Summary: Iron/manganese superoxide dismutases, alpha-hairpin domain
Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.
This is the Wikipedia entry entitled "Superoxide dismutase". More...
The Wikipedia text that you see displayed here is a download from Wikipedia. This means that the information we display is a copy of the information from the Wikipedia database. The button next to the article title ("Edit Wikipedia article") takes you to the edit page for the article directly within Wikipedia. You should be aware you are not editing our local copy of this information. Any changes that you make to the Wikipedia article will not be displayed here until we next download the article from Wikipedia. We currently download new content on a nightly basis.
Does Pfam agree with the content of the Wikipedia entry ?
Pfam has chosen to link families to Wikipedia articles. In some case we have created or edited these articles but in many other cases we have not made any direct contribution to the content of the article. The Wikipedia community does monitor edits to try to ensure that (a) the quality of article annotation increases, and (b) vandalism is very quickly dealt with. However, we would like to emphasise that Pfam does not curate the Wikipedia entries and we cannot guarantee the accuracy of the information on the Wikipedia page.
Editing Wikipedia articles
Before you edit for the first time
Wikipedia is a free, online encyclopedia. Although anyone can edit or contribute to an article, Wikipedia has some strong editing guidelines and policies, which promote the Wikipedia standard of style and etiquette. Your edits and contributions are more likely to be accepted (and remain) if they are in accordance with this policy.
You should take a few minutes to view the following pages:
How your contribution will be recorded
Anyone can edit a Wikipedia entry. You can do this either as a new user or you can register with Wikipedia and log on. When you click on the "Edit Wikipedia article" button, your browser will direct you to the edit page for this entry in Wikipedia. If you are a registered user and currently logged in, your changes will be recorded under your Wikipedia user name. However, if you are not a registered user or are not logged on, your changes will be logged under your computer's IP address. This has two main implications. Firstly, as a registered Wikipedia user your edits are more likely seen as valuable contribution (although all edits are open to community scrutiny regardless). Secondly, if you edit under an IP address you may be sharing this IP address with other users. If your IP address has previously been blocked (due to being flagged as a source of 'vandalism') your edits will also be blocked. You can find more information on this and creating a user account at Wikipedia.
If you have problems editing a particular page, contact us at email@example.com and we will try to help.
The community annotation is a new facility of the Pfam web site. If you have problems editing or experience problems with these pages please contact us.
Superoxide dismutase Edit Wikipedia article
Structure of a human Mn superoxide dismutase 2 tetramer.
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
Superoxide dismutases (SOD, EC 184.108.40.206) are enzymes that alternately catalyze the dismutation (or partitioning) of the superoxide (O2âˆ’) radical into either ordinary molecular oxygen (O2) or hydrogen peroxide (H2O2). Superoxide is produced as a by-product of oxygen metabolism and, if not regulated, causes many types of cell damage. Hydrogen peroxide is also damaging, but less so, and is degraded by other enzymes such as catalase. Thus, SOD is an important antioxidant defense in nearly all living cells exposed to oxygen. One exception is Lactobacillus plantarum and related lactobacilli, which use a different mechanism to prevent damage from reactive (O2âˆ’).
SOD enzymes deal with the superoxide radical by alternately adding or removing an electron from the superoxide molecules it encounters, thus changing the O2âˆ’ into one of two less damaging species: either molecular oxygen (O2) or hydrogen peroxide (H2O2). This SOD-catalyzed dismutation of superoxide may be written, for Cu,Zn SOD, with the following half-reactions :
- Cu2+-SOD + O2âˆ’ â†’ Cu+-SOD + O2
- Cu+-SOD + O2âˆ’ + 2H+ â†’ Cu2+-SOD + H2O2
The general form, applicable to all the different metal-coordinated forms of SOD, can be written as follows:
- M(n+1)+-SOD + O2âˆ’ â†’ Mn+-SOD + O2
- Mn+-SOD + O2âˆ’ + 2H+ â†’ M(n+1)+-SOD + H2O2.
Irwin Fridovich and Joe McCord at Duke University discovered the enzymatic activity of superoxide dismutase in 1968. SODs were previously known as a group of metalloproteins with unknown function; for example, CuZnSOD was known as erythrocuprein (or hemocuprein, or cytocuprein) or as the veterinary anti-inflammatory drug "Orgotein". Likewise, Brewer (1967) identified a protein that later became known as superoxide dismutase as an indophenol oxidase by protein analysis of starch gels using the phenazine-tetrazolium technique.
