View source for Superoxide dismutase

{{short description|Class of enzymes}}
{{cs1 config|name-list-style=vanc}}
{{infobox enzyme
| Name       = Superoxide dismutase
| EC_number  = 1.15.1.1
| CAS_number = 9054-89-1
| GO_code    = 0004784
| image      = Superoxide dismutase 2 PDB 1VAR.png
| width      =
| caption    = Structure of a human Mn superoxide dismutase 2 tetramer<ref name="pmid8605177"/>
| name       =  
}}

'''Superoxide dismutase''' ('''SOD''', {{EC number|1.15.1.1}}) is an [[enzyme]] that alternately catalyzes the [[dismutation]] (or partitioning) of the [[superoxide]] ({{chem|O|2|-}}) anion [[radical (chemistry)|radical]] into normal molecular [[oxygen]] (O<sub>2</sub>) and [[hydrogen peroxide]] ({{chem|H|2|O|2}}). Superoxide is produced as a by-product of oxygen metabolism and, if not regulated, causes many types of [[cell damage]].<ref>{{cite journal | vauthors = Hayyan M, Hashim MA, AlNashef IM | title = Superoxide Ion: Generation and Chemical Implications | journal = Chemical Reviews | volume = 116 | issue = 5 | pages = 3029–3085 | date = March 2016 | pmid = 26875845 | doi = 10.1021/acs.chemrev.5b00407 | doi-access = free }}</ref> Hydrogen peroxide is also damaging 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 [[lactobacillus|lactobacilli]], which use intracellular manganese to prevent damage from reactive {{chem|O|2|-}}.<ref>{{cite journal|vauthors=Archibald FS, Fridovich I|title=Manganese and Defenses against Oxygen Toxicity in ''Lactobacillus plantarum''|journal=Journal of Bacteriology|year=1981|volume=145|issue=1|doi=10.1128/jb.145.1.442-451.1981|pages=442–451|pmid=6257639|pmc=217292}}</ref><ref>{{cite journal|vauthors=Peacock T, Hassan HM|title=Role of the Mn-Catalase in Aerobic Growth of ''Lactobacillus plantarum'' ATCC 14431|journal=Applied Microbiology|volume=1|issue=3|pages=615–625|doi=10.3390/applmicrobiol1030040|doi-access=free|s2cid=245379268|year=2021}}</ref>

== Chemical reaction ==
SODs catalyze the [[disproportionation]] of superoxide:
:{{chem|2H|+}} + {{chem|2O|2|−}} → {{chem|O|2}} + {{chem|H|2|O|2}}
In this way, {{chem|O|2|−}} is converted into two less damaging species.

The general form, applicable to all the different metal−coordinated forms of SOD, can be written as follows:
* {{chem|M|(n+1)+|−SOD}} + {{chem|O|2|−}} → {{chem|M|n+|−SOD}} + {{chem|O|2}}
* {{chem|M|n+|−SOD}} + {{chem|O|2|−}} + {{chem|2H|+}} → {{chem|M|(n+1)+|−SOD}} + {{chem|H|2|O|2}}

The reactions by which SOD−catalyzed [[dismutation]] of [[superoxide]] for Cu,Zn SOD can be written as follows:
* {{chem|Cu|2+|−SOD}} + {{chem|O|2|−}} → {{chem|Cu|+|−SOD}} + {{chem|O|2}} (reduction of copper; oxidation of superoxide)
* {{chem|Cu|+|−SOD}} + {{chem|O|2|−}} + {{chem|2H|+}} → {{chem|Cu|2+|−SOD}} + {{chem|H|2|O|2}} (oxidation of copper; reduction of superoxide)

where M = [[Copper|Cu]] (n=1); [[manganese|Mn]] (n=2); [[iron|Fe]] (n=2); Ni (n=2) only in prokaryotes.

In a series of such reactions, the [[oxidation state]] and the charge of the metal [[cation]] oscillates between n and n+1: +1 and +2 for Cu, or +2 and +3 for the other metals.

== Types ==

=== General ===
{{Further|Nickel superoxide dismutase|Iron superoxide dismutase}}
[[Irwin Fridovich]] and [[Joe M. McCord|Joe McCord]] at [[Duke University]] discovered the enzymatic activity of superoxide dismutase in 1968.<ref name="sodCat">{{cite journal | vauthors = McCord JM, Fridovich I | title = Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein) | journal = The Journal of Biological Chemistry | volume = 244 | issue = 22 | pages = 6049–6055 | date = November 1969 | pmid = 5389100 | doi = 10.1016/S0021-9258(18)63504-5 | doi-access = free }}</ref> SODs were previously known as a group of [[metalloprotein]]s with unknown function; for example, CuZnSOD was known as erythrocuprein (or hemocuprein, or cytocuprein) or as the veterinary anti-inflammatory drug "Orgotein".<ref name="pmid2855736">{{cite journal | vauthors = McCord JM, Fridovich I | title = Superoxide dismutase: the first twenty years (1968–1988) | journal = Free Radical Biology & Medicine | volume = 5 | issue = 5–6 | pages = 363–369 | year = 1988 | pmid = 2855736 | doi = 10.1016/0891-5849(88)90109-8 }}</ref> 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.<ref name="pmid4292999">{{cite journal | vauthors = Brewer GJ | title = Achromatic regions of tetrazolium stained starch gels: inherited electrophoretic variation | journal = American Journal of Human Genetics | volume = 19 | issue = 5 | pages = 674–680 | date = September 1967 | pmid = 4292999 | pmc = 1706241 }}</ref>

There are three major families of superoxide dismutase, depending on the protein fold and the metal [[Cofactor (biochemistry)|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]]).
{|
|- valign=top
| [[Image:2SOD ribbon colorPencil WhBkgd.png|thumb|right|[[Ribbon diagram]] of bovine Cu-Zn SOD subunit<ref name="pmid7175933">{{PDB|2SOD}};{{cite journal | vauthors = Tainer JA, Getzoff ED, Beem KM, Richardson JS, Richardson DC | title = Determination and analysis of the 2 A-structure of copper, zinc superoxide dismutase | journal = Journal of Molecular Biology | volume = 160 | issue = 2 | pages = 181–217 | date = September 1982 | pmid = 7175933 | doi = 10.1016/0022-2836(82)90174-7 | author-link2 = Elizabeth D. Getzoff }}</ref>]]
| [[File:Crystal Structure of Human Manganese SOD.png|thumb|right|Active site of Human Manganese SOD, manganese shown in purple<ref name="pmid16443160">{{cite journal | vauthors = Quint P, Reutzel R, Mikulski R, McKenna R, Silverman DN | title = Crystal structure of nitrated human manganese superoxide dismutase: mechanism of inactivation | journal = Free Radical Biology & Medicine | volume = 40 | issue = 3 | pages = 453–458 | date = February 2006 | pmid = 16443160 | doi = 10.1016/j.freeradbiomed.2005.08.045 }}</ref>]]
| [[File:094-SuperoxideDismutase-Mn Fe 2mers.png|thumb|right|Mn-SOD vs Fe-SOD dimers]]
|}

