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Gene Review

SOD3  -  superoxide dismutase 3, extracellular

Homo sapiens

Synonyms: EC-SOD
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Disease relevance of SOD3


High impact information on SOD3

  • We conclude that oxidative and inflammatory processes in the extracellular lung compartment contribute to hyperoxic-induced lung damage and that overexpression of hEC-SOD mediates a protective response to hyperoxia, at least in part, by attenuating the neutrophil inflammatory response [5].
  • Mice heterozygous for the hEC-SOD transgene showed threefold higher EC-SOD levels in the lung compared with wild-type (Wt) littermate controls [5].
  • To study the biologic role of EC-SOD in hyperoxic-induced pulmonary disease, we created transgenic (Tg) mice that specifically target overexpression of human EC-SOD (hEC-SOD) to alveolar type II and nonciliated bronchial epithelial cells [5].
  • Cu/Zn-SOD is a homodimer containing four cysteine residues within each subunit, and EC-SOD is a tetramer composed of two disulfide-bonded dimers in which each subunit contains six cysteines [6].
  • The amino acid sequences of all EC-SOD subunits are identical [6].

Chemical compound and disease context of SOD3


Biological context of SOD3

  • Exercise-induced eNOS expression is transient and reversible and regulated by factors such as angiogenesis, arteriogenesis and antioxidative effects including upregulation of superoxide dismutases (SOD1, SOD3) and downregulation of NAD(P)H oxidase, which likely blunts the effects of oxidative stress [9].
  • RESULTS: Significantly higher frequencies of the G allele and CG/GG genotype of the 213 SOD3 polymorphism were found in resistant smokers (odds ratios (ORs) 4.3 (95% CI 1.5 to 13.3) and 4.2, 95% CI 1.4 to 13.3), Bonferroni corrected p = 0.02 and p = 0.02, respectively) than in those with COPD [10].
  • We constructed a fusion gene encoding a chimeric SOD consisting of the mature human mitochondrial SOD2 plus the COOH-terminal 26-amino acid heparin-binding "tail" from SOD3 [11].
  • No mutations were found in the 5 exons of SOD1, 5 exons of SOD2, and 3 exons of SOD3, except for 3 of 20 cases with polymorphisms for exon 3 of SOD1 [12].
  • In summary, Atox1 functions not only as a copper chaperone for SOD3 but also as a positive regulator for SOD3 transcription and may have an important role in modulating oxidative stress in the cardiovascular system [13].

Anatomical context of SOD3

  • Furthermore, Candida albicans naturally produces a cytosolic manganese SOD (Ca SOD3), yet when expressed in the cytosol of S. cerevisiae, a large fraction of Ca SOD3 also remained manganese-deficient [14].
  • The molecule binds to endothelial cells, but less tightly than SOD3, and circulates well enough to become widely attached to extracellular surfaces, presumably in many tissues [15].
  • Our data also suggest that the SODs might be important in the pathogenesis of NP; however, the roles these SOD isoforms, especially SOD3, play in both normal nasal mucosa and NP require further clarification [1].
  • SOD3, or EC-SOD (EC, is the most recently characterized SOD, exists as a copper and zinc-containing tetramer, and is synthesized containing a signal peptide that directs this enzyme exclusively to extracellular spaces [16].
  • Cell lines that were examined included the mouse epidermal cell line, JB6 clone 41, and JB6 cells transfected with the human Cu-Zn superoxide dismutase (SOD) genes (SOD3 and SOD15) and human catalase (CAT) genes (CAT13 and CAT10) [17].

Associations of SOD3 with chemical compounds

  • The ligands to Cu and Zn, the cysteines forming the intrasubunit disulfide bridge in the CuZn SODs, and the arginine found in all CuZn SODs in the entrance to the active site can all be identified in EC-SOD [18].
  • Identification of a homozygous missense mutation (Arg to Gly) in the critical binding region of the human EC-SOD gene (SOD3) and its association with dramatically increased serum enzyme levels [19].
  • Cerebral blood flow responses in these genetically altered mice to changes in PO2 demonstrate that SOD3 regulates equilibrium between superoxide (*O2-) and NO*, thereby controlling vascular tone and reactivity in the brain [20].
  • To account for the remaining five cysteine residues we purified human EC-SOD and determined the disulfide bridge pattern [6].
  • While the activities of glutathione peroxidase were comparable in all strains, the concentrations of reduced glutathione (GSH) were significantly lower in SOD 3 and SOD 15 [21].