Several common forms of SOD exist: they are proteins whose active site uses copper and zinc, or manganese, iron, or nickel. Thus, there are three major families of superoxide dismutase, depending on the protein fold and the metal cofactor: the Cu/Zn type (which binds both copper and zinc), Fe and Mn types (which bind either iron or manganese), and the Ni type, which binds nickel.
- Copper and zinc â€“ most commonly used by eukaryotes, including humans. The cytosols of virtually all eukaryotic cells contain an SOD enzyme with copper and zinc (Cu-Zn-SOD). For example, Cu-Zn-SOD available commercially is normally purified from bovine red blood cells. The bovine Cu-Zn enzyme is a homodimer of molecular weight 32,500. It was the first SOD whose atomic-detail crystal structure was solved, in 1975. It is an 8-stranded "Greek key" beta-barrel, with the active site held between the barrel and two surface loops. The two subunits are tightly joined back-to-back, mostly by hydrophobic and some electrostatic interactions. The ligands of the copper and zinc are six histidine and one aspartate side-chains; one histidine is bound between the two metals.
- Iron or manganese â€“ used by prokaryotes and protists, and in mitochondria
- Iron â€“ E. coli and many other bacteria also contain a form of the enzyme with iron (Fe-SOD); some bacteria contain Fe-SOD, others Mn-SOD, and some contain both (e.g., "E. coli"). Fe-SOD can be found in the chloroplasts of plants. The 3D structures of the homologous Mn and Fe superoxide dismutases have the same arrangement of alpha-helices, and their active sites contain the same type and arrangement of amino acid side-chains. They are usually dimers, but occasionally tetramers.
- Manganese â€“ Chicken liver (and nearly all other) mitochondria, and many bacteria (such as E. coli), contain a form with manganese (Mn-SOD): For example, the Mn-SOD found in human mitochondria. The ligands of the manganese ions are 3 histidine side-chains, an aspartate side-chain and a water molecule or hydroxy ligand, depending on the Mn oxidation state (respectively II and III).
- Nickel â€“ prokaryotic. This has a hexameric (6-copy) structure built from right-handed 4-helix bundles, each containing N-terminal hooks that chelate a Ni ion. The Ni-hook contains the motif His-Cys-X-X-Pro-Cys-Gly-X-Tyr; it provides most of the interactions critical for metal binding and catalysis and is, therefore, a likely diagnostic of NiSODs.
In higher plants, SOD isozymes have been localized in different cell compartments. Mn-SOD is present in mitochondria and peroxisomes. Fe-SOD has been found mainly in chloroplasts but has also been detected in peroxisomes, and CuZn-SOD has been localized in cytosol, chloroplasts, peroxisomes, and apoplast.
Three forms of superoxide dismutase are present in humans, in all other mammals, and most chordates. SOD1 is located in the cytoplasm, SOD2 in the mitochondria, and SOD3 is extracellular. The first is a dimer (consists of two units), whereas the others are tetramers (four subunits). SOD1 and SOD3 contain copper and zinc, whereas SOD2, the mitochondrial enzyme, has manganese in its reactive centre. The genes are located on chromosomes 21, 6, and 4, respectively (21q22.1, 6q25.3 and 4p15.3-p15.1).
In higher plants, superoxide dismutase enzymes (SODs) act as antioxidants and protect cellular components from being oxidized by reactive oxygen species (ROS). ROS can form as a result of drought, injury, herbicides and pesticides, ozone, plant metabolic activity, nutrient deficiencies, photoinhibition, temperature above and below ground, toxic metals, and UV or gamma rays. To be specific, molecular O2 is reduced to O2âˆ’ (an ROS called superoxide) when it absorbs an excited electron released from compounds of the electron transport chain. Superoxide is known to denature enzymes, oxidize lipids, and fragment DNA. SODs catalyze the production of O2 and H2O2 from superoxide (O2âˆ’), which results in less harmful reactants.
