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Stefan L. Marklund - One of the best experts on this subject based on the ideXlab platform.
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high activities of erythrocyte glutathione peroxidase in patients with the lesch nyhan syndrome
Acta Medica Scandinavica, 2009Co-Authors: Ola Didrik Saugstad, Stefan L. MarklundAbstract:Antioxidant levels were determined in five patients with the Lesch-Nyhan syndrome. The erythrocyte glutathione peroxidase activity was in average 1.8 times higher in Lesch-Nyhan patients than in controls (1.68 +/- 0.36 versus 0.92 +/- 0.17 mu kat/g hemoglobin, p less than 0.001). Plasma CuZn-superoxide Dismutase activity was two times higher (p less than 0.001) and Mn-superoxide Dismutase activity was 1.5 times higher (p less than 0.05) than in controls, whilst erythrocyte CuZn-superoxide Dismutase, plasma extracellular-superoxide Dismutase and lymphocyte superoxide Dismutase did not differ between Lesch-Nyhan patients and healthy controls. These data might indicate that Lesch-Nyhan patients are exposed to a higher oxidative load than healthy control persons.
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phenotypes of mice lacking extracellular superoxide Dismutase and copper and zinc containing superoxide Dismutase
Journal of Biological Chemistry, 2006Co-Authors: Marielouise Sentman, Micael Granstrom, Hakan Jakobson, Andrew Reaume, Samar Basu, Stefan L. MarklundAbstract:Mice lacking the secreted extracellular superoxide Dismutase (EC-SOD) or the cytosolic copper- and zinc-containing SOD (CuZn-SOD) show relatively mild phenotypes. To explore the possibility that the isoenzymes have partly overlapping functions, single and double knockout mice were examined. The absence of EC-SOD was found to be without effect on the lifespan of mice, and the reduced lifespan of CuZn-SOD knockouts was not further shortened by EC-SOD deficiency. The urinary excretion of isoprostanes was increased in CuZn-SOD knockout mice, and plasma thiobarbituric acid-reactive substances levels were elevated in EC-SOD knockout mice. These oxidant stress markers showed potentiated increases in the absence of both isoenzymes. Other alterations were mainly found in CuZn-SOD knockout mice, such as halved glutathione peroxidase activity in the tissues examined and increased glutathione and iron in the liver. There were no changes in tissue content of the alternative superoxide scavenger ascorbate, but there was a 25% reduction in ascorbate in blood plasma in mice lacking CuZn-SOD. No increase was found in the urinary excretion of the terminal metabolites of NO, nitrite, and nitrate in any of the genotypes. In conclusion, apart from the increases in the global urinary and plasma oxidant stress markers, our phenotype studies revealed no other evidence that the copper- and zinc-containing SOD isoenzymes have overlapping roles.
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regulation by cytokines of extracellular superoxide Dismutase and other superoxide Dismutase isoenzymes in fibroblasts
Journal of Biological Chemistry, 1992Co-Authors: Stefan L. MarklundAbstract:The influence of cytokines on extracellular superoxide Dismutase (EC-SOD) expression by human dermal fibroblasts was investigated. The expression was markedly stimulated by interferon-gamma (IFN-gamma), was varying between fibroblast lines stimulated or depressed by interleukin-1 alpha (IL-1 alpha), was intermediately depressed by tumor necrosis factor-alpha (TNF-alpha), and markedly depressed by transforming growth factor-beta (TGF-beta). TNF-alpha, however, enhanced the stimulation by a high dose of IFN-gamma, whereas TGF-beta markedly depressed the stimulations given by IFN-gamma and IL-1 alpha. The ratio between the maximal stimulation and depression observed was around 30-fold. The responses were generally slow and developed over periods of several days. There were no effects of IFN-alpha, IL-2, IL-3, IL-4, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor, human growth hormone, Escherichia coli lipopolysaccharide, leukotriene B4, prostaglandin E2, formylmethionylleucylphenylalanine, platelet-activating factor, and indomethacin. The cytokines influencing the EC-SOD expression are also known to influence superoxide production by leukocytes and other cell types, and the EC-SOD response pattern is roughly compatible with the notion that its function is to protect cells against extracellular superoxide radicals. The results show that EC-SOD is a participant in the complex inflammatory response orchestrated by cytokines. The CuZn-SOD activity of the fibroblasts was not influenced by any of the cytokines, whereas the Mn-SOD activity was depressed by TGF-beta. TNF-alpha, IL-1 alpha, and IFN-gamma stimulated the Mn-SOD activity, as previously known, and these responses were reduced by TGF-beta. The different responses of the three SOD isoenzymes illustrate their different physiological roles.