* Copper and zinc – most commonly used by [[eukaryote]]s, including humans. The [[cytosol]]s of virtually all [[eukaryote|eukaryotic]] cells contain a 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.<ref name="1SOD">{{cite journal | vauthors = Richardson J, Thomas KA, Rubin BH, Richardson DC | title = Crystal structure of bovine Cu,Zn superoxide dismutase at 3 A resolution: chain tracing and metal ligands | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 72 | issue = 4 | pages = 1349–1353 | date = April 1975 | pmid = 1055410 | pmc = 432531 | doi = 10.1073/pnas.72.4.1349 | doi-access = free }}.</ref> It is an 8-stranded "[[Greek key (protein structure)|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.<ref name="pmid6316150">{{cite journal | vauthors = Tainer JA, Getzoff ED, Richardson JS, Richardson DC | title = Structure and mechanism of copper, zinc superoxide dismutase | journal = Nature | volume = 306 | issue = 5940 | pages = 284–287 | year = 1983 | pmid = 6316150 | doi = 10.1038/306284a0 | s2cid = 4266810 | bibcode = 1983Natur.306..284T }}</ref> 
*[[File:Iron Superoxide Dismutase Active Site.png|thumb|241x241px|Active site for iron superoxide dismutase]]Iron or manganese – used by [[prokaryote]]s and [[protist]]s, and in [[mitochondria]] and [[chloroplast]]s
** Iron – Many bacteria contain a form of the enzyme with iron (Fe-SOD); some bacteria contain Fe-SOD, others Mn-SOD, and some (such as ''[[Escherichia coli|E. coli]]'') contain both. Fe-SOD can also be found in the [[plastid|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 – Nearly all [[mitochondria]], and many bacteria, 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 [[Hydroxyl|hydroxy]] [[ligand]], depending on the Mn oxidation state (respectively II and III).<ref name="pmid1394426">{{PDB|1N0J}}; {{cite journal | vauthors = Borgstahl GE, Parge HE, Hickey MJ, Beyer WF, Hallewell RA, Tainer JA | title = The structure of human mitochondrial manganese superoxide dismutase reveals a novel tetrameric interface of two 4-helix bundles | journal = Cell | volume = 71 | issue = 1 | pages = 107–118 | date = October 1992 | pmid = 1394426 | doi = 10.1016/0092-8674(92)90270-M | s2cid = 41611695 }}</ref>
* Nickel – [[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.<ref name ="pmid15209499">{{cite journal | vauthors = Barondeau DP, Kassmann CJ, Bruns CK, Tainer JA, Getzoff ED | title = Nickel superoxide dismutase structure and mechanism | journal = Biochemistry | volume = 43 | issue = 25 | pages = 8038–8047 | date = June 2004 | pmid = 15209499 | doi = 10.1021/bi0496081 | s2cid = 10700340 }}</ref><ref name ="pmid15173586">{{PDB|1Q0M}}; {{cite journal | vauthors = Wuerges J, Lee JW, Yim YI, Yim HS, Kang SO, Djinovic Carugo K | title = Crystal structure of nickel-containing superoxide dismutase reveals another type of active site | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 23 | pages = 8569–8574 | date = June 2004 | pmid = 15173586 | pmc = 423235 | doi = 10.1073/pnas.0308514101 | doi-access = free | bibcode = 2004PNAS..101.8569W }}</ref>

{|
|- valign=top
|{{Infobox protein family
| Symbol = Sod_Cu
| Name = Copper/zinc superoxide dismutase
| image = 1sdy CuZnSOD dimer ribbon.png
| width = 
| caption = Yeast Cu,Zn superoxide dismutase dimer<ref name="pmid1772629">{{PDB|1SDY}}; {{cite journal | vauthors = Djinović K, Gatti G, Coda A, Antolini L, Pelosi G, Desideri A, Falconi M, Marmocchi F, Rolilio G, Bolognesi M | display-authors = 6 | title = Structure solution and molecular dynamics refinement of the yeast Cu,Zn enzyme superoxide dismutase | journal = Acta Crystallographica Section B: Structural Science | volume = 47 ( Pt 6) | issue = 6 | pages = 918–927 | date = December 1991 | pmid = 1772629 | doi = 10.1107/S0108768191004949 | bibcode = 1991AcCrB..47..918D | doi-access = free }}</ref>
| Pfam = PF00080
| InterPro = IPR001424
| SMART = 
| PROSITE = PDOC00082
| SCOP =1sdy
| TCDB = 
| OPM family = 
| OPM protein = 
}}
|{{Infobox protein family
| Symbol = Sod_Fe_N
| Name = Iron/manganese superoxide dismutases, alpha-hairpin domain
| image = 1n0j H mit MnSOD D1 rib.png
| width = 
| caption = Structure of domain1 (color), human mitochondrial Mn superoxide dismutase<ref name="pmid1394426" />
| Pfam = PF00081
| InterPro = IPR001189
| SMART = 
| PROSITE = PDOC00083
| SCOP = 1n0j
| TCDB = 
| OPM family = 
| OPM protein = 
}}
|{{Infobox protein family
| Symbol = Sod_Fe_C
| Name = Iron/manganese superoxide dismutases, C-terminal domain
| image = 1n0j H mit MnSOD D2 rib.png
| width = 
| caption = Structure of domain2 (color), human mitochondrial Mn superoxide dismutase<ref name="pmid1394426" />
| Pfam = PF02777
| InterPro = IPR001189
| SMART = 
| PROSITE = PDOC00083
| SCOP = 1n0j
| TCDB = 
| OPM family = 
| OPM protein = 
}}
|{{Infobox protein family
| Symbol = Sod_Ni
| Name = Nickel superoxide dismutase
| image = 094-SuperoxideDismutase-Ni 6mer.png
| width = 
| caption = Structure of ''[[Streptomyces]]'' Ni superoxide dismutase hexamer<ref name="pmid15173586" />
| Pfam = PF09055
| InterPro = IPR014123
| SMART = 
| PROSITE = 
| SCOP = 1q0d
| TCDB = 
| OPM family = 
| OPM protein = 
}}
|}

In higher plants, SOD isozymes have been localized in different cell compartments. Mn-SOD is present in mitochondria and [[peroxisome]]s. 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]].<ref name="pmid11286918">{{cite journal | vauthors = Corpas FJ, Barroso JB, del Río LA | title = Peroxisomes as a source of reactive oxygen species and nitric oxide signal molecules in plant cells | journal = Trends in Plant Science | volume = 6 | issue = 4 | pages = 145–150 | date = April 2001 | pmid = 11286918 | doi = 10.1016/S1360-1385(01)01898-2 | bibcode = 2001TPS.....6..145C }}</ref><ref name="pmid16766574">{{cite journal | vauthors = Corpas FJ, Fernández-Ocaña A, Carreras A, Valderrama R, Luque F, Esteban FJ, Rodríguez-Serrano M, Chaki M, Pedrajas JR, Sandalio LM, del Río LA, Barroso JB | display-authors = 6 | title = The expression of different superoxide dismutase forms is cell-type dependent in olive (Olea europaea L.) leaves | journal = Plant & Cell Physiology | volume = 47 | issue = 7 | pages = 984–994 | date = July 2006 | pmid = 16766574 | doi = 10.1093/pcp/pcj071 | doi-access = free }}</ref>

