View source for SOD2

{{for|the video game|State of Decay 2}}
{{short description|Enzyme}}
{{Infobox_gene}}
'''Superoxide dismutase 2, mitochondrial''' ('''SOD2'''), also known as manganese-dependent [[superoxide dismutase]] (MnSOD), is an [[enzyme]] which in humans is encoded by the ''SOD2'' [[gene]] on chromosome 6.<ref name=entrez>{{cite web | title = Entrez Gene: SOD2 superoxide dismutase 2, mitochondrial| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6648}}</ref><ref name=pmid25224035>{{cite journal | vauthors = Becuwe P, Ennen M, Klotz R, Barbieux C, Grandemange S | title = Manganese superoxide dismutase in breast cancer: from molecular mechanisms of gene regulation to biological and clinical significance | journal = Free Radical Biology & Medicine | volume = 77 | pages = 139–151 | date = Dec 2014 | pmid = 25224035 | doi = 10.1016/j.freeradbiomed.2014.08.026 | url = https://hal.archives-ouvertes.fr/hal-01094585/document }}</ref> A related [[pseudogene]] has been identified on chromosome 1. [[Alternative splicing]] of this gene results in multiple transcript variants.<ref name="entrez" /> This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial protein that forms a [[homotetramer]] and binds one manganese ion per subunit. This protein binds to the superoxide byproducts of [[oxidative phosphorylation]] and converts them to [[hydrogen peroxide]] and [[Diatomic Oxygen|diatomic oxygen]]. Mutations in this gene have been associated with idiopathic [[cardiomyopathy]] (IDC), premature aging, sporadic motor neuron disease, and cancer.<ref name="entrez" />
== Structure ==
The ''SOD2'' gene contains five [[exon]]s interrupted by four [[intron]]s, an uncharacteristic 5′-proximal [[promoter (genetics)|promoter]] that possesses a GC-rich region in place of the TATA or CAAT, and an [[enhancer (genetics)|enhancer]] in the second intron. The proximal promoter region contains multiple binding sites for [[transcription factor]]s, including specific-1 ([[Sp1 transcription factor|Sp1]]), activator protein 2 ([[Activating protein 2|AP-2]]), and early growth response 1 ([[Egr-1]]).<ref name=pmid25224035/> This gene is a [[mitochondria]]l member of the iron/manganese [[superoxide dismutase]] family.<ref name=entrez/><ref name=pmid12551919>{{cite journal | vauthors = Pias EK, Ekshyyan OY, Rhoads CA, Fuseler J, Harrison L, Aw TY | title = Differential effects of superoxide dismutase isoform expression on hydroperoxide-induced apoptosis in PC-12 cells | journal = The Journal of Biological Chemistry | volume = 278 | issue = 15 | pages = 13294–301 | date = Apr 2003 | pmid = 12551919 | doi = 10.1074/jbc.M208670200 | doi-access = free }}</ref> It encodes a mitochondrial matrix protein that forms a [[homotetramer]] and binds one manganese ion per [[Protein subunit|subunit]].<ref name=entrez/><ref name=pmid25224035/> The manganese site forms a trigonal bipyramidal geometry with four ligands from the protein and a fifth solvent ligand. This solvent ligand is a hydroxide believed to serve as the electron acceptor of the enzyme. The [[active site]] cavity consists of a network of [[side chain]]s of several residues associated by [[hydrogen bond]]ing, extending from the aqueous ligand of the metal. Of note, the highly conserved [[amino acid|residue]] Tyr34 plays a key role in the hydrogen-bonding network, as [[nitration]] of this residue inhibits the protein's catalytic ability.<ref name=pmid19265433>{{cite journal | vauthors = Perry JJ, Hearn AS, Cabelli DE, Nick HS, Tainer JA, Silverman DN | title = Contribution of human manganese superoxide dismutase tyrosine 34 to structure and catalysis | journal = Biochemistry | volume = 48 | issue = 15 | pages = 3417–24 | date = Apr 2009 | pmid = 19265433 | doi = 10.1021/bi8023288 | pmc=2756076}}</ref> This protein also possesses an [[N-terminal]] mitochondrial [[targeting sequence|leader sequence]] which targets it to the mitochondrial matrix, where it converts mitochondrial-generated [[reactive oxygen species]] from the [[respiratory chain]] to H2.<ref name=pmid25224035/> [[alternative splicing|Alternate transcriptional splice]] variants, encoding different [[isoform]]s, have been characterized.<ref name=entrez/>
== Function ==
As a member of the iron/manganese [[superoxide dismutase]] family, this protein transforms toxic [[superoxide]], a byproduct of the [[mitochondrial electron transport chain]], into [[hydrogen peroxide]] and diatomic [[oxygen]].<ref name=entrez/> This function allows SOD2 to clear mitochondrial [[reactive oxygen species]] (ROS) and, as a result, confer protection against cell death.<ref name=pmid12551919/> As a result, this protein plays an antiapoptotic role against [[oxidative stress]], ionizing [[radiation]], and [[inflammation|inflammatory]] [[cytokine]]s.<ref name=pmid25224035/>
[[File:SOD2_Proton-Coupled_Electron_Transfer_Mechanism.tif|thumb|border|left|text-top|upright=3.2|The SOD2 proton-coupled electron transfer mechanism<ref name=Azadmanesh/>]]
=== Mechanism ===
SOD2 uses cyclic proton-coupled electron transfer reactions to convert superoxide (O<sub>2</sub><sup>•-</sup>) into either oxygen (O<sub>2</sub>) or hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), depending on the oxidation state of the manganese metal and the protonation status of the active site.
