values (-283 or -285 mV and -270 mV, respectively). The redox potentials determined herein provide further direct evidence for the proposed catalytic mechanism of DmTrxR, and cast new light on the essential role of the DmTrx system in cycling GSSG/GSH and maintaining the intracellular redox homeostasis in D. melanogaster where glutathione reductase is absent.
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PMID:The relationship of the redox potentials of thioredoxin and thioredoxin reductase from Drosophila melanogaster to the enzymatic mechanism: reduced thioredoxin is the reductant of glutathione in Drosophila. 1755 Feb 71

Glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the pentose phosphate pathway, is indispensable to maintenance of the cytosolic pool of NADPH and thus the cellular redox balance. The role of G6PD as an antioxidant enzyme has been recognized in erythrocytes for a long time, as its deficiency is associated with neonatal jaundice, drug- or infection-mediated hemolytic crisis, favism and, less commonly, chronic non-spherocytic hemolytic anemia. To a large extent, advances in the field were made on the pathophysiology of G6PD-deficient erythrocytes, and the molecular characterization of different G6PD variants. Not until recently did numerous studies cast light on the importance of G6PD in other aspects of the physiology of both cells and organisms. Deficiency in G6PD activity, and hence a disturbance in redox homeostasis, can lead to dysregulation of cell growth and signaling, anomalous embryonic development, altered susceptibility to viral infection as well as increased susceptibility to degenerative diseases. The present review covers recent developments in this field. Additionally, molecular characterization of G6PD variants, especially those frequently found in Taiwan and Southern China, is also addressed.
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PMID:Glucose-6-phosphate dehydrogenase--from oxidative stress to cellular functions and degenerative diseases. 1762 17

Thioredoxins are small thiol proteins that have a conserved active site sequence, WCGPC, and reduce disulfide bonds in various proteins using the two active site cysteines, a reaction that oxidizes thioredoxin and renders it inactive. Thioredoxin reductase returns thioredoxin to its reduced, active form in a reaction that converts NADPH to NADP(+). The biological functions of thioredoxins vary widely; they have roles in oxidative stress protection, act as electron donors for ribonucleotide reductase, and form structural components of enzymes. To date, three thioredoxin genes have been characterized in Drosophila melanogaster: the generally expressed Thioredoxin-2 (Trx-2) and the two sex-specific genes ThioredoxinT (TrxT) and deadhead (dhd). The male-specific TrxT and the female-specific dhd are located as a gene pair, transcribed in opposite directions, with only 470 bp between their transcription start points. We show in this study that all three D. melanogaster thioredoxins are conserved in 11 other Drosophilid species, which are believed to have diverged up to 40 Ma ago and that Trx-2 is conserved all the way to Tribolium castaneum. We have found that the intriguing gene organization and regulation of TrxT and dhd is remarkably well conserved and identified potential conserved regulatory sequences. In addition, we show that the 50-70 C terminal amino acids of TrxT constitute a hyper-variable domain, which could play a role in sexual conflict and male-female co-evolution.
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PMID:Organization and regulation of sex-specific thioredoxin encoding genes in the genus Drosophila. 1770 Oct 50

The effects of excess copper (Cu) on the accumulation of hydrogen peroxide (H2O2) and antioxidant enzyme activities in roots of the Cu accumulator Elsholtzia haichowensis Sun were investigated. Copper at 100 and 300 microM significantly increased the concentrations of malondialdehyde and H2O2, and the activities of catalase (E.C. 1.11.1.6), ascorbate peroxidase (E.C. 1.11.1.11), guaiacol peroxidase (GPOD, E.C. 1.11.1.7) and superoxide dismutase (SOD, E.C. 1.15.1.1). Isoenzyme pattern and inhibitor studies showed that, among SOD isoforms, only copper-zinc superoxide dismutase (CuZn-SOD) increased. Excess Cu greatly increased the accumulation of superoxide anion (O2 (.-)) and H2O2 in E. haichowensis roots. This study also provides the first cytochemical evidence of an accumulation of H2O2 in the root cell walls as a consequence of Cu treatments. Experiments with diphenyleneiodonium as an inhibitor of NADPH oxidase, 1,2-dihydroxybenzene-3,5-disulphonic acid as an O2 (.-) scavenger, and N-N-diethyldithiocarbamate as an inhibitor of SOD showed that the source of H2O2 in the cell walls could partially be NADPH oxidase. The enzyme can use cytosolic NADPH to produce O2 (.-), which rapidly dismutates to H2O2 by SOD. Apoplastic GPOD and CuZn-SOD activities were induced in roots of E. haichowensis with 100 microM Cu suggesting that these two antioxidant enzymes may be responsible for H2O2 accumulation in the root apoplast.
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PMID:Excess copper induces accumulation of hydrogen peroxide and increases lipid peroxidation and total activity of copper-zinc superoxide dismutase in roots of Elsholtzia haichowensis. 1790 54

We have previously proposed that hypercholesterolemic LDL receptor knockout (k/o) mice mitochondria possess a lower antioxidant capacity due to a large consumption of reducing equivalents from NADPH to sustain high rates of lipogenesis. In this work, we tested the hypothesis that this k/o mice mitochondrial oxidative stress results from the depletion of NADPH-linked substrates. In addition, the oxidative stress was further characterized by showing a lower mitochondrial GSH/GSSG ratio and a higher liver content of protein carbonyls as compared to controls. The activity of the antioxidant enzyme system glutathione reductase/peroxidase did not differ in k/o and control mitochondria. The faster spontaneous oxidation of endogenous NADPH in the k/o mitochondria was prevented by the addition of exogenous catalase, indicating that this oxidation is mediated by mitochondrially generated H(2)O(2). The higher rate of H(2)O(2) production was also prevented by the addition of exogenous isocitrate that maintains NADP fully reduced. The hypothesis that high rates of lipogenesis in the k/o cells decrease mitochondrial NADPH/NADP(+) ratio due to consumption of NADPH-linked substrates was supported by two findings: (i) oxygen consumption supported by endogenous NAD(P)H-linked substrates was slower in k/o than in control mitochondria, but was similar in the presence of exogenous isocitrate; (ii) in vivo treatment of k/o mice with sodium citrate/citric acid drinking solution for 2 weeks partially restored both the rate of oxygen consumption supported by NAD(P)H-linked substrates and the mitochondrial capacity to sustain reduced NADPH. In conclusion, the data demonstrate that the mitochondrial oxidative stress in hypercholesterolemic LDL receptor knockout mice is the result of a low content of mitochondrial NADPH-linked substrates in the intact animal that can be, at least in part, replenished by oral administration of citrate.
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PMID:Oxidative stress in hypercholesterolemic LDL (low-density lipoprotein) receptor knockout mice is associated with low content of mitochondrial NADP-linked substrates and is partially reversed by citrate replacement. 1799 44


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