Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Mutants of Saccharomyces cerevisiae lacking a functional SOD1 gene encoding Cu/Zn superoxide dismutase (SOD) are sensitive to atmospheric levels of oxygen and are auxotrophic for lysine and methionine when grown in air. We have previously shown that these defects of SOD-deficient yeast cells can be overcome through mutations in either the BSD1 or BSD2 (bypass SOD defects) gene. In this study, the wild-type allele of BSD1 was cloned by functional complementation and was physically mapped to the left arm of chromosome VII. BSD1 is identical to PMR1, encoding a member of the P-type ATPase family that localizes to the Golgi apparatus. PMR1 is thought to function in calcium metabolism, and we provide evidence that PMR1 also participates in the homeostasis of manganese ions. Cells lacking a functional PMR1 gene accumulate elevated levels of intracellular manganese and are also extremely sensitive to manganese ion toxicity. We demonstrate that mutations in PMR1 bypass SOD deficiency through a mechanism that depends on extracellular manganese. Collectively, these findings indicate that oxidative damage in a eukaryotic cell can be prevented through alterations in manganese homeostasis.
Mol Cell Biol 1995 Mar
PMID:Mutations in PMR1 suppress oxidative damage in yeast cells lacking superoxide dismutase. 786 31

We have been screening a cohort of 46 sporadic and 10 familial amyotrophic lateral sclerosis patients for mutations in the superoxide dismutase gene (SOD1) using a combination of SSCP and direct PCR sequencing. A novel missense mutation (Asp101Asn) has been detected in one sporadic patient and a previously reported mutation has been found in two familial cases.
Mol Cell Probes 1994 Aug
PMID:Identification of a novel exon 4 SOD1 mutation in a sporadic amyotrophic lateral sclerosis patient. 787 76

Familial amyotrophic lateral sclerosis (FALS), a degenerative disorder of motor neurons, is associated with mutations in the Cu/Zn superoxide dismutase gene SOD1 in some affected families. We confirm a recently reported ala4-->val mutation in exon 1 of the SOD1 gene and report that this mutation is both the most commonly detected of all SOD1 mutations and among the most clinically severe. By comparison with our other FALS families, the exon 1 mutation is associated with reduced survival time after onset: 1.2 years, as compared to 2.5 years for all other FALS patients. We also demonstrate that SOD1 is prominently expressed in normal motor neurons and that neural expression of SOD1 is not prevented by this exon 1 mutation. Assays of SOD1 enzymatic activity in extracts from red blood cells, lymphoblastoid cells, and brain tissues revealed an approximately 50% reduction in activity of cytosolic SOD1 in patients with this mutation compared to normal individuals. By contrast, patients with sporadic ALS had normal levels of SOD1 enzymatic activity. Why this SOD1 mutation causes motor neuron death in FALS remains to be established. While it may be that FALS is a consequence of loss of SOD1 function, it is also possible that motor neuron death in this dominantly inherited disease occurs because the mutations confer an additional, cytotoxic function on the SOD1 protein.
Hum Mol Genet 1994 Jun
PMID:A frequent ala 4 to val superoxide dismutase-1 mutation is associated with a rapidly progressive familial amyotrophic lateral sclerosis. 795 Dec 49

We previously reported that oxidative damage in yeast lacking copper/zinc superoxide dismutase (SOD1) can be alleviated through mutations in PMR1, encoding a calcium P-type ATPase homologue that also functions in manganese homeostasis. In an attempt to further understand the relationship between manganese ions, PMR1 and SOD1, we conducted a search for manganese homeostasis genes that interact with PMR1. A genomic library was screened for genes that, when overexpressed, suppress the manganese hypersensitivity associated with pmr1 mutations. A single clone was isolated that reduced manganese toxicity in both the pmr1 mutant and PMR1 wild-type yeast. This gene was identified as CCC1, previously shown to function in calcium metabolism. Our studies indicate that, like PMR1, CCC1 functions in the homeostasis of both calcium and manganese ions. The Ccc1p polypeptide was found to localize to a Golgi-like organelle in yeast cells. Ccc1p co-fractionated with a Golgi marker in subcellular fractionation studies and, with immunofluorescence microscopy, Ccc1p exhibited a punctate pattern of staining typical of yeast Golgi. Our studies suggest that Ccc1p may act to sequester manganese ions in this organelle and limit the intracellular availability of the metal. First, overexpression of CCC1 reduced manganese cytotoxicity without lowering total accumulation of the metal. Second, overexpression of CCC1 appeared to limit the intracellular availability of the manganese ions needed to support aerobic growth of SOD1 mutants. We provide a model in which Ccc1p and Pmr1p work together to control the intracellular partitioning of manganese ions.
Mol Microbiol 1996 Aug
PMID:The role of the Saccharomyces cerevisiae CCC1 gene in the homeostasis of manganese ions. 886 76