When acclimating to increased levels of oxidative stress, SOD concentrations typically increase with the degree of stress conditions. The compartmentalization of different forms of SOD throughout the plant makes them counteract stress very effectively. There are three well-known and -studied classes of SOD metallic coenzymes that exist in plants. First, Fe SODs consist of two species, one homodimer (containing 1-2 g Fe) and one tetramer (containing 2-4 g Fe). They are thought to be the most ancient SOD metalloenzymes and are found within both prokaryotes and eukaryotes. Fe SODs are most abundantly localized inside plant chloroplasts, where they are indigenous. Second, Mn SODs consist of a homodimer and homotetramer species each containing a single Mn(III) atom per subunit. They are found predominantly in mitochondrion and peroxisomes. Third, Cu-Zn SODs have electrical properties very different from those of the other two classes. These are concentrated in the chloroplast, cytosol, and in some cases the extracellular space. Note that Cu-Zn SODs provide less protection than Fe SODs when localized in the chloroplast.
Human white blood cells generate superoxide and other reactive oxygen species to kill bacteria. During infection, some bacteria (e.g., Burkholderia pseudomallei) therefore produce superoxide dismutase to protect themselves from being killed.
SOD out-competes damaging reactions of superoxide, thus protecting the cell from superoxide toxicity. The reaction of superoxide with non-radicals is spin-forbidden. In biological systems, this means that its main reactions are with itself (dismutation) or with another biological radical such as nitric oxide (NO) or with a transition-series metal. The superoxide anion radical (O2âˆ’) spontaneously dismutes to O2 and hydrogen peroxide (H2O2) quite rapidly (~105 Mâˆ’1sâˆ’1 at pH 7). SOD is necessary because superoxide reacts with sensitive and critical cellular targets. For example, it reacts with the NO radical, and makes toxic peroxynitrite.
Because the uncatalysed dismutation reaction for superoxide requires two superoxide molecules to react with each other, the dismutation rate is second-order with respect to initial superoxide concentration. Thus, the half-life of superoxide, although very short at high concentrations (e.g., 0.05 seconds at 0.1mM) is actually quite long at low concentrations (e.g., 14 hours at 0.1 nM). In contrast, the reaction of superoxide with SOD is first order with respect to superoxide concentration. Moreover, superoxide dismutase has the largest kcat/KM (an approximation of catalytic efficiency) of any known enzyme (~7 x 109 Mâˆ’1sâˆ’1), this reaction being limited only by the frequency of collision between itself and superoxide. That is, the reaction rate is "diffusion-limited".
The high efficiency of superoxide dismutase seems necessary: even at the subnanomolar concentrations achieved by the high concentrations of SOD within cells, superoxide inactivates the citric acid cycle enzyme aconitase, can poison energy metabolism, and releases potentially toxic iron. Aconitase is one of several iron-sulfur-containing (de)hydratases in metabolic pathways shown to be inactivated by superoxide.
Superoxide is one of the main reactive oxygen species in the cell. As a consequence, SOD serves a key antioxidant role. The physiological importance of SODs is illustrated by the severe pathologies evident in mice genetically engineered to lack these enzymes. Mice lacking SOD2 die several days after birth, amid massive oxidative stress. Mice lacking SOD1 develop a wide range of pathologies, including hepatocellular carcinoma, an acceleration of age-related muscle mass loss, an earlier incidence of cataracts and a reduced lifespan. Mice lacking SOD3 do not show any obvious defects and exhibit a normal lifespan, though they are more sensitive to hyperoxic injury. Knockout mice of any SOD enzyme are more sensitive to the lethal effects of superoxide-generating drugs, such as paraquat and diquat.
Drosophila lacking SOD1 have a dramatically shortened lifespan, whereas flies lacking SOD2 die before birth. SOD knockdowns in C. elegans do not cause major physiological disruptions. Knockout or null mutations in SOD1 are highly detrimental to aerobic growth in the yeast Sacchormyces cerevisiae and result in a dramatic reduction in post-diauxic lifespan. SOD2 knockout or null mutations cause growth inhibition on respiratory carbon sources in addition to decreased post-diauxic lifespan.
Several prokaryotic SOD null mutants have been generated, including E. Coli. The loss of periplasmic CuZnSOD causes loss of virulence and might be an attractive target for new antibiotics.
