Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P04179 (MnSOD)
2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 2.9 A resolution structure of iron superoxide dismutase (FeSOD) (EC 1.15.1.1) from Pseudomonas ovalis complexed with the inhibitor azide was solved. Comparison of this structure with free enzyme shows that the inhibitor is bound at the open coordination position of the iron, with a bond length of 2.0 A. The metal moves by 0.4 A into the trigonal plane to produce an orthogonal geometry at the iron. Binding of the inhibitor also causes a movement of the axial ligand (histidine 26) away from the metal, a lengthening of the iron-histidine bond, and a rotation of the histidine 74 ring. The inhibitor possesses contacts in the binding pocket with a pair of conserved tryptophan residues and with the side chains of tyrosine 34 and glutamine 70. This glutamine is conserved between all FeSODs, but is absent in MnSOD. Comparisons with MnSOD show that a different glutamine which possesses the same interactions in the active site as Gln70 in FeSOD is conserved at position 154 in the overall SOD sequence, implying that while manganese and FeSODs are structural homologues in a global sense, their functional and evolutionary relationship is that of second-site mutation revertants.
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PMID:The structure of iron superoxide dismutase from Pseudomonas ovalis complexed with the inhibitor azide. 207 85

The X-ray structure of the tetrameric iron-dependent superoxide dismutase from Mycobacterium tuberculosis has been refined to an R-factor of 0.167 and a correlation coefficient of 0.954 at 2.0 A resolution. The crystals are monoclinic P2(1) and have four subunits related by strong non-crystallographic 222 (or D2) symmetry in the asymmetric unit. 198 of the 207 amino acids of each subunit are defined by the electron density which shows that they adopt the conserved fold of other iron- or manganese-dependent SODs. The structure can be divided into two domains, the N-terminal domain involving an extended region followed by two projecting antiparallel alpha-helices, and the C-terminal domain containing four more helical segments with a three-stranded antiparallel beta-sheet inserted sequentially between the fourth and fifth helices. The catalytic iron is co-ordinated by five ligands: three histidines (residues 28, 76 and 164), one aspartate (160) and a solvent molecule. The inferred positions of protons at the active site are consistent with the solvent ligand being a hydroxide ion. This ligand interacts with His145 in the Mycobacterium tuberculosis SOD. In the highly homologous Mycobacterium leprae Mn-SOD, the histidine is replaced by glutamine, this being the only significant residue difference within 10 A of the Fe3+. The nature of the amino acid at this position may influence the metal ion specificity of these enzymes. The subunits of the Mycobacterium tuberculosis SOD associate by polar contacts to form dimers, which closely resemble those of other dimeric or tetrameric Fe- or Mn-SODs. However, the dimer-dimer interactions within the tetramer are novel, being dominated by dimerisation of the 144 to 152 loop regions which connect the outer two beta-strands of the three-membered beta-sheet. This contrasts strongly with the other tetrameric Fe- or Mn-SODs where the dimer-dimer association is dominated by the projecting alpha alpha-turn in the N-terminal domain.
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PMID:X-ray structure analysis of the iron-dependent superoxide dismutase from Mycobacterium tuberculosis at 2.0 Angstroms resolution reveals novel dimer-dimer interactions. 787 74

