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 familial form of amyotrophic lateral sclerosis is caused by mutations in the SOD1 gene encoding the cytosolic antioxidant enzyme Cu,Zn superoxide dismutase. Although there is no clear correlation between disease and dismutating catalytic activity among the various disease-associated SOD1 alleles, all of the known missense mutations significantly alter the half-life of the encoded polypeptides. Using transient transfection studies in mammalian cells, it was demonstrated that a frameshift mutation in SOD1 which results in a truncated polypeptide is similarly destabilized. Using an epitope-tagging strategy to discriminate between mutant and wild-type SOD1 polypeptides, no evidence for dominant effects on polypeptide stability was detected, including that of a positive effect of the wild-type on mutant SOD1 polypeptides or that of a negative effect of mutant on wild-type SOD1 polypeptides. These experiments thus favor a non-catalytic role of mutant forms of SOD1 in disease progression.
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PMID:Disease-associated mutations in SOD1 are impervious to dominant positive or negative effects. 1102 89

The copper chaperone for superoxide dismutase (CCS) activates the antioxidant enzyme Cu,Zn-SOD (SOD1) by directly inserting the copper cofactor into the apo form of SOD1. Neither the mechanism of protein-protein recognition nor of metal transfer is clear. The metal transfer step has been proposed to occur within a transient copper donor/acceptor complex that is either a heterodimer or heterotetramer (i.e. a dimer of dimers). To determine the nature of this intermediate, we generated a mutant form of SOD1 by replacing a copper binding residue His-48 with phenylalanine. This protein cannot accept copper from CCS but does form a stable complex with apo- and Cu-CCS, as observed by immunoprecipitation and native gel electrophoresis. Fluorescence anisotropy measurements corroborate the formation of this species and further indicate that copper enhances the stability of the dimer by an order of magnitude. The copper form of the heterodimer was isolated by gel filtration chromatography and contains one copper and one zinc atom per heterodimer. These results support a mechanism for copper transfer in which CCS and SOD1 dock via their highly conserved dimer interfaces in a manner that precisely orients the Cys-rich copper donor sites of CCS and the His-rich acceptor sites of SOD1 to form a copper-bridged intermediate.
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PMID:Copper stabilizes a heterodimer of the yCCS metallochaperone and its target superoxide dismutase. 1147 16

The copper chaperone for superoxide dismutase (CCS) activates the eukaryotic antioxidant enzyme copper, zinc superoxide dismutase (SOD1). The 2.9 A resolution structure of yeast SOD1 complexed with yeast CCS (yCCS) reveals that SOD1 interacts with its metallochaperone to form a complex comprising one monomer of each protein. The heterodimer interface is remarkably similar to the SOD1 and yCCS homodimer interfaces. Striking conformational rearrangements are observed in both the chaperone and target enzyme upon complex formation, and the functionally essential C-terminal domain of yCCS is well positioned to play a key role in the metal ion transfer mechanism. This domain is linked to SOD1 by an intermolecular disulfide bond that may facilitate or regulate copper delivery.
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PMID:Heterodimeric structure of superoxide dismutase in complex with its metallochaperone. 1152 66

Presbycusis is a complex of high frequency hearing loss and disproportionate loss of speech discrimination that is seen concomitantly with physical signs of aging. Among the most extensively characterized strains of mice that show an early hearing loss is the C57B16/J strain, a strain that shows early onset of high frequency hearing loss at age 6 months and complete hearing loss by 1 year of age. The histopathology of this strain consists of loss of hair cells and spiral ganglion neurons in the basal turn, with a progression of loss of hair cells and ganglion neurons towards the apical portion of the cochlea as the animal ages. The process of aging has been extensively studied and although details differ in various organisms the consensus today is that oxidative stress, i.e. free radical-mediated tissue damage, is one of the core mechanisms of aging. Aerobic metabolism results in the creation of hydrogen peroxide and reactive oxygen species. These are normally detoxified by a variety of enzymes and free radical scavengers, including superoxide dismutase (SOD), catalase and glutathione. To determine whether oxidative stress plays a role in the pathophysiology of hearing loss in this mouse model of presbycusis we determined the relative change in mRNA production for selected free radical detoxifying enzymes in the C57B16/J mouse cochlea. Using semi-quantitative RT-PCR with tubulin mRNA as a control, relative levels of antioxidant enzyme mRNAs were determined. There was an overall increase in SOD1 mRNA levels when comparing 1 and 9 month time points, and a transient increase in the expression level of catalase mRNA. B6.CAST+ Ahl mice, which carry the C57B16/J genome but receive their Ahl gene from CAST mice, do not show these alteractions in antioxidant enzyme production. Our results suggest that at an age of 9 months, at which point significant hearing loss has developed, the C57B16/J mouse cochlea is exposed to increased levels of free radicals and that the Ahl gene of the C57B16/J mouse mediates this decrease in protective enzymes and therefore increase in levels of oxidative stress.
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PMID:Oxidative stress in aging in the C57B16/J mouse cochlea. 1167 64