Role in disease
Mutations in the first SOD enzyme (SOD1) can cause familial amyotrophic lateral sclerosis (ALS, a form of motor neuron disease). The most common mutation in the U.S. is A4V, while the most intensely studied is G93A. The other two isoforms of SOD have not been linked to any human diseases, however, in mice inactivation of SOD2 causes perinatal lethality and inactivation of SOD1 causes hepatocellular carcinoma. Mutations in SOD1 can cause familial ALS (several pieces of evidence also show that wild-type SOD1, under conditions of cellular stress, is implicated in a significant fraction of sporadic ALS cases, which represent 90% of ALS patients.), by a mechanism that is presently not understood, but not due to loss of enzymatic activity or a decrease in the conformational stability of the SOD1 protein. Overexpression of SOD1 has been linked to the neural disorders seen in Down syndrome. In patients with thalassemia, SOD will increase as a form of compensation mechanism. However, in the chronic stage, SOD does not seem to be insufficient and tends to decrease due to the destruction of proteins from the massive reaction of oxidant-antioxidant.
In mice, the extracellular superoxide dismutase (SOD3, ecSOD) contributes to the development of hypertension. Diminished SOD3 activity has been linked to lung diseases such as Acute Respiratory Distress Syndrome (ARDS) or Chronic obstructive pulmonary disease (COPD).
Superoxide dismutase is also not expressed in neural crest cells in the developing fetus. Hence, high levels of free radicals can cause damage to them and induce dysraphic anomalies (neural tube defects).
SOD has powerful antinflammatory activity. For example, SOD is a highly effective experimental treatment of chronic inflammation in colitis. Treatment with SOD decreases reactive oxygen species generation and oxidative stress and, thus, inhibits endothelial activation and indicate that modulation of factors that govern adhesion molecule expression and leukocyte-endothelial interactions. Therefore, such antioxidants may be important new therapies for the treatment of inflammatory bowel disease.
Likewise, SOD has multiple pharmacological activities. E.g., it ameliorates cis-platinum-induced nephrotoxicity in rodents. As "Orgotein" or "ontosein", a pharmacologically-active purified bovine liver SOD, it is also effective in the treatment of urinary tract inflammatory disease in man. For a time, bovine liver SOD even had regulatory approval in several European countries for such use. This was truncated by concerns about prion disease.
An SOD-mimetic agent, TEMPOL, is currently in clinical trials for radioprotection and to prevent radiation-induced dermatitis. TEMPOL and similar SOD-mimetic nitroxides exhibit a multiplicity of actions in diseases involving oxidative stress.
SOD may reduce free radical damage to skinâ€”for example, to reduce fibrosis following radiation for breast cancer. Studies of this kind must be regarded as tentative, however, as there were not adequate controls in the study including a lack of randomization, double-blinding, or placebo. Superoxide dismutase is known to reverse fibrosis, perhaps through reversion of myofibroblasts back to fibroblasts.[further explanation needed]
SOD is commercially obtained from bovine liver, though it is also found in yeast, spinach, and chicken liver.
- PDB 1VAR; Borgstahl GE, Parge HE, Hickey MJ, Johnson MJ, Boissinot M, Hallewell RA, Lepock JR, Cabelli DE, Tainer JA (April 1996). "Human mitochondrial manganese superoxide dismutase polymorphic variant Ile58Thr reduces activity by destabilizing the tetrameric interface". Biochemistry 35 (14): 4287â€“97. doi:10.1021/bi951892w. PMID 8605177.
- PDB 2SOD;Tainer JA, Getzoff ED, Beem KM, Richardson JS, Richardson DC (September 1982). "Determination and analysis of the 2 A-structure of copper, zinc superoxide dismutase". J. Mol. Biol. 160 (2): 181â€“217. doi:10.1016/0022-2836(82)90174-7. PMID 7175933.
- McCord JM, Fridovich I (1969). "Superoxide Dismutase, An Enzymic Function for Erythrocuprein (Hemocuprein)". Journal of Biological Chemistry 244 (22): 6049â€“6055. PMID 5389100.
- McCord JM, Fridovich I (1988). "Superoxide dismutase: the first twenty years (1968-1988)". Free Radic. Biol. Med. 5 (5â€“6): 363â€“9. doi:10.1016/0891-5849(88)90109-8. PMID 2855736.
- Brewer GJ (September 1967). "Achromatic regions of tetrazolium stained starch gels: inherited electrophoretic variation". American Journal of Human Genetics 19 (5): 674â€“80. PMC 1706241. PMID 4292999.