=== Human ===

There are three forms of superoxide dismutase present in humans, in all other [[mammals]], and most [[chordates]]. [[SOD1]] is located in the [[cytoplasm]], [[SOD2]] in the [[mitochondrion|mitochondria]], and [[SOD3]] is [[extracellular]]. The first is a [[protein dimer|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 [[gene]]s are located on chromosomes 21, 6, and 4, respectively (21q22.1, 6q25.3 and 4p15.3-p15.1).
{|
|- valign=top
|{{infobox protein
| Name = [[SOD1|SOD1, soluble]]
| caption = Crystal structure of the human SOD1 enzyme (rainbow-color [[N-terminus]] = blue, [[C-terminus]] = red) complexed with copper (orange sphere) and zinc (grey sphere)<ref name="pmid">{{PDB|3CQQ}}; {{cite journal | vauthors = 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 | display-authors = 6 | title = Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis | journal = The Journal of Biological Chemistry | volume = 283 | issue = 23 | pages = 16169–16177 | date = June 2008 | pmid = 18378676 | pmc = 2414278 | doi = 10.1074/jbc.M801522200 | doi-access = free }}</ref>
| image = 2c9v CuZn rib n site.png
| width =
| HGNCid = 11179
| Symbol = [[SOD1]]
| AltSymbols = ALS, ALS1
| EntrezGene = 6647
| OMIM = 147450
| RefSeq = NM_000454
| UniProt = P00441
| PDB =
| ECnumber = 1.15.1.1
| Chromosome = 21
| Arm = q
| Band = 22.1
| LocusSupplementaryData =
}}
|{{infobox protein
| Name = [[SOD2|SOD2, mitochondrial]]
| caption = Active site of human mitochondrial Mn superoxide dismutase (SOD2)<ref name="pmid8605177">{{PDB|1VAR}}; {{cite journal | vauthors = Borgstahl GE, Parge HE, Hickey MJ, Johnson MJ, Boissinot M, Hallewell RA, Lepock JR, Cabelli DE, Tainer JA | display-authors = 6 | title = Human mitochondrial manganese superoxide dismutase polymorphic variant Ile58Thr reduces activity by destabilizing the tetrameric interface | journal = Biochemistry | volume = 35 | issue = 14 | pages = 4287–4297 | date = April 1996 | pmid = 8605177 | doi = 10.1021/bi951892w | s2cid = 7450190 }}</ref>
| image = SODsite.gif
| width =
| HGNCid = 11180
| Symbol = [[SOD2]]
| AltSymbols = Mn-SOD; IPO-B; MVCD6
| EntrezGene = 6648
| OMIM = 147460
| RefSeq = NM_000636
| UniProt = P04179
| PDB =
| ECnumber = 1.15.1.1
| Chromosome = 6
| Arm = q
| Band = 25
| LocusSupplementaryData =
}}
|{{infobox protein
| Name = [[SOD3|SOD3, extracellular]]
| caption = Crystallographic structure of the tetrameric human SOD3 enzyme (cartoon diagram) complexed with copper and zinc cations (orange and grey spheres respectively)<ref name="pmid19289127">{{PDB|2JLP}}; {{cite journal | vauthors = Antonyuk SV, Strange RW, Marklund SL, Hasnain SS | title = The structure of human extracellular copper-zinc superoxide dismutase at 1.7 A resolution: insights into heparin and collagen binding | journal = Journal of Molecular Biology | volume = 388 | issue = 2 | pages = 310–326 | date = May 2009 | pmid = 19289127 | doi = 10.1016/j.jmb.2009.03.026 }}</ref>
| image = SOD3_2JLP.png
| width =
| HGNCid = 11181
| Symbol = [[SOD3]]
| AltSymbols = EC-SOD; MGC20077
| EntrezGene = 6649
| OMIM = 185490
| RefSeq = NM_003102
| UniProt = P08294
| PDB =
| ECnumber = 1.15.1.1
| Chromosome = 4
| Arm = p
| Band = ter
| LocusSupplementaryData = -q21
}}
|}

=== Plants ===

In [[higher plants]], superoxide dismutase enzymes (SODs) act as antioxidants and protect cellular components from being oxidized by [[reactive oxygen species]] (ROS).<ref name="Alscher">{{cite journal | vauthors = Alscher RG, Erturk N, Heath LS | title = Role of superoxide dismutases (SODs) in controlling oxidative stress in plants | journal = Journal of Experimental Botany | volume = 53 | issue = 372 | pages = 1331–1341 | date = May 2002 | pmid = 11997379 | doi = 10.1093/jexbot/53.372.1331 | doi-access = free }}</ref> 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.<ref name="Smirnoff">{{cite journal | vauthors = Smirnoff N | title = The role of active oxygen in the response of plants to water deficit and desiccation | journal = The New Phytologist | volume = 125 | issue = 1 | pages = 27–58 | date = September 1993 | pmid = 33874604 | doi = 10.1111/j.1469-8137.1993.tb03863.x | doi-access = free | bibcode = 1993NewPh.125...27S }}</ref><ref name="Raychaudhuri">{{cite journal | vauthors = Raychaudhuri SS, Deng XW | title = The Role of Superoxide Dismutase in Combating Oxidative Stress in Higher Plants | journal = The Botanical Review | volume = 66 | issue = 1| pages = 89–98 | year = 2008 | doi = 10.1007/BF02857783 | s2cid = 7663001 }}</ref> To be specific, molecular O<sub>2</sub> is reduced to {{chem|O|2|-}} (a 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.<ref name="Smirnoff"/> SODs catalyze the production of O<sub>2</sub> and {{chem|H|2|O|2}} from superoxide ({{chem|O|2|-}}), 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.<ref name="Alscher"/><ref name="Smirnoff"/><ref name="Raychaudhuri"/>

=== Bacteria ===

Human white blood cells use enzymes such as [[NADPH oxidase]] to 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.<ref name="pmid21659326">{{cite journal | vauthors = Vanaporn M, Wand M, Michell SL, Sarkar-Tyson M, Ireland P, Goldman S, Kewcharoenwong C, Rinchai D, Lertmemongkolchai G, Titball RW | display-authors = 6 | title = Superoxide dismutase C is required for intracellular survival and virulence of Burkholderia pseudomallei | journal = Microbiology | volume = 157 | issue = Pt 8 | pages = 2392–2400 | date = August 2011 | pmid = 21659326 | doi = 10.1099/mic.0.050823-0 | doi-access = free }}</ref>