Calcineurin is a serine/threonine phosphatase involved in a wide range of cellular responses to calcium mobilizing signals. Previous evidence supports the notion of the existence of a redox regulation of this enzyme, which might be relevant for neurodegenerative processes, where an imbalance between generation and removal of reactive oxygen species could occur. In a recent work, we have observed that calcineurin activity is depressed in two models for familial amyotrophic lateral sclerosis (FALS) associated with mutations of the antioxidant enzyme Cu,Zn superoxide dismutase (SOD1), namely in neuroblastoma cells expressing either SOD1 mutant G93A or mutant H46R and in brain areas from G93A transgenic mice. In this work we report that while wild-type SOD1 has a protective effect, calcineurin is oxidatively inactivated by mutant SOD1s in vitro; this inactivation is mediated by reactive oxygen species and can be reverted by addition of reducing agents. Furthermore, we show that calcineurin is sensitive to oxidation only when it is in an 'open', calcium-activated conformation, and that G93A-SOD1 must have its redox-active copper site available to substrates in order to exert its pro-oxidant properties on calcineurin. These findings demonstrate that both wild-type and mutant SOD1s can interfere directly with calcineurin activity and further support the possibility of a relevant role for calcineurin-regulated biochemical pathways in the pathogenesis of FALS.
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PMID:Oxidative inactivation of calcineurin by Cu,Zn superoxide dismutase G93A, a mutant typical of familial amyotrophic lateral sclerosis. 1170 56

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor function and eventual death as a result of degeneration of motor neurons in the spinal cord and brain. The discovery of mutations in SOD1, the gene encoding the antioxidant enzyme Cu/Zn-superoxide dismutase (CuZnSOD), in a subset of ALS patients has led to new insight into the pathophysiology of ALS. Utilizing a novel adenovirus gene delivery system, our laboratory has developed a human cell culture model using chemically differentiated neuroblastoma cells to investigate how mutations in SOD1 lead to neuronal death. Expression of mutant SOD1 (G37R) resulted in a time and dose-related death of differentiated neuroblastoma cells. This cell death was inhibited by overexpression of the antioxidant enzyme manganese superoxide dismutase (MnSOD). These observations support the hypothesis that mutant SOD1-associated neuronal death is associated with alterations in oxidative stress, and since MnSOD is a mitochondrial enzyme, suggest that mitochondria play a key role in disease pathogenesis. Our findings in this model of inhibition of mutant SOD1-associated death by MnSOD represent an unique approach to explore the underlying mechanisms of mutant SOD1 cytotoxicity and can be used to identify potential therapeutic agents for further testing.
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PMID:Overexpression of manganese superoxide dismutase attenuates neuronal death in human cells expressing mutant (G37R) Cu/Zn-superoxide dismutase. 1206 30

Mutations in Cu/Zn superoxide dismutase (SOD1), a major cytosolic antioxidant enzyme in eukaryotic cells, have been reported in approximately 20% of familial amyotrophic lateral sclerosis (FALS) patients. Hereditary canine spinal muscular atrophy (HCSMA), a fatal inherited motor neuron disease in Brittany spaniels, shares many clinical and pathological features with human motor neuron disease, including FALS. The SOD1 coding region has been sequenced and cloned from several animal species, but not from the dog. We have mapped the chromosomal location, sequenced, and characterized the canine SOD1 gene. Extending this analysis, we have evaluated SOD1 as a candidate for HCSMA. The 462 bp SOD1 coding region in the dog encodes 153 amino acid residues and exhibits more than 83% and 79% sequence identity to other mammalian homologues at both the nucleotide and amino acid levels, respectively. The canine SOD1 gene maps to CFA31 close to syntenic group 13 on the radiation hybrid (RH) map in the vicinity of sodium myo/inositol transporter (SMIT) gene. The human orthologous SOD1 and SMIT genes have been localized on HSA 21q22.1 and HSA 21q21, respectively, confirming the conservation of synteny between dog syntenic group 13 and HSA 21. Direct sequencing of SOD1 cDNA from six dogs with HCSMA revealed no mutations. Northern analysis indicated no differences in steady-state levels of SOD1 mRNA.
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PMID:Structure, chromosomal location, and analysis of the canine Cu/Zn superoxide dismutase (SOD1) gene. 1214 Feb 71