Regulatory relationships of SOD3


Other interactions of SOD3

  • It has the sequence encoding the mature human SOD2 fused to the C-terminus of human SOD3 [15].
  • The results from RT-PCR, ELISA, and WB were paralleled and revealed that the expressions of SOD1 and, to a greater extent, SOD3 were higher in polyp tissues than in the control group [1].
  • Extracellular SOD (EC-SOD/SOD3) is a major superoxide scavenger and it is located on cell surfaces and primarily in extracellular matrix, and binds heparan sulfates by its carboxyterminal portion [24].
  • The polymerase chain reaction was used to amplify and screen tissue specimens for the genes of SOD1, SOD2, and extracellular SOD (SOD3) [12].
  • Manganese superoxide dismutase (MnSOD), copper zinc SOD (CuZnSOD), and extracellular SOD (ECSOD), the first-line antioxidant defenses, were studied in lung carcinomas by immunohistochemical analysis (n = 139, 56, and 37, respectively) and in 8 lung tumor specimens by Western blot analysis and SOD activity measurement [25].

Analytical, diagnostic and therapeutic context of SOD3


  1. Altered expression profile of superoxide dismutase isoforms in nasal polyps from nonallergic patients. Cheng, Y.K., Hwang, G.Y., Lin, C.D., Tsai, M.H., Tsai, S.W., Chang, W.C. Laryngoscope (2006) [Pubmed]
  2. Impaired extracellular secretion of mutant superoxide dismutase 1 associates with neurotoxicity in familial amyotrophic lateral sclerosis. Turner, B.J., Atkin, J.D., Farg, M.A., Zang, d.a. .W., Rembach, A., Lopes, E.C., Patch, J.D., Hill, A.F., Cheema, S.S. J. Neurosci. (2005) [Pubmed]
  3. Effects of recombinant human extracellular-superoxide dismutase type C on myocardial infarct size in pigs. Hatori, N., Sjöquist, P.O., Marklund, S.L., Rydén, L. Free Radic. Biol. Med. (1992) [Pubmed]
  4. Polymorphisms in the Mn-SOD and EC-SOD genes and their relationship to diabetic neuropathy in type 1 diabetes mellitus. Chistyakov, D.A., Savost'anov, K.V., Zotova, E.V., Nosikov, V.V. BMC Med. Genet. (2001) [Pubmed]
  5. Extracellular superoxide dismutase in the airways of transgenic mice reduces inflammation and attenuates lung toxicity following hyperoxia. Folz, R.J., Abushamaa, A.M., Suliman, H.B. J. Clin. Invest. (1999) [Pubmed]
  6. The dual nature of human extracellular superoxide dismutase: one sequence and two structures. Petersen, S.V., Oury, T.D., Valnickova, Z., Thøgersen, I.B., Højrup, P., Crapo, J.D., Enghild, J.J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  7. Extracellular superoxide dismutase, nitric oxide, and central nervous system O2 toxicity. Oury, T.D., Ho, Y.S., Piantadosi, C.A., Crapo, J.D. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  8. Heparin-induced release of extracellular-superoxide dismutase form (V) to plasma. Adachi, T., Yamada, H., Futenma, A., Kato, K., Hirano, K. J. Biochem. (1995) [Pubmed]
  9. Molecular mechanisms of vascular adaptations to exercise. Physical activity as an effective antioxidant therapy? Kojda, G., Hambrecht, R. Cardiovasc. Res. (2005) [Pubmed]
  10. Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function. Young, R.P., Hopkins, R., Black, P.N., Eddy, C., Wu, L., Gamble, G.D., Mills, G.D., Garrett, J.E., Eaton, T.E., Rees, M.I. Thorax (2006) [Pubmed]
  11. Synthesis and anti-inflammatory activity of a chimeric recombinant superoxide dismutase: SOD2/3. Gao, B., Flores, S.C., Leff, J.A., Bose, S.K., McCord, J.M. Am. J. Physiol. Lung Cell Mol. Physiol. (2003) [Pubmed]
  12. Antioxidant enzyme expression and reactive oxygen species damage in prostatic intraepithelial neoplasia and cancer. Bostwick, D.G., Alexander, E.E., Singh, R., Shan, A., Qian, J., Santella, R.M., Oberley, L.W., Yan, T., Zhong, W., Jiang, X., Oberley, T.D. Cancer (2000) [Pubmed]