== Biochemistry ==

SOD out-competes damaging reactions of superoxide, thus protecting the cell from superoxide toxicity.
The reaction of superoxide with non-radicals is [[selection rule|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 ({{chem|O|2|-}}) spontaneously dismutes to O<sub>2</sub> and hydrogen peroxide ({{chem|H|2|O|2}}) quite rapidly (~10<sup>5</sup> M<sup>−1</sup>s<sup>−1</sup> at pH 7).{{Citation needed|reason=Couldn't find reliable source backing the rate constant|date=July 2017}} 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 ''k''<sub>cat</sub>/''K''<sub>M</sub> (an approximation of catalytic efficiency) of any known enzyme (~7 billion M<sup>−1</sup>s<sup>−1</sup>),<ref name="isbn3-540-32680-4">{{cite book | vauthors = Heinrich PC, Löffler G, Petrifies PE | title = Biochemie und Pathobiochemie (Springer-Lehrbuch) | edition = German| publisher = Springer | location = Berlin | year = 2006 | page = 123 | isbn = 978-3-540-32680-9 }}</ref> 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.<ref name="pmid7768942">{{cite journal | vauthors = Gardner PR, Raineri I, Epstein LB, White CW | title = Superoxide radical and iron modulate aconitase activity in mammalian cells | journal = The Journal of Biological Chemistry | volume = 270 | issue = 22 | pages = 13399–13405 | date = June 1995 | pmid = 7768942 | doi = 10.1074/jbc.270.22.13399 | doi-access = free }}</ref>

== Evolution ==
The [[Phylogenetics|phylogenetic]] relationships among superoxide dismutases (SODs) are one of many genetic components that have been used to help reconstruct an early timeline of events and predict the evolutionary descent of species, individuals, or genes from a common ancestor over time. Around the period of Earth's transition from [[Hypoxia (environmental)|anaerobic]] to [[Aerobic respiration|aerobic]] conditions about 2.4 billion years ago (bya), the evolution of SOD enzymes crucially allowed organisms to overcome the effects of [[oxidative stress]] following the surge of molecular oxygen (O<sub>2</sub>) in the atmosphere (Miller 2012). However, evidence suggests that the origination of [[Reactive oxygen species|reactive oxygen species (ROS)]] took place as early as 4.1 to 3.5 bya (Inupakutika ''et al.'' 2016).<ref>Inupakutika ''et al.'' (2016). The evolution of reactive oxygen species metabolism, Journal of Experimental Botany, ''67''(21): 5933–5943. <nowiki>https://doi.org/10.1093/jxb/erw382</nowiki>.</ref> For the first aerobic organisms, survival depended largely on their ability to defend against ROS. For this reason, it is relevant to understand the environmental constraints that allowed such protective defense enzymes to evolve.

=== The Great Oxidation Event ===
Atmospheric and oceanic compositions have drastically changed since the formation of early Earth. One significant event, [[Great Oxidation Event|the Great Oxidation Event (GOE)]], marked the period of time in which oxygen became a major component of Earth's atmosphere and surface ocean. However, the physical or biochemical drivers responsible for the transition from a reducing to oxidizing environment remains up for debate (Olejarz ''et al.'' 2021).<ref>Olejarz ''et al.'' (2021). The Great Oxygenation Event as a consequence of ecological dynamics modulated by planetary change. ''Nat. Commun.,'' ''12'': 3985. doi.org/10.1038/s41467-021-23286-7.</ref> To date, the evolution of [[cyanobacteria]] and cyanobacterial photosynthesis is commonly accepted as the primary driver of oxygen production, alongside several physical events behaving as proximal drivers of environmental state change (Kasting 2013; Inupakutika ''et al.'' 2016).<ref>Kasting (2013). What caused the rise of atmospheric O2?

''Chem. Geo.,'' ''362'': 13-25. doi.org/10.1016/j.chemgeo.2013.05.039.</ref><ref>Inupakutika ''et al.'' (2016). The evolution of reactive oxygen species metabolism, Journal of Experimental Botany, ''67''(21): 5933–5943. <nowiki>https://doi.org/10.1093/jxb/erw382</nowiki>.</ref>

=== Selective Pressure and Enzyme Evolution ===
The atmospheric accumulation of highly reactive O<sub>2</sub> likely exercised a strong selective pressure against anaerobic organisms, and led to the adaptive evolution of oxygen utilization in metabolism (Boden ''et al''. 2021).<ref>Boden ''et al''. (2021). Timing the evolution of antioxidant enzymes in cyanobacteria. ''Nat Commun 12'', 4742. <nowiki>https://doi.org/10.1038/s41467-021-24396-y</nowiki>.</ref> The process of [[oxidative phosphorylation]] and aerobic respiration permitted a 400-fold increase in energy extraction efficiency per mole glucose as compared to anaerobic respiration. Although the increased yield of [[Adenosine triphosphate|adenosine triphosphate (ATP)]], a common form of cellular energy currency, was metabolically beneficial, the tradeoff between efficiency and risk to the metabolic machinery grew more prominent. Behaving as the terminal [[electron acceptor]] during [[cellular respiration]], the high rate of O<sub>2</sub> electron flux is accompanied by an increased risk of ROS formation, which can induce irreversible damage to cellular organelles and their processes (Case 2017).<ref>Case (2017). On the Origin of Superoxide Dismutase: An Evolutionary Perspective of Superoxide-Mediated Redox Signaling. ''Antioxidants,'' ''6''(4): 82. doi.org/10.3390/antiox6040082.</ref> In response to the accumulation of the hazardous metabolic byproducts of aerobic respiration, biological systems evolved various strategies to counteract [[Oxygen toxicity|O<sub>2</sub> toxicity.]] 

=== The Rise of Antioxidants ===
During the transition from aerobic to anaerobic conditions, phylogenetic investigations suggest that SODs are ancient molecules, which were likely selected for before the GOE. While it is intuitively assumed that antioxidants emerged during the GOE to defend against O<sub>2</sub> reactivity and toxicity caused by the accelerated oxygenation of the atmosphere, [[sequencing]] and phylogenetic analyses of antioxidant systems from ancient organisms suggests that antioxidant enzymes including SODs may have originated long before the surge of atmospheric and oceanic O<sub>2</sub> (Wolfe-Simon ''et al''. 2005; Inupakutika ''et al.'' 2016).

=== Necessity of ROS-Defense Mechanisms ===
The oxidizing capacity of O<sub>2</sub> makes it a highly efficient final electron acceptor for several biological processes, producing more energy per mole substrate relative to other available electron acceptors during aerobic respiration (Boden ''et al.'' 2021). On the other hand, its high reactivity also contributes to the uncontrolled removal of electrons, which underlies pathological cell damage through the propagation of highly reactive oxygen-containing molecules. 

[[Superoxide|Superoxide (O2•<sup>−</sup>)]] is the most common reactive free-radical formed by the univalent reduction of O<sub>2</sub>. While they are known to exhibit beneficial roles in some cellular processes, superoxide free radicals also possess the ability to initiate a cascade of ROS and free-radical species formation in biological systems. As a consequence, the unrestrained and potentially lethal accumulation of ROS threatens to damage many biomolecules: lipids, proteins, DNA, and host cells. Additionally, oxidative stress in excess is understood to participate in the dysregulation of cellular processes and disease development (Zewen ''et al.'' 2018).<ref>Zewen ''et al.'' (2018). Role of ROS and Nutritional Antioxidants in Human Diseases. ''Front. Physiol., 9.'' doi.org/10.3389/fphys.2018.00477.     </ref> 

To maintain a balance of intracellular superoxide, organisms have developed strategies to protect against overexposure. One such mechanism functions to catalyze the dismutation of superoxide radicals into hydrogen peroxide and oxygen, which is accomplished by SOD enzymes.