Structural and biochemical characterization of the nonliganding residue glutamine 143 near the manganese of human Mn superoxide dismutase (hMnSOD), a homotetramer of 22 kDa, reveals a functional role for this residue. In the wild-type protein, the side-chain amide group of Gln 143 is about 5 A from the metal and is hydrogen-bonded to Tyr 34, which is a second prominent side chain adjacent to the metal. We have prepared the site-specific mutant of hMnSOD with the conservative replacement of Gln 143 --> Asn (Q143N). The crystal structure of Q143N shows that the side-chain amide nitrogen of residue 143 is 1.7 A more distant from the manganese than in the wild-type enzyme. The Tyr 34 side-chain hydroxyl in Q143N is also moved to become 0.6 A more distant from the metal due to an additional water molecule. Differential scanning calorimetry showed that Q143N is slightly more stable than the wild-type enzyme with Tm for the main unfolding transition increased by 2 degrees C to 90.7 degrees C. Pulse radiolysis and stopped-flow spectrophotometry reveal that unlike wild-type hMnSOD, which is strongly inhibited by peroxide, Q143N MnSOD exhibits no product inhibition even at concentrations of O2. - in the millimolar range, and its catalysis follows Michaelis kinetics with no evidence of cooperativity. However, the overall catalytic activity of this mutant was decreased 2-3 orders of magnitude compared with the wild-type MnSOD, which can account for its lack of product inhibition. Q143N MnSOD lacked the visible absorption spectrum typical of wild-type Mn(III)SOD. Also, unlike the wild-type Mn(III)SOD, which is electron paramagnetic resonance (EPR) silent, Q143N MnSOD has a complex EPR spectrum with many resonances in the region below 2250 G. We conclude that the Gln 143 --> Asn mutation has increased the reduction potential of manganese to stabilize Mn(II), indicating that Gln 143 has a substantial role in maintaining a reduction potential favorable for the oxidation and reduction cycles in the catalytic disproportionation of superoxide. A solvent hydrogen isotope effect near 2 for kcat in catalysis by Q143N hMnSOD indicates rate-contributing proton transfers to form product hydroperoxide anion or hydrogen peroxide. The data demonstrate a prominent role for Gln 143 in maintaining the microenvironment of the manganese and in efficient catalysis of superoxide dismutation to oxygen and hydrogen peroxide.
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PMID:Probing the active site of human manganese superoxide dismutase: the role of glutamine 143. 953 88

This review concerns various minerals (sodium, potassium, calcium, magnesium, phosphorus), trace elements (zinc, manganese, selenium, copper, iron, cobalt, iodine, chromium, fluorine, lead, cadmium) and other biological variables (nitric oxide, L-carnitine, glutamine, serum transferrin receptor, biopyrrins) in relation to hemorheologic effects, stress, immune response and infections during physical and sports activities. In athletes, macroelements in the ionized form contribute to heart and muscle contractions, oxidative phosphorylation and the synthesis and activation of enzymatic systems. Zinc (Zn) protects against the effects of increased free reactive oxygen species such as copper (Cu) and manganese (Mn) (Cu-Zn superoxide dismutases; Mn superoxide dismutase). Selenium in glutathione peroxidase protects the cardiovascular system and the muscles, and helps combat allergic and inflammatory diseases. Copper and iron are involved in many aspects of energy metabolism and are important components in the synthesis of hemoglobin, myoglobin and cytochromes. Fluorine and Cu protect the ligaments and tendons. Physical activity appears to be beneficial to urban residents who are exposed to metal pollution (lead, cadmium). The data cited in this review are often contradictory and incomplete. It is still unclear in many cases how minerals are involved in physiological changes, and much work remains.
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PMID:Minerals, trace elements and related biological variables in athletes and during physical activity. 1158 Sep 4

Kunming mice inoculated with hepatoma cell (H22) suspension subcutaneously at their right axilla were administered orally with antioxidants such as vitamine E, beta-carotene, glutamine, kappa-selenocarrageenan and polysaccharide-peptide of coriolus (PSP) solution. It was found that the inoculated hepatoma growth was suppressed to various extents. The two kinds of polysaccharide antioxidants improved non-specific immunity, enhanced the nitrogen monoxide (NO) content in plasma and strengthened the inhibition of hepatoma. Above antioxidants added in the culture of 7721 human hepatoma cells inhibited the cell proliferation and inducedits apoptosis. Meanwhile, the activity of glutathione peroxidase (GSH-Px) in the plasma of mice increased and the content of malondialdehyde (MDA) decreased. H(2)O(2) in low concentration improved the cancer cell proliferation and inhanced the expression of Mn-SOD c-fos and c-jun, but led to cells apoptosis or necrosis in high concentration. The mechanism of antioxidants inhibiting tumor growth and improving cancer cells apoptosis might be that, on the one hand, the antioxidants blocked the free radicals signal transduction on cancer cells proliferation, and on the other hand, they improved the release of NO through enhancing the non-specific immunity, so inhibiting the cancer cells proliferation directly.
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PMID:Inhibition of Proliferation and Expression of N-ras in Hepatoma Cells by Antioxidation Treatment. 1204 Apr 24

