Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P30044 (antioxidant enzyme)
 8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Copper chaperones are copper-binding proteins that directly insert copper into specific targets, preventing the accumulation of free copper ions that can be toxic to the cell. Despite considerable advances in the understanding of copper transfer from copper chaperones to their target, to date, there is no information regarding how the activity of these proteins is regulated in higher eukaryotes. The insertion of copper into the antioxidant enzyme Cu,Zn superoxide dismutase (SOD1) depends on the copper chaperone for SOD1 (CCS). We have recently reported that CCS protein is increased in tissues of rats fed copper-deficient diets suggesting that copper may regulate CCS expression. Here we show that whereas copper deficiency increased CCS protein in rats, mRNA level was unaffected. Rodent and human cell lines cultured in the presence of the specific copper chelator 2,3,2-tetraamine displayed a dose-dependent increase in CCS protein that could be reversed with the addition of copper but not iron or zinc to the cells. Switching cells from copper-deficient to copper-rich medium promoted the rapid degradation of CCS, which could be blocked by the proteosome inhibitors MG132 and lactacystin but not a cysteine protease inhibitor or inhibitors of the lysosomal degradation pathway. In addition, CCS degradation was slower in copper-deficient cells than in cells cultured in copper-rich medium. Together, these data show that copper regulates CCS expression by modulating its degradation by the 26 S proteosome and suggest a novel role for CCS in prioritizing the utilization of copper when it is scarce.
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PMID:Copper modulates the degradation of copper chaperone for Cu,Zn superoxide dismutase by the 26 S proteosome. 1283 19

CYP2E1 induction by ethanol is one mechanism by which ethanol creates oxidative stress in the liver. The superoxide dismutases (SODs) are an important antioxidant enzyme defense system against reactive oxygen species (ROS). To investigate the protective role of SOD against CYP2E1-dependent toxicity, a transfected HepG2 cell line overexpressing CYP2E1 (E47 cells) was infected with adenoviral vectors containing Cu/Zn-SOD complementary DNA (cDNA) (Ad.SOD1) and Mn-SOD cDNA (Ad.SOD2). Forty-eight hours after infection, intracellular levels and activity of Cu/Zn-SOD and Mn-SOD were increased about 2- and 3-fold, respectively. Localization of the overexpressed Cu/Zn-SOD in the cytosol and Mn-SOD in the mitochondria was confirmed by assaying the levels and activity of SOD in the corresponding isolated fractions. Arachidonic acid (AA) plus iron-induced cell death was partially prevented in both Ad.SOD1- and Ad.SOD2-infected E47 cells. Overexpression of Cu/Zn-SOD and Mn-SOD also partially protected E47 cells from the increase in reactive oxygen production and lipid peroxidation and the loss of mitochondrial membrane potential induced by AA and iron. Infection with Cu/Zn-SOD and Mn-SOD also protected the E47 cells against AA toxicity or buthionine sulfoximine (BSO)-dependent toxicity. CYP2E1 levels and catalytic activity were not altered by overexpression of Cu/Zn-SOD or Mn-SOD. Cu/Zn-SOD in the cytosol and Mn-SOD in mitochondria each are capable of protecting HepG2 cells expressing CYP2E1 against cytotoxicity induced by pro-oxidants. In conclusion, these enzymes may be useful in the prevention or improvement of liver injury produced by agents known to be metabolized by CYP2E1 to reactive intermediates and to cause oxidative stress.
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PMID:Adenovirus-mediated expression of Cu/Zn- or Mn-superoxide dismutase protects against CYP2E1-dependent toxicity. 1457 53

The antioxidant enzyme Cu,Zn-superoxide dismutase (SOD1) has the distinction of being one of the most abundant disulfide-containing protein known in the eukaryotic cytosol; however, neither catalytic nor physiological roles for the conserved disulfide are known. Here we show that the disulfide status of Saccharomyces cerevisiae SOD1 significantly affects the monomer-dimer equilibrium, the interaction with the copper chaperone CCS, and the activity of the enzyme itself. Disulfide formation in SOD1 by O2 is slow but is greatly accelerated by the Cu-bound form of CCS (Cu-CCS) in vivo and in vitro even in the presence of excess reductants; once formed, this disulfide is kinetically stable. Biochemical assays reveal that Cu-CCS facilitates Cys oxidation and disulfide isomerization in the stepwise conversion of the immature form of the enzyme to the active state. The immature form of SOD1 is most susceptible to oxidative insult and to aggregation reminiscent of that observed in amyotrophic lateral sclerosis. Thus Cu-CCS mediation of correct disulfide formation in SOD1 is important for regulation of enzyme activity and for prevention of misfolding or aggregation.
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PMID:Oxygen-induced maturation of SOD1: a key role for disulfide formation by the copper chaperone CCS. 1521 95