=== Independent Evolution of SOD Families ===
Studies examining the phylogenetic distribution of SODs support the proposal that the major [[Physiology|physiological]] function of SOD is to act as a protective mechanism among oxygen-metabolizing organisms against the formation of superoxide free radicals (McCord ''et al.'' 1971).<ref>McCord ''et al.'' (1971). An enzyme-based theory of obligate anaerobiosis: the physiological function of superoxide dismutase. ''Proc. Nat. Acad. Sci. USA, 68''(5): 1024-1027. pnas.org/doi/pdf/10.1073/pnas.68.5.1024. </ref> Although the enzyme is functionally limited to the conversion of superoxide radicals into less toxic oxygen-containing molecules, methodological approaches utilizing phylogenetic and structural protein analysis suggest that three SOD [[Protein isoform|isoforms]] have evolved independently to combat superoxide accumulation. Each enzyme family is characterized by a distinct 3D structure, amino acid sequence, and with regard to the metal-binding [[Cofactor (biochemistry)|cofactor]](s) used to support its structural stability and [[Catalysis|catalytic]] activity (Case 2017): either manganese (MnSOD), nickel (NiSOD), or both copper and zinc (Miller 2012).<ref>Miller (2012). Superoxide dismutases: Ancient enzymes and new insights, ''FEBS Open Bio'', 586, doi:10.1016/j.febslet.2011.10.048.</ref> An additional family utilizing an iron cofactor (FeSOD) has also been identified, which is evolutionarily related to MnSOD (Wolfe-Simon ''et al.'' 2005). The evolution of metalliform diversity can likely be explained by changes in heavy metal bioavailability that took place during large compositional changes of the earth's early atmosphere and oceans.

==== Fe/MnSODs ====
SODs containing Fe (FeSOD), Mn (MnSOD), or may contain either (Fe/MnSOD) are believed to have been the earliest SOD isoforms among life on early earth. During this time, Fe and Mn would have been highly bioavailable. The differences between the [[Redox|oxidation and reduction]] potentials of each metal is thought to have been advantageous to organism survival, allowing them to exist in environments with varying O<sub>2</sub> concentration and metal availability.

==== CuZnSODs ====
The most modern SOD family is believed to utilize both Cu and Zn ions (CuZnSOD). The absence of CuZnSODs from [[Archaea|archaeal]] and [[protist]] genomes coupled with the post-GOE increased bioavailability of Cu and Zn suggests that the development of this isoform took place at a later period in evolutionary time (Banci ''et al.'' 2005; Wilkinson ''et al.'' 2006).<ref>Banci ''et al''. (2005). A prokaryotic superoxide dismutase paralog lacking two Cu ligands: From largely unstructured in solution to ordered in the crystal. ''Proc. Natl. Acad. Sci. USA'', ''102'':7541–7546. doi:10.1073/pnas.0502450102.</ref><ref>Wilkinson ''et al.'' (2006). Functional characterisation of the iron superoxide dismutase gene repertoire in ''Trypanosoma brucei''. ''Free Radic. Biol. Med. 40'':198–209. doi:10.1016/j.freeradbiomed.2005.06.022.</ref>

==== NiSODs ====
The family of Ni-containing SODs (NiSOD) is less understood. Evidence suggests that these isoforms are largely distributed among [[Marine prokaryotes#Marine bacteria|marine bacteria]] and [[algae]] (Wolfe-Simon ''et al.'' 2005; Dupont ''et al.'' 2008).<ref>Wolfe-Simon ''et al.'' (2005). THE ROLE AND EVOLUTION OF SUPEROXIDE DISMUTASES IN ALGAE. ''Journal of Phycology'', 41: 453-465. doi-org.reed.idm.oclc.org/10.1111/j.1529-8817.2005.00086.x.</ref><ref>Dupont ''et al.'' (2008). Diversity, function and evolution of genes coding for putative Ni-containing superoxide dismutases. ''Environ. Microbiol. 10'':1831–1843. doi:10.1111/j.1462-2920.2008.01604.x.</ref> The evolution of NiSOD is currently predicted to have occurred around the time of the GOE when a decrease in aquatic bioavailability of Fe took place.

== Stability and folding mechanism ==

SOD1 is an extremely stable protein. In the holo form (both copper and zinc bound) the melting point is > 90&nbsp;°C.  In the apo form (no copper or zinc bound) the melting point is ~60&nbsp;°C.<ref name="Stathopulos-2006">{{cite journal | vauthors = Stathopulos PB, Rumfeldt JA, Karbassi F, Siddall CA, Lepock JR, Meiering EM | title = Calorimetric analysis of thermodynamic stability and aggregation for apo and holo amyotrophic lateral sclerosis-associated Gly-93 mutants of superoxide dismutase | journal = The Journal of Biological Chemistry | volume = 281 | issue = 10 | pages = 6184–6193 | date = March 2006 | pmid = 16407238 | doi = 10.1074/jbc.M509496200 | doi-access = free }}</ref>  By [[differential scanning calorimetry]] (DSC), holo SOD1 [[Protein folding|unfolds]] by a two-state mechanism: from dimer to two unfolded monomers.<ref name="Stathopulos-2006" /> In chemical [[Denaturation (biochemistry)|denaturation]] experiments, holo SOD1 unfolds by a three-state mechanism with observation of a folded monomeric intermediate.<ref>{{cite journal | vauthors = Rumfeldt JA, Stathopulos PB, Chakrabarrty A, Lepock JR, Meiering EM | title = Mechanism and thermodynamics of guanidinium chloride-induced denaturation of ALS-associated mutant Cu,Zn superoxide dismutases | journal = Journal of Molecular Biology | volume = 355 | issue = 1 | pages = 106–123 | date = January 2006 | pmid = 16307756 | doi = 10.1016/j.jmb.2005.10.042 }}</ref>

== Physiology ==

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]].<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 | display-authors = 6 | title = Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase | journal = Nature Genetics | volume = 11 | issue = 4 | pages = 376–381 | date = December 1995 | pmid = 7493016 | doi = 10.1038/ng1295-376 | s2cid = 10900822 }}</ref> Mice lacking SOD1 develop a wide range of pathologies, including hepatocellular carcinoma,<ref name="pmid15531919">{{cite journal | vauthors = Elchuri S, Oberley TD, Qi W, Eisenstein RS, Jackson Roberts L, Van Remmen H, Epstein CJ, Huang TT | display-authors = 6 | title = CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life | journal = Oncogene | volume = 24 | issue = 3 | pages = 367–380 | date = January 2005 | pmid = 15531919 | doi = 10.1038/sj.onc.1208207 | doi-access = free }}</ref> an acceleration of age-related muscle mass loss,<ref name="pmid16716900">{{cite journal | vauthors = 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 | display-authors = 6 | title = Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy | journal = Free Radical Biology & Medicine | volume = 40 | issue = 11 | pages = 1993–2004 | date = June 2006 | pmid = 16716900 | doi = 10.1016/j.freeradbiomed.2006.01.036 }}</ref> 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.<ref name="pmid16377630">{{cite journal | vauthors = Sentman ML, Granström M, Jakobson H, Reaume A, Basu S, Marklund SL | title = Phenotypes of mice lacking extracellular superoxide dismutase and copper- and zinc-containing superoxide dismutase | journal = The Journal of Biological Chemistry | volume = 281 | issue = 11 | pages = 6904–6909 | date = March 2006 | pmid = 16377630 | doi = 10.1074/jbc.M510764200 | doi-access = free }}</ref> [[Knockout mouse|Knockout mice]] of any SOD enzyme are more sensitive to the lethal effects of superoxide-generating compounds, such as [[paraquat]] and [[diquat]] ([[herbicide]]s).