A growing body of data suggests that free radicals are involved in the pathogenesis of Alzheimer's disease (AD). Increased expression of antioxidant enzymes, such as superoxide dismutase (SOD), and their co-localization to senile plaques and dystrophic neurites have established a firm association between free-radical mediated injury and the disease neuropathology. While several studies have confirmed these findings, there is conflicting information regarding the activity of some of the enzymes. In the current report, we assayed the activity of superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px) from the same areas of the tissue showing increased expression of SOD1 and SOD2 (parallel sequential slices). Nine brains with neuropathologically confirmed AD and six neuropathologically normal, age-matched, controls were examined. Despite marked increased expression of SOD1 and SOD2 within senile plaques in all the cases studied, the activities of SOD, GSH-Px and catalase were significantly lower in AD than in control brains. The difference was most profound in the case of catalase followed by GSH-Px and SOD. These data are in qualitative agreement with that of several laboratories, and support a decrease rather than an increase, in antioxidant enzyme activity. The findings suggest two main possibilities. On one hand, the observed reduced activity along with antigenically increased expression may be consistent with inactivation of excess protein that has been synthesized under conditions of high oxidative stress. Increased protein oxidation coupled with enzyme inactivation is a documented, aging-associated phenomenon. Alternatively, the increased immuno-reactivity may reflect a redistribution phenomenon as the enzymes become more concentrated at the sites of increased oxidative stress, despite an over all reduction in their activity.
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PMID:Increased Expression but Reduced Activity of Antioxidant Enzymes in Alzheimer's Disease. 1221 99

Oxidative stress has been widely implicated as an important factor in the aging process. Because mitochondrial respiration is the principal source of reactive oxygen within cells, the mitochondrially localized superoxide dismutase (SOD) 2 is thought to play an important front-line defensive role against aging-related oxidative stress. Although genetic studies with mutants deficient in SOD1, the predominantly cytosolic isoform of SOD, have been instrumental in elucidating the role of reactive oxygen metabolism in aging in Drosophila, the lack of available mutations in the Sod2 gene has hampered an equivalent analysis of the participation of this important antioxidant enzyme in the Drosophila aging model. Here we report that ablation of mitochondrial SOD2 through expression of a GAL4-regulated, inverted-repeat Sod2 RNA-interference transgene in an otherwise normal animal causes increased endogenous oxidative stress, resulting in loss of essential enzymatic components of the mitochondrial respiratory chain and the tricarboxylic acid cycle, enhances sensitivity to applied oxidative stress, and causes early-onset mortality in young adults. In sharp contrast, ablation of SOD2 has no overt effect on the development of larvae and pupae, which may reflect a fundamental transition in oxygen utilization andor reactive oxygen metabolism that occurs during metamorphosis from larval to adult life.
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PMID:RNA interference-mediated silencing of Sod2 in Drosophila leads to early adult-onset mortality and elevated endogenous oxidative stress. 1245 85

We investigated through a population-based case-control study the hypothesis that disturbances in the chemistry of copper and zinc and in activity of the antioxidant enzyme copper/zinc superoxide-dismutase (SOD1) are involved in the etiopathogenesis of sporadic amyotrophic lateral sclerosis (ALS). We recruited 20 patients with sporadic ALS and 22 population controls from three northern Italian provinces, and we analyzed zinc and copper content and SOD1 activity in erythrocytes. These variables were unrelated to disease progression as evaluated through a disability score; zinc concentrations inversely correlated with copper in referents but not in patients. SOD1 activity was lower and erythrocyte zinc and copper levels were slightly higher in patients than in referents. Comparing the second to the bottom tertile of erythrocyte SOD1 activity, relative risk of ALS was 0.4 (95% confidence interval 0.1-2.0); the risk further decreased to 0.1 (95% confidence interval 0-0.9) for comparison of highest to lowest tertile (P for trend 0.027). Copper and zinc levels were not associated with disease risk. Our findings indicate that a lower SOD1 activity is associated with ALS, but we cannot be sure whether this association is a marker of causal action or is secondary to a confounder, or to disease onset itself.
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PMID:Erythrocyte zinc, copper, and copper/zinc superoxide dismutase and risk of sporadic amyotrophic lateral sclerosis: a population-based case-control study. 1271 May 10


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