Mn<sup>3+</sup> + O<sub>2</sub><sup>•-</sup> ↔ Mn<sup>2+</sup> + O<sub>2</sub>
Mn<sup>2+</sup> + O<sub>2</sub><sup>•-</sup> + 2H<sup>+</sup> ↔ Mn<sup>3+</sup> + H<sub>2</sub>O<sub>2</sub>
The protons of the active site have been directly visualized and revealed that SOD2 utilizes a series of proton transfers among its active site residues per electron transfer step.<ref name=Azadmanesh>{{cite journal | vauthors = Azadmanesh J, Lutz WE, Coates L, Weiss KL, Borgstahl GE | title = Direct detection of coupled proton and electron transfers in human manganese superoxide dismutase | journal = Nature Communications | volume = 12 | issue = 1 | pages = 2079 | date = April 2021 | pmid = 33824320 | doi = 10.1038/s41467-021-22290-1 | pmc = 8024262 | bibcode = 2021NatCo..12.2079A | doi-access = free }}</ref> The findings demonstrate the use of unusual chemistry by the enzyme that include a glutamine that is cyclically deprotonated and protonated and amino acids with pK<sub>a</sub>s that are significantly different from expected values. Low-barrier and short-strong hydrogen bonds are seen contributing to catalysis by promoting proton transfers and stabilizing intermediates in a fashion similar to those of some catalytic Asp-Ser-His triads.<ref>{{cite journal | vauthors = Agback P, Agback T | title = Direct evidence of a low barrier hydrogen bond in the catalytic triad of a Serine protease | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 10078 | date = July 2018 | pmid = 29973622 | pmc = 6031666 | doi = 10.1038/s41598-018-28441-7 | bibcode = 2018NatSR...810078A }}</ref>
== Clinical significance ==
The SOD2 enzyme is an important constituent in apoptotic signaling and [[oxidative stress]], most notably as part of the mitochondrial death pathway and cardiac myocyte apoptosis signaling.<ref>{{cite journal | vauthors = Danial NN, Korsmeyer SJ | title = Cell death: critical control points | journal = Cell | volume = 116 | issue = 2 | pages = 205–19 | date = January 2004 | pmid = 14744432 | doi = 10.1016/s0092-8674(04)00046-7 | s2cid = 10764012 | doi-access = free }}</ref> Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics a normal [[embryologic]] processes, or during cell injury (such as ischemia-reperfusion injury during [[heart attacks]] and [[strokes]]) or during developments and processes in [[cancer]], an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the [[DNA]] and [[Cell nucleus|nucleus]]. This is followed by fragmentation into apoptotic bodies that are quickly removed by [[phagocytes]], thereby preventing an [[inflammation|inflammatory]] response.<ref>{{cite journal | vauthors = Kerr JF, Wyllie AH, Currie AR | title = Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics | journal = British Journal of Cancer | volume = 26 | issue = 4 | pages = 239–57 | date = Aug 1972 | pmid = 4561027 | doi=10.1038/bjc.1972.33 | pmc=2008650}}</ref> It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite [[mitosis]] in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of [[necrosis]] is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many [[physiological]] and [[pathological]] processes. It plays an important role during [[embryonal]] development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
===Cancer risk===