Amyotrophic lateral sclerosis (ALS) is a paralytic disorder caused by degeneration of motor neurons in the brain and spinal cord. Identification of mutations in the gene for Cu,Zn superoxide dismutase (SOD1) in a subset of ALS families made it possible to develop a transgenic mouse model of ALS and to investigate its pathogenesis. These investigations suggest that mutant SOD1 acts through a toxic gain of function which may involve generation of free radicals. Conformational change in the mutant SOD1 protein, especially the distortion of the 'rim' of the electrostatic guidance channel may be central to this toxic gain of function and to the pathogenesis of ALS.
Hum Mol Genet 1996
PMID:Genetics of amyotrophic lateral sclerosis. 887 53

Oxygen toxicity in Saccharomyces cerevisiae lacking the copper/zinc superoxide dismutase (SOD1) can be suppressed by overexpression of the S. cerevisiae ATX2 gene. Multiple copies of ATX2 were found to reverse the aerobic auxotrophies of sod1(delta) mutants for lysine and methionine and also to enhance the resistance of these yeast strains to paraquat and atmospheric levels of oxygen. ATX2 encodes a novel 34.4-kDa polypeptide with a number of potential membrane-spanning domains. Our studies indicate that Atx2p localizes to the membrane of a vesicular compartment in yeast cells reminiscent of the Golgi apparatus. With indirect immunofluorescence microscopy, Atx2p exhibited a punctate pattern of staining typical of the Golgi apparatus, and upon subcellular fractionation, Atx2p colocalized with a biochemical marker for the yeast Golgi apparatus. We demonstrate here that this vesicle protein normally functions in the homeostasis of manganese ions and that this role in metal metabolism is necessary for the ATX1 suppression of SOD1 deficiency. First, overexpression of ATX2 caused cells to accumulate increased levels of manganese. Second, a deletion in ATX2 caused a decrease in the apparent available level of intracellular manganese and caused sod1(delta) mutants to become dependent upon exogenous manganese for aerobic growth. Third, ATX2 was incapable of suppressing oxidative damage in cells depleted of manganese ions or lacking the plasma membrane transporter for manganese. The effect of ATX2 overexpression on manganese accumulation and oxygen resistance is similar to what we have previously reported for mutations in PMR1, which encodes a manganese-trafficking protein that also resides in a vesicular compartment. Our studies are consistent with a model in which Atx2p and Pmr1p work in opposite directions to control manganese homeostasis.
Mol Cell Biol 1996 Nov
PMID:Suppression of oxidative damage by Saccharomyces cerevisiae ATX2, which encodes a manganese-trafficking protein that localizes to Golgi-like vesicles. 888 60

All mutations in the human gene for CuZn superoxide dismutase (CuZnSOD) reported to date are associated with the disease amyotrophic lateral sclerosis (ALS). These mutations, mostly of a familial nature (ALS 1, MIM 105400), span all of the coding region of this enzyme except for a highly conserved centrally located domain that includes all of exon III. We describe the identification and characterization of two mutations in this region, both found in mice. One mutation, a glutamate to lysine amino acid substitution was found in position 77 (E77K) of the strain SOD1/Ei distributed by the Jackson Laboratory. The other mutation, a lysine to glutamate substitution at position 70 (K70E) of a human transgene, was discovered in mouse line TgHS/SF-155. Enzyme activity measurements and heterodimer analysis of the CuZn SOD variant in SOD1/Ei suggest a mild loss of activity, which differs from the enzyme activity losses detected in patients with autosomal dominant ALS 1. Similarly, the presence of the mutant transgene in TgHS/SF 155 does not produce any phenotypic manifestations.
Mol Cell Biochem 1997 Mar
PMID:Novel mutations in an otherwise strictly conserved domain of CuZn superoxide dismutase. 906 9