- Richardson J, Thomas KA, Rubin BH, Richardson DC (1975). "Crystal Structure of Bovine Cu,Zn Superoxide Dismutase at 3Ã… Resolution: Chain Tracing and Metal Ligands". Proc. Natl. Acad. Sci. U.S.A. 72 (4): 1349â€“53. doi:10.1073/pnas.72.4.1349. PMC 432531. PMID 1055410..
- Tainer JA, Getzoff ED, Richardson JS, Richardson DC (1983). "Structure and mechanism of copper, zinc superoxide dismutase". Nature 306 (5940): 284â€“7. doi:10.1038/306284a0. PMID 6316150..
- Quint, P; Reutzel, R; Mikulski, R; McKenna, R; Silverman, D. N. (2006). "Crystal structure of nitrated human manganese superoxide dismutase: Mechanism of inactivation". Free Radical Biology and Medicine 40 (3): 453â€“8. doi:10.1016/j.freeradbiomed.2005.08.045. PMID 16443160.
- PDB 1N0J; Borgstahl GE, Parge HE, Hickey MJ, Beyer WF, Hallewell RA, Tainer JA (1992). "The structure of human mitochondrial manganese superoxide dismutase reveals a novel tetrameric interface of two 4-helix bundles". Cell 71 (1): 107â€“18. doi:10.1016/0092-8674(92)90270-M. PMID 1394426.
- Barondeau DP, Kassmann CJ, Bruns CK, Tainer JA, Getzoff ED (2004). "Nickel superoxide dismutase structure and mechanism". Biochemistry 43 (25): 8038â€“47. doi:10.1021/bi0496081. PMID 15209499.
- PDB 1Q0M; Wuerges J, Lee JW, Yim YI, Yim HS, Kang SO, Djinovic Carugo K (2004). "Crystal structure of nickel-containing superoxide dismutase reveals another type of active site". Proc. Natl. Acad. Sci. U.S.A. 101 (23): 8569â€“74. doi:10.1073/pnas.0308514101. PMC 423235. PMID 15173586.
- PDB 1SDY; DjinoviÄ‡ K, Gatti G, Coda A, Antolini L, Pelosi G, Desideri A, Falconi M, Marmocchi F, Rolilio G, Bolognesi M (December 1991). "Structure solution and molecular dynamics refinement of the yeast Cu,Zn enzyme superoxide dismutase". Acta Crystallogr., B. 47 ( Pt 6): 918â€“27. doi:10.1107/S0108768191004949. PMID 1772629.
- Corpas FJ, Barroso JB, del RÃo LA (April 2001). "Peroxisomes as a source of reactive oxygen species and nitric oxide signal molecules in plant cells". Trends Plant Sci. 6 (4): 145â€“50. doi:10.1016/S1360-1385(01)01898-2. PMID 11286918.
- Corpas FJ, FernÃ¡ndez-OcaÃ±a A, Carreras A, Valderrama R, Luque F, Esteban FJ, RodrÃguez-Serrano M, Chaki M, Pedrajas JR, Sandalio LM, del RÃo LA, Barroso JB (July 2006). "The expression of different superoxide dismutase forms is cell-type dependent in olive (Olea europaea L.) leaves". Plant Cell Physiol. 47 (7): 984â€“94. doi:10.1093/pcp/pcj071. PMID 16766574.
- PDB 3CQQ; Cao X, Antonyuk SV, Seetharaman SV, Whitson LJ, Taylor AB, Holloway SP, Strange RW, Doucette PA, Valentine JS, Tiwari A, Hayward LJ, Padua S, Cohlberg JA, Hasnain SS, Hart PJ (June 2008). "Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis". J. Biol. Chem. 283 (23): 16169â€“77. doi:10.1074/jbc.M801522200. PMC 2414278. PMID 18378676.
- PDB 2JLP; Antonyuk SV, Strange RW, Marklund SL, Hasnain SS (May 2009). "The structure of human extracellular copper-zinc superoxide dismutase at 1.7 A resolution: insights into heparin and collagen binding". J. Mol. Biol. 388 (2): 310â€“26. doi:10.1016/j.jmb.2009.03.026. PMID 19289127.
- Alscher RG, Erturk N, Heath LS (May 2002). "Role of superoxide dismutases (SODs) in controlling oxidative stress in plants". J. Exp. Bot. 53 (372): 1331â€“41. doi:10.1093/jexbot/53.372.1331. PMID 11997379.