Edith Butler Gralla - One of the best experts on this subject based on the ideXlab platform.
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sod2 functions downstream of sch9 to extend longevity in yeast
Genetics, 2003Co-Authors: Paola Fabrizio, Leeloung Liou, Vanessa N Moy, Alberto Diaspro, Joan Selverstone Valentine, Edith Butler Gralla, Valter D LongoAbstract:Signal transduction pathways inactivated during periods of starvation are implicated in the regulation of longevity in organisms ranging from yeast to mammals, but the mechanisms responsible for life-span extension are poorly understood. Chronological life-span extension in S. cerevisiae cyr1 and sch9 mutants is mediated by the stress-resistance proteins Msn2/Msn4 and Rim15. Here we show that mitochondrial superoxide Dismutase (Sod2) is required for survival extension in yeast. Deletion of SOD2 abolishes life-span extension in sch9Delta mutants and decreases survival in cyr1:mTn mutants. The overexpression of Sods--mitochondrial Sod2 and cytosolic CuZnSod (Sod1)--delays the age-dependent reversible inactivation of mitochondrial aconitase, a superoxide-sensitive enzyme, and extends survival by 30%. Deletion of the RAS2 gene, which functions upstream of CYR1, also doubles the mean life span by a mechanism that requires Msn2/4 and Sod2. These findings link mutations that extend chronological life span in S. cerevisiae to superoxide Dismutases and suggest that the induction of other stress-resistance genes regulated by Msn2/4 and Rim15 is required for maximum longevity extension.
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mutations in copper zinc superoxide Dismutase that cause amyotrophic lateral sclerosis alter the zinc binding site and the redox behavior of the protein
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Thomas J Lyons, H Liu, Joy J Goto, Aram M Nersissian, James A Roe, Janet A Graden, Carla Cafe, Lisa M Ellerby, Dale E Bredesen, Edith Butler GrallaAbstract:Abstract A series of mutant human and yeast copper-zinc superoxide Dismutases has been prepared, with mutations corresponding to those found in familial amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease). These proteins have been characterized with respect to their metal-binding characteristics and their redox reactivities. Replacement of Zn2+ ion in the zinc sites of several of these proteins with either Cu2+ or Co2+ gave metal-substituted derivatives with spectroscopic properties different from those of the analogous derivative of the wild-type proteins, indicating that the geometries of binding of these metal ions to the zinc site were affected by the mutations. Several of the ALS-associated mutant copper-zinc superoxide Dismutases were also found to be reduced by ascorbate at significantly greater rate than the wild-type proteins. We conclude that similar alterations in the properties of the zinc binding site can be caused by mutations scattered throughout the protein structure. This finding may help to explain what is perhaps the most perplexing question in copper-zinc superoxide Dismutase-associated familial ALS-i.e., how such a diverse set of mutations can result in the same gain of function that causes the disease.
Giuseppe Rotilio - One of the best experts on this subject based on the ideXlab platform.