Numerous studies have reported associations between SOD2 [[Polymorphism (biology)|polymorphisms]] and cancer risk, but results have been inconsistent.  An updated [[meta-analysis]] of such studies revealed that SOD2 polymorphisms are related to the development of [[non-Hodgkin lymphoma]], [[lung cancer]], and [[colorectal cancer]].<ref name="pmid26628947">{{cite journal |vauthors=Kang SW |title=Superoxide dismutase 2 gene and cancer risk: evidence from an updated meta-analysis |journal=Int J Clin Exp Med |volume=8 |issue=9 |pages=14647–55 |date=2015 |pmid=26628947 |pmc=4658836 }}</ref>
=== Role in oxidative stress ===
Most notably, SOD2 is pivotal in [[reactive oxygen species]] (ROS) release during oxidative stress by ischemia-reperfusion injury, specifically in the myocardium as part of a [[heart attack]] (also known as [[ischemic heart disease]]). Ischemic heart disease, which results from an [[Vascular occlusion|occlusion]] of one of the major [[coronary arteries]], is currently still the leading cause of [[morbidity]] and [[cause of death|mortality]] in western society.<ref>{{cite journal | vauthors = Murray CJ, Lopez AD | title = Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study | journal = Lancet | volume = 349 | issue = 9064 | pages = 1498–504 | date = May 1997 | pmid = 9167458 | doi = 10.1016/S0140-6736(96)07492-2 | s2cid = 10556268 }}</ref><ref>{{cite journal | vauthors = Braunwald E, Kloner RA | title = Myocardial reperfusion: a double-edged sword? | journal = The Journal of Clinical Investigation | volume = 76 | issue = 5 | pages = 1713–9 | date = Nov 1985 | pmid = 4056048 | doi = 10.1172/JCI112160 | pmc=424191}}</ref> During ischemia reperfusion, ROS release substantially contribute to the cell damage and death via a direct effect on the cell as well as via apoptotic signals. SOD2 is known to have a capacity to limit the detrimental effects of ROS. As such, SOD2 is important for its cardioprotective effects.<ref>{{cite journal | vauthors = Maslov LN, Naryzhnaia NV, ((Podoksenov IuK)), Prokudina ES, Gorbunov AS, Zhang I, ((Peĭ ZhM)) | title = [Reactive oxygen species are triggers and mediators of an increase in cardiac tolerance to impact of ischemia-reperfusion] | journal = Rossiĭskii Fiziologicheskiĭ Zhurnal Imeni I.M. Sechenova / Rossiĭskaia Akademiia Nauk | volume = 101 | issue = 1 | pages = 3–24 | date = Jan 2015 | pmid = 25868322 }}</ref> In addition, SOD2 has been implicated in cardioprotection against ischemia-reperfusion injury, such as during [[ischemic preconditioning]] of the heart.<ref>{{cite journal | vauthors = Liem DA, Honda HM, Zhang J, Woo D, Ping P | title = Past and present course of cardioprotection against ischemia-reperfusion injury | journal = Journal of Applied Physiology | volume = 103 | issue = 6 | pages = 2129–36 | date = Dec 2007 | pmid = 17673563 | doi = 10.1152/japplphysiol.00383.2007 | s2cid = 24815784 }}</ref> Although a large burst of ROS is known to lead to cell damage, a moderate release of ROS from the mitochondria, which occurs during nonlethal short episodes of ischemia, can play a significant triggering role in the signal transduction pathways of ischemic preconditioning leading to reduction of cell damage. It has even observed that during this release of ROS, SOD2 plays an important role hereby regulating apoptotic signaling and cell death.