''[[Drosophila]]'' lacking SOD1 have a dramatically shortened lifespan, whereas flies lacking SOD2 die before birth.  Depletion of [[SOD1]] and [[SOD2]] in the nervous system and muscles of ''[[Drosophila melanogaster|Drosophila]]'' is associated with reduced lifespan.<ref name="pmid25801590">{{cite journal | vauthors = Oka S, Hirai J, Yasukawa T, Nakahara Y, Inoue YH | title = A correlation of reactive oxygen species accumulation by depletion of superoxide dismutases with age-dependent impairment in the nervous system and muscles of Drosophila adults | journal = Biogerontology | volume = 16 | issue = 4 | pages = 485–501 | date = August 2015 | pmid = 25801590 | doi = 10.1007/s10522-015-9570-3 | s2cid = 18050827 }}</ref>  The accumulation of neuronal and muscular [[Reactive oxygen species|ROS]] appears to contribute to age-associated impairments.  When overexpression of mitochondrial SOD2 is induced, the lifespan of adult ''Drosophila'' is extended.<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 = 661–672 | date = June 2002 | pmid = 12072463 | pmc = 1462135 | doi = 10.1093/genetics/161.2.661 }}</ref>

Among [[black garden ant]]s (''Lasius niger''), the lifespan of [[queen ant|queens]] is an order of magnitude greater than of workers despite no systematic nucleotide sequence difference between them.<ref name = Lucas2018>{{cite journal | vauthors = Lucas ER, Keller L | title = Elevated expression of ageing and immunity genes in queens of the black garden ant | journal = Experimental Gerontology | volume = 108 | pages = 92–98 | date = July 2018 | pmid = 29625209 | doi = 10.1016/j.exger.2018.03.020 | s2cid = 5045743 | doi-access = free }}</ref>  The ''[[SOD3]]'' gene was found to be the most differentially over-expressed in the brains of queen vs worker ants.  This finding raises the possibility of an important role of antioxidant function in modulating lifespan.<ref name = Lucas2018/>

SOD knockdowns in the worm ''[[Caenorhabditis elegans|C. elegans]]'' do not cause major physiological disruptions. However, the lifespan of [[Caenorhabditis elegans|''C. elegans'']] can be extended by superoxide/[[catalase]] mimetics suggesting that [[oxidative stress]] is a major determinant of the rate of [[ageing|aging]].<ref name="pmid10968795">{{cite journal | vauthors = Melov S, Ravenscroft J, Malik S, Gill MS, Walker DW, Clayton PE, Wallace DC, Malfroy B, Doctrow SR, Lithgow GJ | display-authors = 6 | title = Extension of life-span with superoxide dismutase/catalase mimetics | journal = Science | volume = 289 | issue = 5484 | pages = 1567–1569 | date = September 2000 | pmid = 10968795 | doi = 10.1126/science.289.5484.1567 | s2cid = 21519801 | bibcode = 2000Sci...289.1567M }}</ref>

Knockout or null mutations in SOD1 are highly detrimental to aerobic growth in the budding yeast ''[[Saccharomyces cerevisiae]]'' and result in a dramatic reduction in post-diauxic lifespan. In wild-type [[Saccharomyces cerevisiae|''S. cerevisiae'']], [[DNA damage theory of aging|DNA damage]] rates increased 3-fold with age, but more than 5-fold in mutants deleted for either the ''[[SOD1]]'' or ''[[SOD2]]'' genes.<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 = Biochemical and Biophysical Research Communications | volume = 444 | issue = 2 | pages = 260–263 | date = February 2014 | pmid = 24462872 | doi = 10.1016/j.bbrc.2014.01.056 | bibcode = 2014BBRC..444..260M | hdl-access = free | hdl = 11147/5542 }}</ref>   [[Reactive oxygen species]] levels increase with age in these mutant strains and show a similar pattern to the pattern of [[DNA damage (naturally occurring)|DNA damage]] increase with age.  Thus it appears that superoxide dismutase plays a substantial role in preserving genome integrity during [[ageing|aging]] in ''S. cerevisiae''.
SOD2 knockout or null mutations cause growth inhibition on respiratory carbon sources in addition to decreased post-diauxic lifespan.

In the fission yeast ''[[Schizosaccharomyces pombe]]'', deficiency of mitochondrial superoxide dismutase [[SOD2]] accelerates chronological aging.<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 Biology International | volume = 40 | issue = 1 | pages = 100–106 | date = January 2016 | pmid = 26507459 | doi = 10.1002/cbin.10556 | s2cid = 205563521 | doi-access = free }}</ref>