Ten years ago, the linkage between mutations in the gene coding for the antioxidant enzyme Cu,Zn superoxide dismutase (SOD1) and the neurodegenerative disease known as familial amyotrophic lateral sclerosis (FALS) was established. This finding has prompted a myriad of new studies in experimental models aimed at investigating the toxic function of the mutant enzymes. The cellular functions that are impaired in motoneurons as a consequence of molecular alterations induced by the expression of FALS SOD1 converge on pathways that might be activated in sporadic ALS by other toxic factors. Recent data demonstrate that, although motoneurons are lost in patients, other cell types are also affected and actively contribute to the pathogenesis of the disease.
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PMID:Lessons from models of SOD1-linked familial ALS. 1531 Apr 60

Docosahexaenoic acid (DHA, 22:6 n-3), a polyunsaturated fatty acid found in fish oil, exerts cytotoxic effects on cancer cells. Although DHA was toxic toward five human cancer cell lines (MCF-7, MDA-MB-231, SiHa, Raji, and DHL-4), the lines were not uniformly sensitive. DHL-4, a bcl-2 overexpressing lymphoid line, was the most sensitive (IC50, 5.2 micromol/L) and the cervical cancer cell line, SiHa, was the most resistant (IC50, >300 micromol/L). Lipid peroxidation has been cited by others as an important component of DHA toxicity, and we confirmed that vitamin E prevents the cytotoxic effects of DHA. Lipid peroxidation was greater following DHA treatment of the sensitive DHL-4 cells than in the resistant SiHa cells, as assessed by thiobarbituric acid reactive substance generation. DHL-4 cells treated with DHA for 20 hours showed a 3.5-fold increase in thiobarbituric acid reactive substances, whereas SiHa cells showed no increase. Reverse transcription-PCR analysis detected a down-regulation of the expression of the major antioxidant enzyme, superoxide dismutase (SOD) 1, in DHL-4 cells but not in SiHa cells after DHA treatment. Knockdown of SOD1 expression in SiHa cells with small interfering RNA significantly enhanced lipid peroxidation and cytotoxicity on exposure to DHA. These results show that DHL-4 cells are highly sensitive to the cytotoxic effect of DHA and that regulation of SOD1 expression may play an important role in determining the sensitivity of different tumor cells to the cytotoxic effects of DHA.
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PMID:Differential sensitivity of cancer cells to docosahexaenoic acid-induced cytotoxicity: the potential importance of down-regulation of superoxide dismutase 1 expression. 1536 5

The homeostasis of intracellular cholesterol in animal cells is highly regulated by a complex system in which the microsomal rate-limiting enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase plays a key role in cholesterol synthesis. Substantial evidence has demonstrated that the cytosolic antioxidant enzyme CuZn superoxide dismutase (SOD1) inhibits the HMG-CoA reductase activity in rat hepatocytes and in human fibroblasts by decreasing cholesterol synthesis. Although these data suggest that SOD1 exerts a physiological role in cholesterol metabolism, it is still unclear whether the decrease of HMG-CoA reductase activity is mediated by transcriptional or by posttranscriptional events. The results of the present study, obtained by one-step RT-PCR assay, demonstrated that both SOD1 and the metal-free form of enzyme (Apo SOD1) inhibit HMG-CoA reductase gene expression in hepatocarcinoma HepG2 cells, in normal human fibroblasts, and in fibroblasts of subjects affected by familiar hypercholesterolemia. Accordingly, SOD1 could be used as a potential agent in the treatment of hypercholesterolemia, even in subjects lacking a functional LDL receptor pathway.
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PMID:Modulation of 3-hydroxy-3-methylglutaryl-CoA reductase gene expression by CuZn superoxide dismutase in human fibroblasts and HepG2 cells. 1547 58

In forensic medicine practice poisonings are rather frequent, and among them, those caused by fatal "substitution" of ethyl alcohol. One of the most frequently encountered "substitutes" for ethyl alcohol is methanol. The purpose of our research was to determine the concentration of malonic dialdehyde as the expression of lipid peroxidation and antioxidant enzyme activity after dosed chronic ethyl and methyl alcohol intoxication. The experiment was conducted on approx. 6 month-old male inbred Lewis rats each weighing approx. 250 g. Ethanol and methanol solution was given in the concentration 1.0 M. The control group of rats received water. Each experimental group numbered 30 rats, this number was divided into three sub-groups, which were put-down at 4, 8 and 12 weeks. The activity of superoxide dismutase (CuZu-SOD) was determined by the Misra-Fridovich method, catalase (CAT) by the Beers-Sizer method. The concentration of malonic dialdehyde (MDA) was determined using the method of Placer et al. by assessing the concentration of TBARS compounds. Results are expressed as a mean +/- SD. The paired Student's test for small groups were used. Superoxide dismutase SOD1 activity decreased compared with the control group throughout the duration of the experiment from 2212 U/gHb to 1676 U/gHb for ethanol and from 2212 U/gHb to 945 U/gHb for methanol. Catalase activity for methanol decreased from 9.1 U/gHb to 5.1 U/gHb, for ethanol to 7.4 U/gHb. In the 4th week of the experiment increase of malonyl dialdehyde concentration for methanol group was observed--from 0.14 umol/gHb to 0.34 umol/Hb; after 8th weeks it decreased to 0.2 umol/gHb and in the 12th week increased to 0.23 umol/gHb. For ethanol these changes was less visible and reached the level of 0.24 umol/l. The statistical processing of the results was performed on the basis of parametric tests (the t-Student test for small experiments) and computer software Statistica. The statistical significance was set for p<0.05.
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PMID:[Selected alcohols on the pro- and anti-oxidative processes in rat erythrocytes]. 1549 56