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a novel heme protein the cu zn superoxide Dismutase from haemophilus ducreyi
Journal of Biological Chemistry, 2001Co-Authors: Francesca Pacello, Paul R Langford, Simon J Kroll, Giulietta Smulevich, Alessandro Desideri, Giuseppe Rotilio, Andrea BattistoniAbstract:Abstract Haemophilus ducreyi, the causative agent of the genital ulcerative disease known as chancroid, is unable to synthesize heme, which it acquires from humans, its only known host. Here we provide evidence that the periplasmic Cu,Zn-superoxide Dismutase from this organism is a heme-binding protein, unlike all the other known Cu,Zn-superoxide Dismutases from bacterial and eukaryotic species. When the H. ducreyi enzyme was expressed inEscherichia coli cells grown in standard LB medium, it contained only limited amounts of heme covalently bound to the polypeptide but was able efficiently to bind exogenously added hemin. Resonance Raman and electronic spectra at neutral pH indicate thatH. ducreyi Cu,Zn-superoxide Dismutase contains a 6-coordinated low spin heme, with two histidines as the most likely axial ligands. By site-directed mutagenesis and analysis of a structural model of the enzyme, we identified as a putative axial ligand a histidine residue (His-64) that is present only in theH. ducreyi enzyme and that was located at the bottom of the dimer interface. The introduction of a histidine residue in the corresponding position of the Cu,Zn-superoxide Dismutase fromHaemophilus parainfluenzae was not sufficient to confer the ability to bind heme, indicating that other residues neighboring His-64 are involved in the formation of the heme-binding pocket. Our results suggest that periplasmic Cu,Zn-superoxide Dismutase plays a role in heme metabolism of H. ducreyi and provide further evidence for the structural flexibility of bacterial enzymes of this class.
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evolutionary conservativeness of electric field in the cu zn superoxide Dismutase active site evidence for co ordinated mutation of charged amino acid residues
Journal of Molecular Biology, 1992Co-Authors: Alessandro Desideri, Mattia Falconi, Fabio Polticelli, Martino Bolognesi, K Djinovic, Giuseppe RotilioAbstract:Abstract Equipotential lines were calculated, using the Poisson-Boltzmann equation, for six Cu,Zn superoxide Dismutases with different protein electric charge and various degrees of sequence homology, namely those from ox, pig, sheep, yeast and the isoenzymes A and B from the amphibian Xenopus laevis. The three-dimensional structures of the porcine and ovine superoxide Dismutases were obtained by molecular modelling reconstruction using the structure of the highly homologous bovine enzyme as a template. The three-dimensional structure of the evolutionary distant yeast Cu,Zn superoxide Dismutase was recently resolved by us, while computer-modelled structures are available for X. laevis isoenzymes. The six proteins display large differences in the net protein charge and distribution of electrically charged surface residues but the trend of the equipotential lines in the proximity of the active sites was found to be constant in all cases. These results are in line with the very similar catlytic rate constants experimentally measured for the corresponding enzyme activities. This analysis shows that electrostatic guidance for the enzyme-substrate interaction in Cu,Zn superoxide Dismutases is related to a spatial distribution of charges, arranged so as to maintain, in the area surrounding the active sites, an identical electrostatic potential distribution, which is conserved in the evolution of this protein family.
Alessandro Desideri - One of the best experts on this subject based on the ideXlab platform.
