Superoxide dismutase

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 = Cu (n=1); Mn (n=2); 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.

{{Further|Nickel superoxide dismutase|Iron superoxide dismutase}}

Irwin Fridovich and Joe McCord at Duke University discovered the enzymatic activity of superoxide dismutase in 1968.{{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 }} 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".{{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 }} 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.{{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 }}

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 – most commonly used by eukaryotes, including humans. The cytosols of virtually all 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.{{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 }}. 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.{{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 }}
• File:Iron Superoxide Dismutase Active Site.pngIron or manganese – used by prokaryotes and protists, and in mitochondria and chloroplasts
• 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 E. coli) contain both. Fe-SOD can also 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 – 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 hydroxy ligand, depending on the Mn oxidation state (respectively II and III).{{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 }}
• 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.{{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 }}{{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 }}

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.{{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 }}{{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 }}

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 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).{{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 }} 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.{{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 }}{{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 }} To be specific, molecular O₂ 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. SODs catalyze the production of O₂ 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.

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.{{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 }}

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 ({{chem|O|2|-}}) spontaneously dismutes to O₂ and hydrogen peroxide ({{chem|H|2|O|2}}) quite rapidly (~10⁵ M⁻¹s⁻¹ 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_cat/K_M (an approximation of catalytic efficiency) of any known enzyme (~7 × 10⁹ M⁻¹s⁻¹),{{cite book | vauthors = Heinrich PC, Löffler G, Petrifies PE | title = Biochemie und Pathobiochemie (Springer-Lehrbuch) | edition = German| publisher = Springer | location = Berlin | year = 2006 | pages = 123 | isbn = 978-3-540-32680-9 }} 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.{{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 }}

The 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 anaerobic to 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 (O₂) in the atmosphere (Miller 2012). However, evidence suggests that the origination of reactive oxygen species (ROS) took place as early as 4.1 to 3.5 bya (Inupakutika et al. 2016).Inupakutika et al. (2016). The evolution of reactive oxygen species metabolism, Journal of Experimental Botany, 67(21): 5933–5943. https://doi.org/10.1093/jxb/erw382. 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.

Atmospheric and oceanic compositions have drastically changed since the formation of early Earth. One significant 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).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. 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).Kasting (2013). What caused the rise of atmospheric O2?

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

The atmospheric accumulation of highly reactive O₂ likely exercised a strong selective pressure against anaerobic organisms, and led to the adaptive evolution of oxygen utilization in metabolism (Boden et al. 2021).Boden et al. (2021). Timing the evolution of antioxidant enzymes in cyanobacteria. Nat Commun 12, 4742. https://doi.org/10.1038/s41467-021-24396-y. 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 (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 O₂ electron flux is accompanied by an increased risk of ROS formation, which can induce irreversible damage to cellular organelles and their processes (Case 2017).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. In response to the accumulation of the hazardous metabolic byproducts of aerobic respiration, biological systems evolved various strategies to counteract O₂ toxicity.

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 O₂ 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 O₂ (Wolfe-Simon et al. 2005; Inupakutika et al. 2016).

The oxidizing capacity of O₂ 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 (O2•⁻) is the most common reactive free-radical formed by the univalent reduction of O₂. 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).Zewen et al. (2018). Role of ROS and Nutritional Antioxidants in Human Diseases. Front. Physiol., 9. doi.org/10.3389/fphys.2018.00477.    

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.

Studies examining the phylogenetic distribution of SODs support the proposal that the major 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).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. 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 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(s) used to support its structural stability and catalytic activity (Case 2017): either manganese (MnSOD), nickel (NiSOD), or both copper and zinc (Miller 2012).Miller (2012). Superoxide dismutases: Ancient enzymes and new insights, FEBS Open Bio, 586, doi:10.1016/j.febslet.2011.10.048. 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.

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 oxidation and reduction potentials of each metal is thought to have been advantageous to organism survival, allowing them to exist in environments with varying O₂ concentration and metal availability.

The most modern SOD family is believed to utilize both Cu and Zn ions (CuZnSOD). The absence of CuZnSODs from 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).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.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.

The family of Ni-containing SODs (NiSOD) is less understood. Evidence suggests that these isoforms are largely distributed among marine bacteria and algae (Wolfe-Simon et al. 2005; Dupont et al. 2008).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.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. 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.