The aim of this study was to investigate the role of nitric oxide (NO) in hepatic ischemia-reperfusion (I/R) injury in rats. Immunohistochemistry was used to examine the protein expression of endothelial and inducible nitric oxide synthases (eNOS, iNOS) and nitrotyrosine after I/R challenges to the liver, and blood levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactic dehydrogenase (LDH), hydroxyl radical and NO were measured before ischemia and after reperfusion. Ischemia was induced by occlusion of the common hepatic artery and portal vein for 40 min, followed by reperfusion for 90 min. Reperfusion of the liver induced a significant increase in the blood concentrations of AST, ALT, LDH (n = 8; P < 0.001), hydroxyl radical (n = 8; P < 0.001) and NO (n = 8; P < 0.01). The eNOS, iNOS, nitrotyrosine, SOD1 and SOD2 protein expression was also found to increase significantly after reperfusion (n = 3). Administration of the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) (n = 8) had a protective effect on the I/R-related injury, but the NO donor L-arginine (L-Arg) (n = 8) potentiated the damage caused by I/R. These results suggest that reperfusion of the liver induces expression of NOS, which is related to the elevation of blood NO. The increase in hydroxyl radical concentration was accompanied by an increase in antioxidant enzyme expression (SOD1 and SOD2), and an increase in nitrotyrosine expression was also observed, reflecting the increased production of NO and oxygen radicals. We concluded from the protective effect of L-NAME and the potentiation by L-Arg that NOS expression and increases in NO and hydroxyl radical production have deleterious effects on the response to I/R in the liver.
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PMID:Ischemia and reperfusion of liver induces eNOS and iNOS expression: effects of a NO donor and NOS inhibitor. 1561 29

Although oxidative stress has been strongly implicated in the pathogenesis of Alzheimer disease (AD) and Parkinson disease (PD), the identities of specific protein targets of oxidative damage remain largely unknown. Here, we report that Cu,Zn-superoxide dismutase (SOD1), a key antioxidant enzyme whose mutations have been linked to autosomal dominant neurodegenerative disorder familial amyotrophic lateral sclerosis (ALS), is a major target of oxidative damage in AD and PD brains. By using a combination of two-dimensional gel electrophoresis, immunoblot analysis, and mass spectrometry, we have identified four human brain SOD1 isoforms with pI values of 6.3, 6.0, 5.7, and 5.0, respectively. Of these, the SOD1 pI 6.0 isoform is oxidatively modified by carbonylation, and the pI 5.0 isoform is selectively accumulated in AD and PD. Moreover, Cys-146, a cysteine residue of SOD1 that is mutated in familial ALS, is oxidized to cysteic acid in AD and PD brains. Quantitative Western blot analyses demonstrate that the total level of SOD1 isoforms is significantly increased in both AD and PD. Furthermore, immunohistochemical and double fluorescence labeling studies reveal that SOD1 forms proteinaceous aggregates that are associated with amyloid senile plaques and neurofibrillary tangles in AD brains. These findings implicate, for the first time, the involvement of oxidative damage to SOD1 in the pathogenesis of sporadic AD and PD. This work suggests that AD, PD, and ALS may share a common or overlapping pathogenic mechanism(s) that could potentially be targeted by similar therapeutic strategies.
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PMID:Oxidative modifications and aggregation of Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases. 1565 87

Copper-zinc superoxide dismutase (CuZnSOD, SOD1 protein) is an abundant copper- and zinc-containing protein that is present in the cytosol, nucleus, peroxisomes, and mitochondrial intermembrane space of human cells. Its primary function is to act as an antioxidant enzyme, lowering the steady-state concentration of superoxide, but when mutated, it can also cause disease. Over 100 different mutations have been identified in the sod1 genes of patients diagnosed with the familial form of amyotrophic lateral sclerosis (fALS). These mutations result in a highly diverse group of mutant proteins, some of them very similar to and others enormously different from wild-type SOD1. Despite their differences in properties, each member of this diverse set of mutant proteins causes the same clinical disease, presenting a challenge in formulating hypotheses as to what causes SOD1-associated fALS. In this review, we draw together and summarize information from many laboratories about the characteristics of the individual mutant SOD1 proteins in vivo and in vitro in the hope that it will aid investigators in their search for the cause(s) of SOD1-associated fALS.
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PMID:Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis. 1595 98


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