| caption = Structure of a human Mn superoxide dismutase 2 tetramer.<ref name="pmid8605177"/>
}}
'''Superoxide dismutase''' ('''SOD''', {{EC number|1.15.1.1}}) is an [[enzyme]] that alternately catalyzes the [[dismutation]] (or partitioning) of the [[superoxide]] (O<sub>2</sub><sup>−</sup>) [[radical (chemistry)|radical]] into either ordinary molecular [[oxygen]] (O<sub>2</sub>) or [[hydrogen peroxide]] (H<sub>2</sub>O<sub>2</sub>). 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, Al Nashef IM | year = 2016 | title = Superoxide Ion: Generation and Chemical Implications | url = | journal = Chem. Rev. | volume = 116 | issue = 5| pages = 3029–3085 | doi = 10.1021/acs.chemrev.5b00407 }}</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 a different mechanism to prevent damage from reactive (O<sub>2</sub><sup>−</sup>).
== Chemical reaction ==
SODs catalyze the [[disproportionation]] of superoxide:
where M = [[Copper|Cu]] (n=1) ; [[manganese|Mn]] (n=2) ; [[iron|Fe]] (n=2) ; [[nickel|Ni]] (n=2).
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 ===
[[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 = 6049–55 | date = Nov 1969 | pmid = 5389100 }}</ref> 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".<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 = 363–9 | 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 = 674–80 | date = Sep 1967 | pmid = 4292999 | pmc = 1706241 | doi = }}</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 = J. Mol. Biol. | volume = 160 | issue = 2 | pages = 181–217 |date=September 1982 | pmid = 7175933 | doi = 10.1016/0022-2836(82)90174-7| url = | issn = }}</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 = 453–8 | date = Feb 2006 | pmid = 16443160 | doi = 10.1016/j.freeradbiomed.2005.08.045 }}</ref>]]
| [[File:94-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 an SOD enzyme with [[copper]] and [[zinc]] (Cu-Zn-SOD). For example, Cu-Zn-SOD available commercially is normally purified from bovine red blood cells. The bovine Cu-Zn enzyme is a homodimer of molecular weight 32,500. It was the first SOD whose atomic-detail crystal structure was solved, in 1975.<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 = 1349–53 | date = Apr 1975 | pmid = 1055410 | pmc = 432531 | doi = 10.1073/pnas.72.4.1349 }}.</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 = 284–7 | year = 1983 | pmid = 6316150 | doi = 10.1038/306284a0 }}</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 = 107–18 | date = Oct 1992 | pmid = 1394426 | doi = 10.1016/0092-8674(92)90270-M }}</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 = 8038–47 | date = Jun 2004 | pmid = 15209499 | doi = 10.1021/bi0496081 }}</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 = 8569–74 | date = Jun 2004 | pmid = 15173586 | pmc = 423235 | doi = 10.1073/pnas.0308514101 }}</ref>
{|
|- valign=top
|{{Pfam_box
| 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 | title = Structure solution and molecular dynamics refinement of the yeast Cu,Zn enzyme superoxide dismutase | journal = Acta Crystallogr. B | volume = 47 | issue = 6| pages = 918–27 |date=December 1991 | pmid = 1772629 | doi = 10.1107/S0108768191004949 }}</ref>
| Pfam = PF00080
| InterPro = IPR001424
| SMART =
| PROSITE = PDOC00082
| SCOP =1sdy
| TCDB =
| OPM family =
| OPM protein =
}}
|{{Pfam_box
| 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 =
}}
|{{Pfam_box
| 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 =
}}
|{{Pfam_box
| Symbol = Sod_Ni
| Name = Nickel superoxide dismutase
| image = 94-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 = 145–50 | date = Apr 2001 | pmid = 11286918 | doi = 10.1016/S1360-1385(01)01898-2 | url = http://linkinghub.elsevier.com/retrieve/pii/S1360-1385(01)01898-2 }}</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 | 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 = 984–94 | date = Jul 2006 | pmid = 16766574 | doi = 10.1093/pcp/pcj071 }}</ref>
[[Image:SOD.gif|thumb|left|250px|Structure of the monomeric unit of human superoxide dismutase 2]]
=== Human ===
{{protein
Three forms of superoxide dismutase are present in humans, in all other [[mammals]], and most [[chordates]]. [[SOD1]] is located in the [[cytoplasm]], [[SOD2]] in the [[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).