Due to its cytoprotective effects, overexpression of SOD2 has been linked to increased invasiveness of [[tumor]] [[metastasis]].<ref name=pmid12551919/> Its role in controlling ROS levels also involves it in [[ageing]], [[cancer]], and [[neurodegenerative disease]].<ref name=pmid19265433/> Mutations in this gene have been associated with [[idiopathic]] [[cardiomyopathy]] (IDC), sporadic motor neuron disease, and cancer. A common polymorphism associated with greater susceptibility to various pathologies is found in the mitochondrial leader targeting sequence (Val9Ala).<ref name="pmid17640558">{{cite journal | vauthors = Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H | title = Trends in oxidative aging theories | journal = Free Radical Biology & Medicine | volume = 43 | issue = 4 | pages = 477–503 | date = Aug 2007 | pmid = 17640558 | doi = 10.1016/j.freeradbiomed.2007.03.034 }}</ref> Mice lacking Sod2 die shortly after birth, indicating that unchecked levels of superoxide are incompatible with mammalian life.<ref name="pmid7493016">{{cite journal | vauthors = Li Y, Huang TT, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C, Chan PH, Wallace DC, Epstein CJ | title = Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase | journal = Nature Genetics | volume = 11 | issue = 4 | pages = 376–81 | date = Dec 1995 | pmid = 7493016 | doi = 10.1038/ng1295-376 | s2cid = 10900822 }}</ref> However, mice 50% deficient in Sod2 have a normal lifespan and minimal phenotypic defects but do suffer increased DNA damage and increased incidence of cancer.<ref name="pmid14679299">{{cite journal | vauthors = Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang TT, Nelson J, Strong R, Richardson A | title = Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging | journal = Physiological Genomics | volume = 16 | issue = 1 | pages = 29–37 | date = Dec 2003 | pmid = 14679299 | doi = 10.1152/physiolgenomics.00122.2003 }}</ref> In ''[[Drosophila melanogaster]]'', over-expression of Sod2 has been shown to increase [[maximum lifespan]] by 20% in one study,<ref name="pmid18067683">{{cite journal | vauthors = Curtis C, Landis GN, Folk D, Wehr NB, Hoe N, Waskar M, Abdueva D, Skvortsov D, Ford D, Luu A, Badrinath A, Levine RL, Bradley TJ, Tavaré S, Tower J | title = Transcriptional profiling of MnSOD-mediated lifespan extension in Drosophila reveals a species-general network of aging and metabolic genes | journal = Genome Biology | volume = 8 | issue = 12 | pages = R262 | year = 2007 | pmid = 18067683 | pmc = 2246264 | doi = 10.1186/gb-2007-8-12-r262 | doi-access = free }}</ref> and by as much as 37% in another study.<ref name="pmid12072463">{{cite journal |vauthors=Sun J, Folk D, Bradley TJ, Tower J |title=Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster |journal=Genetics |volume=161 |issue=2 |pages=661–72 |date=June 2002 |doi=10.1093/genetics/161.2.661 |pmid=12072463 |pmc=1462135 }}</ref>
==Yeast studies==
In wild-type budding yeast ''[[Saccharomyces cerevisiae]]'' nuclear [[DNA fragmentation]] increased 3-fold during cellular aging, whereas in the absence of SOD2 nuclear DNA fragmentation increased by 5-fold during aging.<ref name="pmid24462872">{{cite journal |vauthors=Muid KA, Karakaya HÇ, Koc A |title=Absence of superoxide dismutase activity causes nuclear DNA fragmentation during the aging process |journal=Biochem. Biophys. Res. Commun. |volume=444 |issue=2 |pages=260–3 |date=February 2014 |pmid=24462872 |doi=10.1016/j.bbrc.2014.01.056 |hdl=11147/5542 |hdl-access=free }}</ref>  Production of [[reactive oxygen species]] also increased with cellular age, but by a greater amount in SOD2 mutant cells than in wild-type cells.  In the fission yeast ''[[Schizosaccharomyces pombe]]'', SOD2 deficiency, drastically increased cellular aging and decreased cell viability in the [[stationary phase (biology)|stationary phase]] of the growth cycle.<ref name="pmid26507459">{{cite journal |vauthors=Ogata T, Senoo T, Kawano S, Ikeda S |title=Mitochondrial superoxide dismutase deficiency accelerates chronological aging in the fission yeast Schizosaccharomyces pombe |journal=Cell Biol. Int. |volume=40 |issue=1 |pages=100–6 |date=January 2016 |pmid=26507459 |doi=10.1002/cbin.10556 |s2cid=205563521 |doi-access=free }}</ref>
==Role in invertebrates==