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a novel heme protein the cu zn superoxide Dismutase from haemophilus ducreyi
Journal of Biological Chemistry, 2001Co-Authors: Francesca Pacello, Paul R Langford, Simon J Kroll, Giulietta Smulevich, Alessandro Desideri, Giuseppe Rotilio, Andrea BattistoniAbstract:Abstract Haemophilus ducreyi, the causative agent of the genital ulcerative disease known as chancroid, is unable to synthesize heme, which it acquires from humans, its only known host. Here we provide evidence that the periplasmic Cu,Zn-superoxide Dismutase from this organism is a heme-binding protein, unlike all the other known Cu,Zn-superoxide Dismutases from bacterial and eukaryotic species. When the H. ducreyi enzyme was expressed inEscherichia coli cells grown in standard LB medium, it contained only limited amounts of heme covalently bound to the polypeptide but was able efficiently to bind exogenously added hemin. Resonance Raman and electronic spectra at neutral pH indicate thatH. ducreyi Cu,Zn-superoxide Dismutase contains a 6-coordinated low spin heme, with two histidines as the most likely axial ligands. By site-directed mutagenesis and analysis of a structural model of the enzyme, we identified as a putative axial ligand a histidine residue (His-64) that is present only in theH. ducreyi enzyme and that was located at the bottom of the dimer interface. The introduction of a histidine residue in the corresponding position of the Cu,Zn-superoxide Dismutase fromHaemophilus parainfluenzae was not sufficient to confer the ability to bind heme, indicating that other residues neighboring His-64 are involved in the formation of the heme-binding pocket. Our results suggest that periplasmic Cu,Zn-superoxide Dismutase plays a role in heme metabolism of H. ducreyi and provide further evidence for the structural flexibility of bacterial enzymes of this class.
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evolutionary conservativeness of electric field in the cu zn superoxide Dismutase active site evidence for co ordinated mutation of charged amino acid residues
Journal of Molecular Biology, 1992Co-Authors: Alessandro Desideri, Mattia Falconi, Fabio Polticelli, Martino Bolognesi, K Djinovic, Giuseppe RotilioAbstract:Abstract Equipotential lines were calculated, using the Poisson-Boltzmann equation, for six Cu,Zn superoxide Dismutases with different protein electric charge and various degrees of sequence homology, namely those from ox, pig, sheep, yeast and the isoenzymes A and B from the amphibian Xenopus laevis. The three-dimensional structures of the porcine and ovine superoxide Dismutases were obtained by molecular modelling reconstruction using the structure of the highly homologous bovine enzyme as a template. The three-dimensional structure of the evolutionary distant yeast Cu,Zn superoxide Dismutase was recently resolved by us, while computer-modelled structures are available for X. laevis isoenzymes. The six proteins display large differences in the net protein charge and distribution of electrically charged surface residues but the trend of the equipotential lines in the proximity of the active sites was found to be constant in all cases. These results are in line with the very similar catlytic rate constants experimentally measured for the corresponding enzyme activities. This analysis shows that electrostatic guidance for the enzyme-substrate interaction in Cu,Zn superoxide Dismutases is related to a spatial distribution of charges, arranged so as to maintain, in the area surrounding the active sites, an identical electrostatic potential distribution, which is conserved in the evolution of this protein family.
Daret K St Clair - One of the best experts on this subject based on the ideXlab platform.
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regulation of superoxide Dismutase genes implications in disease
Free Radical Biology and Medicine, 2009Co-Authors: Lu Miao, Daret K St ClairAbstract:Numerous short-lived and highly reactive oxygen species (ROS) such as superoxide (O2(.-)), hydroxyl radical, and hydrogen peroxide are continuously generated in vivo. Depending upon concentration, location, and intracellular conditions, ROS can cause toxicity or act as signaling molecules. The cellular levels of ROS are controlled by antioxidant enzymes and small-molecule antioxidants. As major antioxidant enzymes, superoxide Dismutases (SODs), including copper-zinc superoxide Dismutase (Cu/ZnSOD), manganese superoxide Dismutase, and extracellular superoxide Dismutase, play a crucial role in scavenging O2(.-). This review focuses on the regulation of the sod genes coding for these enzymes, with an emphasis on the human genes. Current knowledge about sod structure and regulation is summarized and depicted as diagrams. Studies to date on genes coding for Cu/ZnSOD (sod1) are mostly focused on alterations in the coding region and their associations with amyotrophic lateral sclerosis. Evaluation of nucleotide sequences reveals that regulatory elements of the sod2 gene reside in both the noncoding and the coding region. Changes associated with sod2 lead to alterations in expression levels as well as protein function. We also discuss the structural basis for the changes in SOD expression associated with pathological conditions and where more work is needed to establish the relationship between SODs and diseases.