Point mutations of Cu,Zn-superoxide dismutase (Cu,Zn-SOD) have been linked to familial amyotrophic lateral sclerosis (FALS). We reported that Cu,Zn-SOD can catalyze free radical generation and a FALS mutant, G93A, exhibits an enhanced free radical-generating activity, while its dismutation activity is identical to that of the wild-type enzyme (Yim, M. B., Kang, J.-H., Yim, H.-S., Kwak, H.-S., Chock, P. B., and Stadtman, E. R. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 5709-5714). The A4V mutation is both the most commonly detected of FALS-associated SOD1 mutations and among the most clinically severe (Rosen, D. R., Bowling, A. C., Patterson, D., Usdin, T. B., Sapp, P., Mezey, E., McKenna-Yasek, D., O'Regan, J. P., Rahmani, Z., Ferrante, R. J., Brownstein, M. J., Kowall, N. W., Beal, M. F., Horvitz, H. R., and Brown, R. H., Jr. (1994) Hum. Mol. Genet. 3, 981-987). We cloned the cDNA for the FALS A4V mutant, overexpressed the protein in Sf9 insect cells, purified the protein, and studied its enzymic activities. Our results show that the mutant and wild-type enzymes contain one copper ion per subunit and have identical dismutation activities. However, the free radical-generating activity of the mutant, as measured by the spin trapping method at low H2O2 concentration, is enhanced relative to that of the wild-type and G93A enzyme (wild-type < G93A < A4V). This is due to the decrease in the Km value for H2O2, wild-type > G93A > A4V, while the kcat is identical for these enzymes. Thus, the FALS symptoms are not associated with the reduction in the dismutation activity of the mutant enzyme. The fact that the A4V mutant has the lowest Km for H2O2 is correlated to the clinical severity observed with the A4V patients, if FALS is associated with a differential gain of the free radical-generating function of the Cu,Zn-SOD mutant.
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PMID:A familial amyotrophic lateral sclerosis-associated A4V Cu, Zn-superoxide dismutase mutant has a lower Km for hydrogen peroxide. Correlation between clinical severity and the Km value. 908 2

This study describes the histological localization of two CuZn superoxide dismutases (SOD1 and SOD2) in the parasitic nematode Onchocerca volvulus, and a functional characterization of the 'extracellular' form of this enzyme (SOD2) which provides evidence that it is involved in the defense against environmental superoxide anion radicals. These essential enzymes are detected in larval and adult stages of the parasite, determined at the mRNA and protein levels by in situ hybridization and immunolocalization studies. These proteins are distributed throughout the worm, at various concentrations with particularly high levels produced in the hypodermis. In vitro maintenance of parasites indicated that SOD2 was secreted outside the parasite into the medium. Baculovirus constructs designed to test the ability of the SOD2 hydrophobic N-terminal region to function in processing and secretion confirmed the ability of this polypeptide sequence to direct the secretion of a marker protein, as well as of the mature SOD2 enzyme. Analyses of the native, mature SOD2 enzyme molecular mass, and the primary and quaternary structure, indicate that unlike other extracellular SODs, the SOD2 is active as a non-glycosylated dimer, rather than as a tetrameric glycoprotein. The detection of SOD2 outside of the parasite maintained in vitro, and the confirmation that the SOD2 is a secreted enzyme, indicate that this enzyme plays a role in the interactive biology of parasitic nematodes with their hosts.
Mol Biochem Parasitol 1997 Sep
PMID:Localization and functional analysis of the cytosolic and extracellular CuZn superoxide dismutases in the human parasitic nematode Onchocerca volvulus. 927 79

Overexpression of Alzheimer amyloid precursor protein (APP) produces dramatically different phenotypes in transgenic mice depending on the genetic background. For example, concentrations of APP that produce amyloid plaques in outbred transgenic lines are lethal for inbred FVB/N or C57BL/6J mice. Expression of SOD1 transgenes is protective, suggesting involvement of oxidative damage in premature death, but ablation of Apoe had no significant effect. In contrast, FGF2 transgene overexpression enhances the lethal effects of APP. Differential survival does not appear to reflect genetic differences in APP processing, but rather host responses to APP or its derivatives.
Hum Mol Genet 1997 Oct
PMID:Genetic modification of the phenotypes produced by amyloid precursor protein overexpression in transgenic mice. 930 76


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