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]]).<ref name="pmid21603028">{{cite journal | vauthors = Milani P, Gagliardi S, Cova E, Cereda C | title = SOD1 Transcriptional and Posttranscriptional Regulation and Its Potential Implications in ALS | journal = Neurology Research International | volume = 2011 | article-number = 458427 | year = 2011 | pmid = 21603028 | pmc = 3096450 | doi = 10.1155/2011/458427 | doi-access = free }}</ref><ref name="pmid8351519">{{cite journal | vauthors = Deng HX, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung WY, Getzoff ED, Hu P, Herzfeldt B, Roos RP | display-authors = 6 | title = Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase | journal = Science | volume = 261 | issue = 5124 | pages = 1047–1051 | date = August 1993 | pmid = 8351519 | doi = 10.1126/science.8351519 | bibcode = 1993Sci...261.1047D }}</ref><ref name="pmid17070848">{{cite journal | vauthors = Conwit RA | title = Preventing familial ALS: a clinical trial may be feasible but is an efficacy trial warranted? | journal = Journal of the Neurological Sciences | volume = 251 | issue = 1–2 | pages = 1–2 | date = December 2006 | pmid = 17070848 | doi = 10.1016/j.jns.2006.07.009 | s2cid = 33105812 | url = https://zenodo.org/record/1259145 }}</ref><ref name="pmid10970056">{{cite journal | vauthors = Al-Chalabi A, Leigh PN | title = Recent advances in amyotrophic lateral sclerosis | journal = Current Opinion in Neurology | volume = 13 | issue = 4 | pages = 397–405 | date = August 2000 | pmid = 10970056 | doi = 10.1097/00019052-200008000-00006 | s2cid = 21577500 }}</ref> The most common mutation in the U.S. is [[SOD1#A4V|A4V]], while the most intensely studied is [[SOD1#G93A|G93A]]. Inactivation of SOD1 causes [[hepatocellular carcinoma]].<ref name="pmid15531919"/> Diminished SOD3 activity has been linked to lung diseases such as [[acute respiratory distress syndrome]] (ARDS) or [[chronic obstructive pulmonary disease]] (COPD).<ref name="pmid16467073">{{cite journal | vauthors = Young RP, Hopkins R, Black PN, Eddy C, Wu L, Gamble GD, Mills GD, Garrett JE, Eaton TE, Rees MI | display-authors = 6 | title = Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function | journal = Thorax | volume = 61 | issue = 5 | pages = 394–399 | date = May 2006 | pmid = 16467073 | pmc = 2111196 | doi = 10.1136/thx.2005.048512 }}</ref><ref name="pmid19318538">{{cite journal | vauthors = 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 | display-authors = 6 | title = Superoxide dismutase 3, extracellular (SOD3) variants and lung function | journal = Physiological Genomics | volume = 37 | issue = 3 | pages = 260–267 | date = May 2009 | pmid = 19318538 | pmc = 2685504 | doi = 10.1152/physiolgenomics.90363.2008 }}</ref><ref name="pmid18787098">{{cite journal | vauthors = Gongora MC, Lob HE, Landmesser U, Guzik TJ, Martin WD, Ozumi K, Wall SM, Wilson DS, Murthy N, Gravanis M, Fukai T, Harrison DG | display-authors = 6 | title = Loss of extracellular superoxide dismutase leads to acute lung damage in the presence of ambient air: a potential mechanism underlying adult respiratory distress syndrome | journal = The American Journal of Pathology | volume = 173 | issue = 4 | pages = 915–926 | date = October 2008 | pmid = 18787098 | pmc = 2543061 | doi = 10.2353/ajpath.2008.080119 }}</ref> Superoxide dismutase is 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).{{citation needed|date=May 2019}}

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.),<ref name="pmid20399857">{{cite journal | vauthors = Gagliardi S, Cova E, Davin A, Guareschi S, Abel K, Alvisi E, Laforenza U, Ghidoni R, Cashman JR, Ceroni M, Cereda C | display-authors = 6 | title = SOD1 mRNA expression in sporadic amyotrophic lateral sclerosis | journal = Neurobiology of Disease | volume = 39 | issue = 2 | pages = 198–203 | date = August 2010 | pmid = 20399857 | doi = 10.1016/j.nbd.2010.04.008 | s2cid = 207065284 }}</ref> 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]].<ref name="pmid7999984">{{cite journal | vauthors = Groner Y, Elroy-Stein O, Avraham KB, Schickler M, Knobler H, Minc-Golomb D, Bar-Peled O, Yarom R, Rotshenker S | display-authors = 6 | title = Cell damage by excess CuZnSOD and Down's syndrome | journal = Biomedicine & Pharmacotherapy | volume = 48 | issue = 5–6 | pages = 231–240 | year = 1994 | pmid = 7999984 | doi = 10.1016/0753-3322(94)90138-4 }}</ref> In patients with thalassemia, SOD will increase as a form of compensation mechanism. However, in the chronic stage, SOD does not seem to be sufficient and tends to decrease due to the destruction of proteins from the massive reaction of oxidant-antioxidant.<ref>{{cite journal | vauthors = Rujito L, Mulatsih S, Sofro AS | title = Status of Superoxide Dismutase in Transfusion Dependent Thalassaemia | journal = North American Journal of Medical Sciences | volume = 7 | issue = 5 | pages = 194–198 | date = May 2015 | pmid = 26110130 | pmc = 4462814 | doi = 10.4103/1947-2714.157480 | doi-access = free }}</ref>

In mice, the extracellular superoxide dismutase (SOD3, ecSOD) contributes to the development of [[hypertension]].<ref name="pmid16864745">{{cite journal | vauthors = Gongora MC, Qin Z, Laude K, Kim HW, McCann L, Folz JR, Dikalov S, Fukai T, Harrison DG | display-authors = 6 | title = Role of extracellular superoxide dismutase in hypertension | journal = Hypertension | volume = 48 | issue = 3 | pages = 473–481 | date = September 2006 | pmid = 16864745 | doi = 10.1161/01.HYP.0000235682.47673.ab | doi-access = free }}</ref><ref name="pmid20008675">{{cite journal | vauthors = Lob HE, Marvar PJ, Guzik TJ, Sharma S, McCann LA, Weyand C, Gordon FJ, Harrison DG | display-authors = 6 | title = Induction of hypertension and peripheral inflammation by reduction of extracellular superoxide dismutase in the central nervous system | journal = Hypertension | volume = 55 | issue = 2 | pages = 277–83, 6p following 283 | date = February 2010 | pmid = 20008675 | pmc = 2813894 | doi = 10.1161/HYPERTENSIONAHA.109.142646 }}</ref> Inactivation of SOD2 in mice causes perinatal lethality.<ref name="pmid7493016"/>

== Medical uses ==

Supplementary superoxide dimutase has been suggested as a treatment to prevent [[bronchopulmonary dysplasia]] in infants who are born [[Preterm birth|preterm]], however, the effectiveness of his treatment is not clear.<ref>{{cite journal | vauthors = Albertella M, Gentyala RR, Paraskevas T, Ehret D, Bruschettini M, Soll R | title = Superoxide dismutase for bronchopulmonary dysplasia in preterm infants | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 10 | article-number = CD013232 | date = October 2023 | pmid = 37811631 | pmc = 10561150 | doi = 10.1002/14651858.CD013232.pub2 | collaboration = Cochrane Neonatal Group }}</ref>

== Research ==
SOD has been used in experimental treatment of chronic inflammation in [[Inflammatory bowel disease|inflammatory bowel]] conditions.<ref>{{cite journal | vauthors = Seguí J, Gironella M, Sans M, Granell S, Gil F, Gimeno M, Coronel P, Piqué JM, Panés J | display-authors = 6 | title = Superoxide dismutase ameliorates TNBS-induced colitis by reducing oxidative stress, adhesion molecule expression, and leukocyte recruitment into the inflamed intestine | journal = Journal of Leukocyte Biology | volume = 76 | issue = 3 | pages = 537–544 | date = September 2004 | pmid = 15197232 | doi = 10.1189/jlb.0304196 | s2cid = 15028921 }}</ref><ref name="pmid15197232">{{cite journal | vauthors = Seguí J, Gironella M, Sans M, Granell S, Gil F, Gimeno M, Coronel P, Piqué JM, Panés J | display-authors = 6 | title = Superoxide dismutase ameliorates TNBS-induced colitis by reducing oxidative stress, adhesion molecule expression, and leukocyte recruitment into the inflamed intestine | journal = Journal of Leukocyte Biology | volume = 76 | issue = 3 | pages = 537–544 | date = September 2004 | pmid = 15197232 | doi = 10.1189/jlb.0304196 | s2cid = 15028921 | doi-access = free }}</ref> SOD may ameliorate [[Cisplatin|cis-platinum]]-induced [[nephrotoxicity]] (rodent studies).<ref>{{cite journal | vauthors = McGinness JE, Proctor PH, Demopoulos HB, Hokanson JA, Kirkpatrick DS | title = Amelioration of cis-platinum nephrotoxicity by orgotein (superoxide dismutase) | journal = Physiological Chemistry and Physics | volume = 10 | issue = 3 | pages = 267–277 | year = 1978 | pmid = 733940 }}</ref> 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.<ref>{{cite journal | vauthors = Marberger H, Huber W, Bartsch G, Schulte T, Swoboda P | title = Orgotein: a new antiinflammatory metalloprotein drug evaluation of clinical efficacy and safety in inflammatory conditions of the urinary tract | journal = International Urology and Nephrology | volume = 6 | issue = 2 | pages = 61–74 | year = 1974 | pmid = 4615073 | doi = 10.1007/bf02081999 | s2cid = 23880216 }}</ref> For a time, bovine liver SOD even had regulatory approval in several European countries for such use. This was cut short by concerns about [[prion disease]].{{Citation needed|date=August 2017}}