SOD2's significant role in oxidative stress management makes it an essential component of the mitochondria. As a result, SOD2 similarly to SOD1 and SOD3 is highly conserved in vertebrates as well as in invertebrates. In the study Multiple measures of functionality exhibit progressive decline in a parallel, stochastic fashion in ''Drosophilla'' Sod2 mutants.<ref name="pmid19148770">{{cite journal | vauthors = Piazza N, Hayes M, Martin I, Duttaroy A, Grotewiel M, Wessells R | title = Multiple measures of functionality exhibit progressive decline in a parallel, stochastic fashion in Drosophila Sod2 null mutants | journal = Biogerontology | volume = 10 | issue = 5 | pages = 637–48 | year = 2009 | pmid = 19148770 | pmc = 2800787 | doi = 10.1007/s10522-008-9210-2 }}</ref> In SOD2 mutants there was a cascade of deterioration within the organ systems. These deterioration were not linear in that one organ's system would fail then the other, rather on the contrary the deterioration were parallel, meaning that various systems would be affected at any given time. The build up of ROS's in the flies did play a substantial role in affecting the organ system s of the flies in such a way, that though not all observed flies suffered permanent damage, the damages that were observed were like those associated with old age in mature fruit flies.<ref name="pmid14679299"/> The tissues that are affected in light of defective SOD2 in invertebrates are the muscles, heart, and brain. ROS's effect on these tissue results in not only loss of cellular function in most cases, but a substantial loss in longevity.<ref name="pmid18067683"/> Though SOD2's role in oxidative stress management is one that has been accepted for both vertebrates and invertebrates, its necessity has been questioned by a study that was conducted on ''Caenorhabditis elegans'' (''C. elegans''). The correlation between the lack of defective SOD2 and loss of longevity and function is generally understood, however it was discovered that the removal of some of the five members of the SOD family including SOD2 resulted in the increase in longevity in mutant C. elegans compared to the wild type.<ref>{{cite journal | vauthors = Van Raamsdonk JM, Hekimi S | title = Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans | journal = PLOS Genetics | volume = 5 | issue = 2 | pages = e1000361 | date = February 2009 | pmid = 19197346 | pmc = 2628729 | doi = 10.1371/journal.pgen.1000361 | doi-access = free }}</ref>
== Animal studies ==
When animals are exercised at a relatively high work rate, exercise training promotes an increase in myocardial MnSOD activity. Increased MnSOD activity is required to achieve optimal training-induced protection against both ischemia/reperfusion(IR)-induced cardiac arrhythmias and infarction Using an antisense oligonucleotide against MnSOD to prevent ExTr-induced increases in myocardial MnSOD activity, it was demonstrated that an increase in myocardial MnSOD activity is required to provide training-induced protection against IR-induced myocardial infarction.<ref name="pmid10359573">{{cite journal | vauthors = Yamashita N, Hoshida S, Otsu K, Asahi M, Kuzuya T, Hori M | title = Exercise provides direct biphasic cardioprotection via manganese superoxide dismutase activation | journal = The Journal of Experimental Medicine | volume = 189 | issue = 11 | pages = 1699–706 | year = 1999 | pmid = 10359573 | pmc = 2193084 | doi = 10.1084/jem.189.11.1699}}</ref> Using a MnSOD gene silencing approach, reported that prevention of the ExTr-induced increase in myocardial MnSOD resulted in a loss of training-induced protection against IR-mediated arrhythmias.<ref name="pmid15454275">{{cite journal | vauthors = Hamilton KL, Quindry JC, French JP, Staib J, Hughes J, Mehta JL, Powers SK | title = MnSOD antisense treatment and exercise-induced protection against arrhythmias | journal = Free Radical Biology & Medicine | volume = 37 | issue = 9 | pages = 1360–8 | year = 2004 | pmid = 15454275 | doi = 10.1016/j.freeradbiomed.2004.07.025 }}</ref>
In a mouse model, [[mitochondria]]l [[oxidative stress]] caused by SOD2 deficiency promoted cellular [[senescence]] and aging phenotypes in the skin including an increase in DNA double-strand breaks<ref name="pmid22278880">{{cite journal |vauthors=Velarde MC, Flynn JM, Day NU, Melov S, Campisi J |title=Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin |journal=Aging (Albany NY) |volume=4 |issue=1 |pages=3–12 |date=January 2012 |pmid=22278880 |pmc=3292901 |doi=10.18632/aging.100423 }}</ref> (see [[DNA damage theory of aging]]).  Loss of epidermal SOD2 in mice induced cellular [[senescence]], which irreversibly arrested proliferation of a fraction of keratinocytes.<ref name="pmid26240345">{{cite journal |vauthors=Velarde MC, Demaria M, Melov S, Campisi J |title=Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=112 |issue=33 |pages=10407–12 |date=August 2015 |pmid=26240345 |pmc=4547253 |doi=10.1073/pnas.1505675112 |bibcode=2015PNAS..11210407V |doi-access=free }}</ref>  In older mice SOD2 deficiency delayed wound closure and reduced epidermal thickness.