The structurally homologous mononuclear iron and manganese superoxide dismutases (FeSOD and MnSOD, respectively) contain a highly conserved glutamine residue in the active site which projects toward the active-site metal centre and participates in an extensive hydrogen bonding network. The position of this residue is different for each SOD isoenzyme (Q69 in FeSOD and Q146 in MnSOD of Escherichia coli). Although site-directed mutant enzymes lacking this glutamine residue (FeSOD[Q69G] and MnSOD[Q146A]) demonstrated a higher degree of selectivity for their respective metal, they showed little or no activity compared with wild types. FeSOD double mutants (FeSOD[Q69G/A141Q]), which mimic the glutamine position in MnSOD, elicited 25% the activity of wild-type FeSOD while the activity of the corresponding MnSOD double mutant (MnSOD[G77Q/Q146A]) increased to 150% (relative to wild-type MnSOD). Both double mutants showed reduced selectivity toward their metal. Differences exhibited in the thermostability of SOD activity was most obvious in the mutants that contained two glutamine residues (FeSOD[A141Q] and MnSOD[G77Q]), where the MnSOD mutant was thermostable and the FeSOD mutant was thermolabile. Significantly, the MnSOD double mutant exhibited a thermal-inactivation profile similar to that of wild-type FeSOD while that of the FeSOD double mutant was similar to wild-type MnSOD. We conclude therefore that the position of this glutamine residue contributes to metal selectivity and is responsible for some of the different physicochemical properties of these SODs, and in particular their characteristic thermostability.
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PMID:Thermostability of manganese- and iron-superoxide dismutases from Escherichia coli is determined by the characteristic position of a glutamine residue. 1239 45

Spinocerebellar ataxia 1 (SCA1) is an inherited neurodegenerative disorder caused by expansion of the polyglutamine stretch in ataxin-1, the SCA1 gene product. Polyglutamine expansion leads to the aggregation of ataxin-1 proteins. Superoxide dismutases (SODs) are involved in the pathogenesis of other aggregate-forming neurodegenerative diseases and are known to localize in the cytoplasm. Here, we show that Cu/Zn-SOD is translocated into the nucleus of HeLa cells in the presence of expanded ataxin-1, whereas Mn-SOD is localized in the cytoplasm: the longer the expansion of polyglutamine, the higher the level of translocation of Cu/Zn-SOD. In addition, the oxidation of intracellular proteins occurs with higher frequency in the presence of mutant ataxin-1 (82Q), suggesting that the functional activity of Cu/Zn-SOD might be decreased by mutant ataxin-1. We demonstrate that mutant ataxin-1-expressing cells encounter mitochondrial dysfunction in the conditions of oxidative stress. Our results suggest that polyglutamine-expanded ataxin-1 increases the levels of reactive oxygen species in HeLa cells.
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PMID:Polyglutamine-expanded ataxin-1 recruits Cu/Zn-superoxide dismutase into the nucleus of HeLa cells. 1289 74