An [[Superoxide dismutase mimetics|SOD-mimetic]] agent, [[TEMPOL]], is currently in clinical trials for radioprotection and to prevent radiation-induced [[dermatitis]].<ref>{{ClinicalTrialsGov|NCT01324141|Topical MTS-01 for Dermatitis During Radiation and Chemotherapy for Anal Cancer}}</ref> TEMPOL and similar SOD-mimetic nitroxides exhibit a multiplicity of actions in diseases involving oxidative stress.<ref>{{cite journal | vauthors = Wilcox CS | title = Effects of tempol and redox-cycling nitroxides in models of oxidative stress | journal = Pharmacology & Therapeutics | volume = 126 | issue = 2 | pages = 119–145 | date = May 2010 | pmid = 20153367 | pmc = 2854323 | doi = 10.1016/j.pharmthera.2010.01.003 }}</ref>

The synthesis of enzymes such as superoxide dismutase, [[L-ascorbate oxidase]],  and Delta 1 [[DNA polymerase]] is initiated in plants with the activation of [[gene]]s associated with stress conditions for plants.<ref name="FH">{{cite journal |first1= Kamile |last1= Ulukapi | first2= Ayse Gul |last2= Nasircilar | title = The role of exogenous glutamine on germination, plant development and transcriptional expression of some stress-related genes in onion under salt stres | journal = [[Folia Horticulturae]] | volume = 36 | issue = 1 | pages = 19–34 | date = February 2024 | pmid = | doi = 10.2478/fhort-2024-0002 | publisher = Polish Society of Horticultural Science | s2cid = 19887643 | doi-access = free }}</ref> The most common stress conditions can be injury, drought or [[soil salinity]]. Limiting this process initiated by the conditions of strong soil salinity can be achieved by administering exogenous [[glutamine]] to plants. The decrease in the level of expression of genes responsible for the synthesis of superoxide dismutase increases with the increase in glutamine concentration.<ref name="FH"/>

== Cosmetic uses ==

SOD may reduce free radical damage to skin—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.<ref name="pmid15090266">{{cite journal | vauthors = Campana F, Zervoudis S, Perdereau B, Gez E, Fourquet A, Badiu C, Tsakiris G, Koulaloglou S | display-authors = 6 | title = Topical superoxide dismutase reduces post-irradiation breast cancer fibrosis | journal = Journal of Cellular and Molecular Medicine | volume = 8 | issue = 1 | pages = 109–116 | year = 2004 | pmid = 15090266 | pmc = 6740277 | doi = 10.1111/j.1582-4934.2004.tb00265.x | citeseerx = 10.1.1.336.8033 }}</ref> Superoxide dismutase is known to reverse [[fibrosis]], possibly through de-[[Cellular differentiation|differentiation]] of [[myofibroblasts]] back to [[fibroblasts]].<ref name="pmid11134893">{{cite journal | vauthors = Vozenin-Brotons MC, Sivan V, Gault N, Renard C, Geffrotin C, Delanian S, Lefaix JL, Martin M | display-authors = 6 | title = Antifibrotic action of Cu/Zn SOD is mediated by TGF-beta1 repression and phenotypic reversion of myofibroblasts | journal = Free Radical Biology & Medicine | volume = 30 | issue = 1 | pages = 30–42 | date = January 2001 | pmid = 11134893 | doi = 10.1016/S0891-5849(00)00431-7 }}</ref>{{explain| date=April 2013}}

== Commercial sources ==

SOD is commercially obtained from marine [[phytoplankton]], bovine liver, [[horseradish]], [[cantaloupe]], and certain bacteria. For therapeutic purpose, SOD is usually injected locally. There is no evidence that ingestion of unprotected SOD or SOD-rich foods can have any physiological effects, as all ingested SOD is [[Protein (nutrient)#Digestion|broken down]] into [[amino acid]]s before [[intestinal permeability|being absorbed]]. However, ingestion of SOD bound to wheat proteins could improve its therapeutic activity, at least in theory.<ref name=Romao2015>{{cite journal | vauthors = Romao S | title = Therapeutic value of oral supplementation with melon superoxide dismutase and wheat gliadin combination | journal = Nutrition | volume = 31 | issue = 3 | pages = 430–436 | date = March 2015 | pmid = 25701330 | doi = 10.1016/j.nut.2014.10.006 | doi-access = free }}</ref>

== See also ==
* [[Catalase]]
* [[Glutathione peroxidase]]
* [[NADPH oxidase]], an enzyme which ''produces'' superoxide
* [[Peroxidase]]

== References ==
{{reflist|33em}}

== External links ==
* {{OMIM|105400}} (ALS)
* [http://alsod.iop.kcl.ac.uk/ The ALS Online Database]
* [http://www.worthington-biochem.com/SODBE/default.html A short but substantive overview of SOD and its literature.]
* [http://www.senescence.info/causes_of_aging.html Damage-Based Theories of Aging] Includes a discussion of the roles of SOD1 and SOD2 in aging.
* [http://www.pcrm.org Physicians' Comm. For Responsible Med. ]
* [http://www.sigmaaldrich.com/life-science/metabolomics/enzyme-explorer/cell-signaling-enzymes/superoxide-dismutase.html SOD and Oxidative Stress Pathway Image]
* [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P00441 PDBe-KB] provides an overview of all the structure information available in the PDB for Human Superoxide dismutase [Cu-Zn]
* [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P04179 PDBe-KB] provides an overview of all the structure information available in the PDB for Human Superoxide dismutase [Mn], mitochondrial
* [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P08294 PDBe-KB] provides an overview of all the structure information available in the PDB for Human Extracellular superoxide dismutase [Cu-Zn]

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[[Category:Antioxidants]]
[[Category:Metalloproteins]]
[[Category:Oxidoreductases]]
[[Category:EC 1.15.1]]
[[Category:Copper enzymes]]
[[Category:Aging-related enzymes]]
[[Category:Iron enzymes]]
[[Category:Zinc enzymes]]
[[Category:Nickel enzymes]]
[[Category:Manganese enzymes]]