  13. Role of antioxidant-1 in extracellular superoxide dismutase function and expression. Jeney, V., Itoh, S., Wendt, M., Gradek, Q., Ushio-Fukai, M., Harrison, D.G., Fukai, T. Circ. Res. (2005) [Pubmed]
  14. Manganese activation of superoxide dismutase 2 in the mitochondria of Saccharomyces cerevisiae. Luk, E., Yang, M., Jensen, L.T., Bourbonnais, Y., Culotta, V.C. J. Biol. Chem. (2005) [Pubmed]
  15. Anti-inflammatory properties of a chimeric recombinant superoxide dismutase: SOD2/3. Hernandez-Saavedra, D., Zhou, H., McCord, J.M. Biomed. Pharmacother. (2005) [Pubmed]
  16. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Zelko, I.N., Mariani, T.J., Folz, R.J. Free Radic. Biol. Med. (2002) [Pubmed]
  17. Hydroxyl radical production by mouse epidermal cell lines in the presence of quinone anti-cancer compounds. Li, B., Gutierrez, P.L., Amstad, P., Blough, N.V. Chem. Res. Toxicol. (1999) [Pubmed]
  18. Isolation and sequence of complementary DNA encoding human extracellular superoxide dismutase. Hjalmarsson, K., Marklund, S.L., Engström, A., Edlund, T. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  19. Identification of a homozygous missense mutation (Arg to Gly) in the critical binding region of the human EC-SOD gene (SOD3) and its association with dramatically increased serum enzyme levels. Folz, R.J., Peno-Green, L., Crapo, J.D. Hum. Mol. Genet. (1994) [Pubmed]
  20. Regulation of the brain's vascular responses to oxygen. Demchenko, I.T., Oury, T.D., Crapo, J.D., Piantadosi, C.A. Circ. Res. (2002) [Pubmed]
  21. The balance between Cu,Zn-superoxide dismutase and catalase affects the sensitivity of mouse epidermal cells to oxidative stress. Amstad, P., Peskin, A., Shah, G., Mirault, M.E., Moret, R., Zbinden, I., Cerutti, P. Biochemistry (1991) [Pubmed]
  22. Antioxidant enzymes in renal cell carcinoma. Soini, Y., Kallio, J.P., Hirvikoski, P., Helin, H., Kellokumpu-Lehtinen, P., Tammela, T.L., Peltoniemi, M., Martikainen, P.M., Kinnula, L.V. Histol. Histopathol. (2006) [Pubmed]
  23. Heparin-, dextran sulfate- and protamine-induced release of extracellular-superoxide dismutase to plasma in pigs. Karlsson, K., Marklund, S.L. Biochim. Biophys. Acta (1988) [Pubmed]
  24. Extracellular superoxide dismutase (EC-SOD) gene mutations screening in a sample of Mediterranean population. Campo, S., Sardo, A.M., Campo, G.M., D'Ascola, A., Avenoso, A., Castaldo, M., Saitta, C., Lania, A., Saitta, A., Calatroni, A. Mutat. Res. (2005) [Pubmed]
  25. Differential expression of superoxide dismutases in lung cancer. Svensk, A.M., Soini, Y., Pääkkö, P., Hiravikoski, P., Kinnula, V.L. Am. J. Clin. Pathol. (2004) [Pubmed]
  26. Assignment of SOD3 to human chromosome band 4p15.3-->p15.1 with somatic cell and radiation hybrid mapping, linkage mapping, and fluorescent in-situ hybridization. Stern, L.F., Chapman, N.H., Wijsman, E.M., Altherr, M.R., Rosen, D.R. Cytogenet. Genome Res. (2003) [Pubmed]
  27. Extracellular superoxide dismutase (SOD3): tissue-specific expression, genomic characterization, and computer-assisted sequence analysis of the human EC SOD gene. Folz, R.J., Crapo, J.D. Genomics (1994) [Pubmed]
  28. Heterogeneous basal expression of nitric oxide synthase and superoxide dismutase isoforms in mammalian heart : implications for mechanisms governing indirect and direct nitric oxide-related effects. Brahmajothi, M.V., Campbell, D.L. Circ. Res. (1999) [Pubmed]
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