- Smirnoff, Nicholas (1993). "Tansley Review No. 52 The role of active oxygen in the response of plants to water deficit and desiccation". Plant Phytology 125.
- Raychaudhuri SS, Deng XW (2008). "The Role of Superoxide Dismutase in Combating Oxidative Stress in Higher Plants". The Botanical Review 66 (1): 89â€“98. doi:10.1007/BF02857783.
- Vanaporn M, Wand M, Michell SL, Sarkar-Tyson M, Ireland P, Goldman S, Kewcharoenwong C, Rinchai D, Lertmemongkolchai G, Titball RW (2011). "Superoxide dismutase C is required for intracellular survival and virulence of Burkholderia pseudomallei". Microbiology (Reading, Engl.) 157 (Pt 8): 2392â€“400. doi:10.1099/mic.0.050823-0. PMID 21659326.
- Heinrich, Peter; Georg LÃ¶ffler; Petro E. Petrides (2006). Biochemie und Pathobiochemie (Springer-Lehrbuch) (German Edition). Berlin: Springer. p. 123. ISBN 3-540-32680-4.
- Gardner PR, Raineri I, Epstein LB, White CW (June 1995). "Superoxide radical and iron modulate aconitase activity in mammalian cells". J. Biol. Chem. 270 (22): 13399â€“405. doi:10.1074/jbc.270.22.13399. PMID 7768942.
- Li Y, Huang TT, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C, Chan PH, Wallace DC, Epstein CJ (December 1995). "Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase". Nat. Genet. 11 (4): 376â€“81. doi:10.1038/ng1295-376. PMID 7493016.
- Elchuri S, Oberley TD, Qi W, Eisenstein RS, Jackson Roberts L, Van Remmen H, Epstein CJ, Huang TT (January 2005). "CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life". Oncogene 24 (3): 367â€“80. doi:10.1038/sj.onc.1208207. PMID 15531919.
- Muller FL, Song W, Liu Y, Chaudhuri A, Pieke-Dahl S, Strong R, Huang TT, Epstein CJ, Roberts LJ, Csete M, Faulkner JA, Van Remmen H (June 2006). "Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy". Free Radic. Biol. Med. 40 (11): 1993â€“2004. doi:10.1016/j.freeradbiomed.2006.01.036. PMID 16716900.
- Sentman ML, GranstrÃ¶m M, Jakobson H, Reaume A, Basu S, Marklund SL (March 2006). "Phenotypes of mice lacking extracellular superoxide dismutase and copper- and zinc-containing superoxide dismutase". J. Biol. Chem. 281 (11): 6904â€“9. doi:10.1074/jbc.M510764200. PMID 16377630.
- Milani P, Gagliardi S, Cova E, Cereda C (2011). "SOD1 Transcriptional and Posttranscriptional Regulation and Its Potential Implications in ALS.". Neurol Res Int. 2011: 458427. doi:10.1155/2011/458427. PMC 3096450. PMID 21603028.
- Deng HX, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung WY, Getzoff ED, Hu P, Herzfeldt B, Roos RP (1993). "Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase". Science 261 (5124): 1047â€“51. doi:10.1126/science.8351519. PMID 8351519.
- Conwit RA (December 2006). "Preventing familial ALS: a clinical trial may be feasible but is an efficacy trial warranted?". J. Neurol. Sci. 251 (1â€“2): 1â€“2. doi:10.1016/j.jns.2006.07.009. PMID 17070848.
- Al-Chalabi A, Leigh PN (August 2000). "Recent advances in amyotrophic lateral sclerosis". Current Opinion in Neurology 13 (4): 397â€“405. doi:10.1097/00019052-200008000-00006. PMID 10970056.
- Gagliardi S, Cova E, Davin A, Guareschi S, Abel K, Alvisi E, Laforenza U, Ghidoni R, Cashman JR, Ceroni M, Cereda C (August 2010). "SOD1 mRNA expression in sporadic amyotrophic lateral sclerosis". Neurobiol. Dis. 39 (2): 198â€“203. doi:10.1016/j.nbd.2010.04.008. PMID 20399857.