SOD1 is an extremely stable protein. In the holo form (both copper and zinc bound) the melting point is > 90 °C. In the apo form (no copper or zinc bound) the melting point is ~60 °C.{{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 }} By differential scanning calorimetry (DSC), holo SOD1 unfolds by a two-state mechanism: from dimer to two unfolded monomers. In chemical denaturation experiments, holo SOD1 unfolds by a three-state mechanism with observation of a folded monomeric intermediate.{{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 }}

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.{{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 }} Mice lacking SOD1 develop a wide range of pathologies, including hepatocellular carcinoma,{{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 }} an acceleration of age-related muscle mass loss,{{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 }} 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.{{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 }} Knockout mice of any SOD enzyme are more sensitive to the lethal effects of superoxide-generating compounds, such as paraquat and diquat (herbicides).

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 is associated with reduced lifespan.{{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 }} The accumulation of neuronal and muscular ROS appears to contribute to age-associated impairments. When overexpression of mitochondrial SOD2 is induced, the lifespan of adult Drosophila is extended.{{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 }}

Among black garden ants (Lasius niger), the lifespan of queens is an order of magnitude greater than of workers despite no systematic nucleotide sequence difference between them.{{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 }} 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.

SOD knockdowns in the worm C. elegans do not cause major physiological disruptions. However, the lifespan of C. elegans can be extended by superoxide/catalase mimetics suggesting that oxidative stress is a major determinant of the rate of aging.{{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 }}

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 S. cerevisiae, DNA damage rates increased 3-fold with age, but more than 5-fold in mutants deleted for either the SOD1 or SOD2 genes.{{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 | hdl-access = free | hdl = 11147/5542 }} Reactive oxygen species levels increase with age in these mutant strains and show a similar pattern to the pattern of DNA damage increase with age. Thus it appears that superoxide dismutase plays a substantial role in preserving genome integrity during 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.{{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 }}

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.

Mutations in the first SOD enzyme (SOD1) can cause familial amyotrophic lateral sclerosis (ALS, a form of motor neuron disease).{{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 | pages = 458427 | year = 2011 | pmid = 21603028 | pmc = 3096450 | doi = 10.1155/2011/458427 | doi-access = free }}{{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 }}{{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 }}{{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 }} The most common mutation in the U.S. is A4V, while the most intensely studied is G93A. Inactivation of SOD1 causes hepatocellular carcinoma. Diminished SOD3 activity has been linked to lung diseases such as acute respiratory distress syndrome (ARDS) or chronic obstructive pulmonary disease (COPD).{{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 }}{{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 }}{{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 }} 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.),{{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 }} 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.{{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 }} 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.{{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 }}

In mice, the extracellular superoxide dismutase (SOD3, ecSOD) contributes to the development of hypertension.{{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 }}{{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 }} Inactivation of SOD2 in mice causes perinatal lethality.

Supplementary superoxide dimutase has been suggested as a treatment to prevent bronchopulmonary dysplasia in infants who are born preterm, however, the effectiveness of his treatment is not clear.{{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 | pages = CD013232 | date = October 2023 | pmid = 37811631 | pmc = 10561150 | doi = 10.1002/14651858.CD013232.pub2 | collaboration = Cochrane Neonatal Group }}

SOD has been used in experimental treatment of chronic inflammation in inflammatory bowel conditions.{{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 }}{{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 }} SOD may ameliorate cis-platinum-induced nephrotoxicity (rodent studies).{{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 }} 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.{{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 }} 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 SOD-mimetic agent, TEMPOL, is currently in clinical trials for radioprotection and to prevent radiation-induced dermatitis.{{ClinicalTrialsGov|NCT01324141|Topical MTS-01 for Dermatitis During Radiation and Chemotherapy for Anal Cancer}} TEMPOL and similar SOD-mimetic nitroxides exhibit a multiplicity of actions in diseases involving oxidative stress.{{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 }}

The synthesis of enzymes such as superoxide dismutase, L-ascorbate oxidase, and Delta 1 DNA polymerase is initiated in plants with the activation of genes associated with stress conditions for plants.{{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 }} 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.

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.{{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 }} Superoxide dismutase is known to reverse fibrosis, possibly through de-differentiation of myofibroblasts back to fibroblasts.{{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 }}{{explain| date=April 2013}}

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 broken down into amino acids before being absorbed. However, ingestion of SOD bound to wheat proteins could improve its therapeutic activity, at least in theory.{{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 }}

• Catalase
• Glutathione peroxidase
• NADPH oxidase, an enzyme which produces superoxide
• Peroxidase

{{reflist|33em}}

• {{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:Metalloproteins

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