Autophagy is involved in human diseases and is regulated by reactive oxygen species (ROS) including superoxide (O(2)(*-)) and hydrogen peroxide (H(2)O(2)). However, the relative functions of O(2)(*-) and H(2)O(2) in regulating autophagy are unknown. In this study, autophagy was induced by starvation, mitochondrial electron transport inhibitors, and exogenous H(2)O(2). We found that O(2)(*-) was selectively induced by starvation of glucose, L-glutamine, pyruvate, and serum (GP) whereas starvation of amino acids and serum (AA) induced O(2)(*-) and H(2)O(2). Both types of starvation induced autophagy and autophagy was inhibited by overexpression of SOD2 (manganese superoxide dismutase, Mn-SOD), which reduced O(2)(*-) levels but increased H(2)O(2) levels. Starvation-induced autophagy was also inhibited by the addition of catalase, which reduced both O(2)(*-) and H(2)O(2) levels. Starvation of GP or AA also induced cell death that was increased following treatment with autophagy inhibitors 3-methyladenine, and wortamannin. Mitochondrial electron transport chain (mETC) inhibitors in combination with the SOD inhibitor 2-methoxyestradiol (2-ME) increased O(2)(*-) levels, lowered H(2)O(2) levels, and increased autophagy. In contrast to starvation, cell death induced by mETC inhibitors was increased by 2-ME. Finally, adding exogenous H(2)O(2) induced autophagy and increased intracellular O(2)(*-) but failed to increase intracellular H(2)O(2). Taken together, these findings indicate that O(2)(*-) is the major ROS-regulating autophagy.
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PMID:Superoxide is the major reactive oxygen species regulating autophagy. 1940 26

Caloric restriction (CR) is the most robust and reproducible intervention that can extend lifespan in rodents. Studies in invertebrates have led to the identification of genes that regulate lifespan, some of which encode components of the insulin or insulin-like signaling pathway, including DAF-16 (C. elegans) and dFOXO (Drosophila). Mice subjected to CR for 8 weeks showed an increase in FOXO1 mRNA and other longevity-related genes: Gadd 45alpha, glutamine synthase, and catalase in skeletal muscle. To investigate whether FOXO1 expression affects longevity in mammals, transgenic mice were studied that over-express FOXO1 in their skeletal muscle (FOXO1 mice), and in which muscle atrophy occurs. FOXO1 mice showed increases in Gadd 45alpha, and glutamine synthase proteins in skeletal muscle. In FOXO1 mice, the phosphorylation/dephosphorylation state of the p70 S6K and 4E-BP1 proteins were not altered, suggesting that translation initiation of protein synthesis might not be suppressed. The lifespan of FOXO1 mice was similar to their wild-type littermates. FOXO1 overexpression could not prevent aging-induced reduction in catalase, CuZu-SOD, and Mn-SOD mRNA in skeletal muscle. These data suggest that an increase in FOXO1 protein and its activation in skeletal muscle does not extend lifespan in mice.
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PMID:Overexpression of FOXO1 in skeletal muscle does not alter longevity in mice. 1942 53

Radiotherapy exerts part of its antineoplastic effect by generating oxidative stress, therefore genetic variation in oxidative stress-related enzymes may influence survival of rectal cancer patients. We hypothesized that genetic polymorphisms associated with higher amounts of reactive oxygen species (ROS) that exaggerate cytotoxic activity could improve survival after radiotherapy. We followed 114 rectal cancer patients who received radiotherapy for an average of 42.5 months. Associations between genotypes (GSTP1, GSTM1, GSTT1, CAT, MnSOD, MPO and eNOS) and overall survival were assessed using Kaplan-Meier curves and Cox proportional hazards regression. As hypothesized, patients carrying low ROS producing eNOS Glu298Asp asparagine allele showed an increased hazard of death compared to homozygous carriers of the glutamine allele (hazard ratio (HR): 2.10, 95% confidence interval (CI): 1.01-4.38). However, carriers of low ROS producing MPO G463A A allele had a decreased hazard of death compared to patients homozygous for the G allele (HR: 0.44, 95% CI: 0.21-0.93) although patients homozygous for the A allele had a slightly increased hazard (HR: 1.12, 95% CI: 0.25-5.08). This explorative study provides first results and highlights the need for further, larger studies to investigate association between genetic variation in oxidative stress genes and survival of rectal cancer patients who received radiotherapy.
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PMID:Genetic Polymorphisms in Genes Related to Oxidative Stress (GSTP1, GSTM1, GSTT1, CAT, MnSOD, MPO, eNOS) and Survival of Rectal Cancer Patients after Radiotherapy. 2044


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