- Groner Y, Elroy-Stein O, Avraham KB, Schickler M, Knobler H, Minc-Golomb D, Bar-Peled O, Yarom R, Rotshenker S (1994). "Cell damage by excess CuZnSOD and Down syndrome". Biomed. Pharmacother. 48 (5â€“6): 231â€“40. doi:10.1016/0753-3322(94)90138-4. PMID 7999984.
- Rujito L, Mulatsih S, Sofro ASM (2015). "Status of Superoxide dismutase in transfusion dependent thalassaemia". North Am J Med Sci 7 (5): 194â€“98. doi:10.4103/1947-2714.157480.
- Gongora MC, Qin Z, Laude K, Kim HW, McCann L, Folz JR, Dikalov S, Fukai T, Harrison DG (2006). "Role of extracellular superoxide dismutase in hypertension". Hypertension 48 (3): 473â€“81. doi:10.1161/01.HYP.0000235682.47673.ab. PMID 16864745.
- Lob HE, Marvar PJ, Guzik TJ, Sharma S, McCann LA, Weyand C, Gordon FJ, Harrison DG (2010). "Induction of hypertension and peripheral inflammation by reduction of extracellular superoxide dismutase in the central nervous system". Hypertension 55 (2): 277â€“83, 6p following 283. doi:10.1161/HYPERTENSIONAHA.109.142646. PMC 2813894. PMID 20008675.
- Young RP, Hopkins R, Black PN, Eddy C, Wu L, Gamble GD, Mills GD, Garrett JE, Eaton TE, Rees MI (2006). "Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function". Thorax 61 (5): 394â€“9. doi:10.1136/thx.2005.048512. PMC 2111196. PMID 16467073.
- Ganguly K, Depner M, Fattman C, Bein K, Oury TD, Wesselkamper SC, Borchers MT, Schreiber M, Gao F, von Mutius E, Kabesch M, Leikauf GD, Schulz H (2009). "Superoxide dismutase 3, extracellular (SOD3) variants and lung function". Physiol. Genomics 37 (3): 260â€“7. doi:10.1152/physiolgenomics.90363.2008. PMC 2685504. PMID 19318538.
- Gongora MC, Lob HE, Landmesser U, Guzik TJ, Martin WD, Ozumi K, Wall SM, Wilson DS, Murthy N, Gravanis M, Fukai T, Harrison DG (2008). "Loss of extracellular superoxide dismutase leads to acute lung damage in the presence of ambient air: a potential mechanism underlying adult respiratory distress syndrome". Am. J. Pathol. 173 (4): 915â€“26. doi:10.2353/ajpath.2008.080119. PMC 2543061. PMID 18787098.
- SeguÃ J, Gironella M, Sans M, Granell S, Gil F, Gimeno M, Coronel P, PiquÃ© JM, PanÃ©s J (September 2004). "Superoxide dismutase ameliorates TNBS-induced colitis by reducing oxidative stress, adhesion molecule expression, and leukocyte recruitment into the inflamed intestine". J. Leukoc. Biol. 76 (3): 537â€“44. doi:10.1189/jlb.0304196. PMID 15197232.
- McGinness JE, Proctor PH, Demopoulos HB, Hokanson JA, Kirkpatrick DS (1978). "Amelioration of cis-platinum nephrotoxicity by orgotein (superoxide dismutase)". Physiol. Chem. Phys. 10 (3): 267â€“77. PMID 733940.
- Marberger H, Huber W, Bartsch G, Schulte T, Swoboda P (1974). "Orgotein: a new antiinflammatory metalloprotein drug evaluation of clinical efficacy and safety in inflammatory conditions of the urinary tract". Int Urol Nephrol 6 (2): 61â€“74. doi:10.1007/bf02081999. PMID 4615073.
- Clinical trial number NCT01324141 for "Topical MTS-01 for Dermatitis During Radiation and Chemotherapy for Anal Cancer" at ClinicalTrials.gov
- Wilcox CS (May 2010). "Effects of tempol and redox-cycling nitroxides in models of oxidative stress". Pharmacol. Ther. 126 (2): 119â€“45. doi:10.1016/j.pharmthera.2010.01.003. PMC 2854323. PMID 20153367.
- Campana F, Zervoudis S, Perdereau B, Gez E, Fourquet A, Badiu C, Tsakiris G, Koulaloglou S (2004). "Topical superoxide dismutase reduces post-irradiation breast cancer fibrosis". J. Cell. Mol. Med. 8 (1): 109â€“16. doi:10.1111/j.1582-4934.2004.tb00265.x. PMID 15090266.