Mutant mice with a [[connective tissue]] specific lack of SOD2 had a reduced lifespan and a premature onset of aging-related phenotypes such as weight loss, skin atrophy, [[kyphosis]] (curvature of the spine), [[osteoporosis]], and muscle degeneration.<ref name="pmid21108731">{{cite journal |vauthors=Treiber N, Maity P, Singh K, Kohn M, Keist AF, Ferchiu F, Sante L, Frese S, Bloch W, Kreppel F, Kochanek S, Sindrilaru A, Iben S, Högel J, Ohnmacht M, Claes LE, Ignatius A, Chung JH, Lee MJ, Kamenisch Y, Berneburg M, Nikolaus T, Braunstein K, Sperfeld AD, Ludolph AC, Briviba K, Wlaschek M, Florin L, Angel P, Scharffetter-Kochanek K |title=Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue |journal=Aging Cell |volume=10 |issue=2 |pages=239–54 |date=April 2011 |pmid=21108731 |doi=10.1111/j.1474-9726.2010.00658.x |s2cid=46458295 |doi-access= }}</ref>
SOD2 over-expression was found to extend lifespan in mice.<ref name="pmid17129739">{{cite journal |vauthors=Hu D, Cao P, Thiels E, Chu CT, Wu GY, Oury TD, Klann E |title=Hippocampal long-term potentiation, memory, and longevity in mice that overexpress mitochondrial superoxide dismutase |journal=Neurobiol Learn Mem |volume=87 |issue=3 |pages=372–84 |date=March 2007 |pmid=17129739 |pmc=1847321 |doi=10.1016/j.nlm.2006.10.003 }}</ref>
== Interactions ==
The ''SOD2'' gene has been shown to bind:
{{div col|colwidth=20em}}
*[[Sp1 transcription factor|Sp1]],<ref name=pmid25224035/>
*[[NF-κB]],<ref name=pmid25224035/>
*[[AP-1 (transcription factor)|AP-1]],<ref name=pmid25224035/>
*[[Activating protein 2|AP-2]],<ref name=pmid25224035/>
*[[Egr-1]],<ref name=pmid25224035/>
*[[CREB]],<ref name=pmid25224035/>
*[[p53]],<ref name=pmid25224035/> and
*[[NFE2L2]].<ref name=pmid25224035/>
{{Div col end}}
The SOD2 protein has been shown to interact with HIV-1 Tat and HIV-1 Vif.<ref>{{cite journal | vauthors = Woollard SM, Bhargavan B, Yu F, Kanmogne GD | title = Differential effects of Tat proteins derived from HIV-1 subtypes B and recombinant CRF02_AG on human brain microvascular endothelial cells: implications for blood-brain barrier dysfunction | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 34 | issue = 6 | pages = 1047–59 | date = Jun 2014 | pmid = 24667918 | pmc = 4050250 | doi = 10.1038/jcbfm.2014.54 }}</ref>
== References ==
{{reflist|33em}}
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Zelko IN, Mariani TJ, Folz RJ | title = Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression | journal = Free Radical Biology & Medicine | volume = 33 | issue = 3 | pages = 337–49 | date = Aug 2002 | pmid = 12126755 | doi = 10.1016/S0891-5849(02)00905-X }}
* {{cite journal | vauthors = Faraci FM, Didion SP | title = Vascular protection: superoxide dismutase isoforms in the vessel wall | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 24 | issue = 8 | pages = 1367–73 | date = Aug 2004 | pmid = 15166009 | doi = 10.1161/01.ATV.0000133604.20182.cf | doi-access = free }}
{{refend}}
{{PDB Gallery|geneid=6648}}
{{Other oxidoreductases}}
[[Category:Metalloproteins]]
[[Category:Aging-related enzymes]]
[[Category:Oxidoreductases]]
[[Category:Manganese enzymes]]