- Vozenin-Brotons MC, Sivan V, Gault N, Renard C, Geffrotin C, Delanian S, Lefaix JL, Martin M (January 2001). "Antifibrotic action of Cu/Zn SOD is mediated by TGF-beta1 repression and phenotypic reversion of myofibroblasts". Free Radic. Biol. Med. 30 (1): 30â€“42. doi:10.1016/S0891-5849(00)00431-7. PMID 11134893.
- Editors of Pharmacist's letter, Prescriber's letter, ed. (2007). Natural medicines comprehensive database (10th ed.). Therapeutic Research Faculty. p. 1405. ISBN 0978820533.
- Online 'Mendelian Inheritance in Man' (OMIM) 105400 (ALS)
- The ALS Online Database
- A short but substantive overview of SOD and its literature.
- Damage-Based Theories of Aging Includes a discussion of the roles of SOD1 and SOD2 in aging.
- Physicians' Comm. For Responsible Med.
- SOD and Oxidative Stress Pathway Image
- Historical information on SOD research"The evolution of Free Radical Biology & Medicine: A 20-year history" and "Free Radical Biology & Medicine The last 20 years: The most highly cited papers"
- JM McCord discusses the discovery of SOD
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Iron/manganese superoxide dismutases, alpha-hairpin domain Provide feedback
superoxide dismutases (SODs) catalyse the conversion of superoxide radicals to hydrogen peroxide and molecular oxygen. Three evolutionarily distinct families of SODs are known, of which the Mn/Fe-binding family is one. In humans, there is a cytoplasmic Cu/Zn SOD, and a mitochondrial Mn/Fe SOD. N-terminal domain is a long alpha antiparallel hairpin. A small fragment of YTRE_LEPBI matches well - sequencing error?
Knapp S, Kardinahl S, Hellgren N, Tibbelin G, Schafer G, Ladenstein R; , J Mol Biol 1999;285:689-702.: Refined crystal structure of a superoxide dismutase from the hyperthermophilic archaeon Sulfolobus acidocaldarius at 2.2 A resolution. PUBMED:9878438 EPMC:9878438
Internal database links
|SCOOP:||DUF1394 DUF1635 Hrs_helical DUF4600|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR019831
Superoxide dismutases (SODs) (EC) catalyse the conversion of superoxide radicals to molecular oxygen. Their function is to destroy the radicals that are normally produced within cells and are toxic to biological systems. Three evolutionarily distinct families of SODs are known, of which the Mn/Fe-binding family is one [PUBMED:3315461, PUBMED:3345848, PUBMED:1556751]. This family includes both single metal-binding SODs and cambialistic SOD, which can bind either Mn or Fe. Fe/MnSODs are ubiquitous enzymes that are responsible for the majority of SOD activity in prokaryotes, fungi, blue-green algae and mitochondria. Fe/MnSODs are found as homodimers or homotetramers.
The structure of Fe/MnSODs can be divided into two domains, an alpha N-terminal domain and an alpha/beta C-terminal domain, connected by a loop. The structure of the N-terminal domain consists of a two helices in an antiparallel hairpin, with a left-handed twist [PUBMED:9537987]. The structure of the C-terminal domain is of the alpha/beta type, and consists of a three-stranded antiparallel beta-sheet in the order 213, along with four helices in the arrangement alpha/beta(2)/alpha/beta/alpha(2) [PUBMED:9931259].
This entry represents the N-terminal domain of Manganese/iron superoxide dismutase.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||superoxide dismutase activity (GO:0004784)|
|metal ion binding (GO:0046872)|
|Biological process||superoxide metabolic process (GO:0006801)|
|oxidation-reduction process (GO:0055114)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
- Pfam viewer
- an HTML-based viewer that uses DAS to retrieve alignment fragments on request
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Overington and HMM_iterative_training|
|Author:||Eddy SR, Griffiths-Jones SR|
|Number in seed:||24|
|Number in full:||30824|
|Average length of the domain:||83.70 aa|
|Average identity of full alignment:||48 %|
|Average coverage of the sequence by the domain:||41.80 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||18|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Sod_Fe_N domain has been found. There are 386 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
Loading structure mapping...