| Name = [[SOD1|superoxide dismutase 1, soluble]]
{|
| caption =
|- valign=top
| image =
|{{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 | title = Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis | journal = J. Biol. Chem. | volume = 283 | issue = 23 | pages = 16169–77 |date=June 2008 | pmid = 18378676| doi = 10.1074/jbc.M801522200 | url = | issn = | pmc = 2414278 }}</ref>
| image = 2c9v CuZn rib n site.png
| width =
| width =
| HGNCid = 11179
| HGNCid = 11179
Line 22:
Line 139:
| LocusSupplementaryData =
| LocusSupplementaryData =
}}
}}
{{protein
|{{infobox protein
| Name = [[SOD2|superoxide dismutase 2, mitochondrial]]
| Name = [[SOD2|SOD2, mitochondrial]]
| caption =
| 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 | title = Human mitochondrial manganese superoxide dismutase polymorphic variant Ile58Thr reduces activity by destabilizing the tetrameric interface | journal = Biochemistry | volume = 35 | issue = 14 | pages = 4287–97 |date=April 1996 | pmid = 8605177 | doi = 10.1021/bi951892w | url = | issn = }}</ref>
| image =
| image = SODsite.gif
| width =
| width =
| HGNCid = 11180
| HGNCid = 11180
| Symbol = [[SOD2]]
| Symbol = [[SOD2]]
| AltSymbols =
| AltSymbols = Mn-SOD; IPO-B; MVCD6
| EntrezGene = 6648
| EntrezGene = 6648
| OMIM = 147460
| OMIM = 147460
Line 41:
Line 158:
| LocusSupplementaryData =
| LocusSupplementaryData =
}}
}}
{{protein
|{{infobox protein
| Name = superoxide dismutase 3, extracellular
| Name = [[SOD3|SOD3, extracellular]]
| caption =
| 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 = J. Mol. Biol. | volume = 388 | issue = 2 | pages = 310–26 |date=May 2009 | pmid = 19289127 | doi = 10.1016/j.jmb.2009.03.026 | url = | issn = }}</ref>
| image =
| image = SOD3_2JLP.png
| width =
| width =
| HGNCid = 11181
| HGNCid = 11181
| Symbol = SOD3
| Symbol = [[SOD3]]
| AltSymbols =
| AltSymbols = EC-SOD; MGC20077
| EntrezGene = 6649
| EntrezGene = 6649
| OMIM = 185490
| OMIM = 185490
Line 56:
Line 173:
| ECnumber = 1.15.1.1
| ECnumber = 1.15.1.1
| Chromosome = 4
| Chromosome = 4
| Arm =
| Arm = p
| Band =
| Band = ter
| LocusSupplementaryData = pter-q21
| LocusSupplementaryData = -q21
}}
}}
{{SI}}
|}
==Overview==
=== Plants ===
The enzyme '''superoxide dismutase''' ('''SOD''', {{EC number|1.15.1.1}}), catalyzes the [[dismutation]] of [[superoxide]] into [[oxygen]] and [[hydrogen peroxide]]. As such, it is an important [[antioxidant]] defense in nearly all cells exposed to oxygen. One of the exceedingly rare exceptions is ''[[Lactobacillus plantarum]]'' and related [[lactobacillus|lactobacilli]], which use a different mechanism.
==Reaction==
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 = 1331–41 | date = May 2002 | pmid = 11997379 | doi = 10.1093/jexbot/53.372.1331 }}</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, Nicholas | title = Tansley Review No. 52 The role of active oxygen in the response of plants to water deficit and desiccation | journal = The New Phytologist | volume = 125 | year = 1993}}</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 }}</ref> To be specific, molecular O<sub>2</sub> is reduced to O<sub>2</sub><sup>−</sup> (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 H<sub>2</sub>O<sub>2</sub> from superoxide (O<sub>2</sub><sup>−</sup>), which results in less harmful reactants.
The SOD-catalysed [[dismutation]] of [[superoxide]] may be written with the following half-reactions :
where M = [[Cu]] (n=1) ; [[manganese|Mn]] (n=2) ; [[iron|Fe]] (n=2) ; [[nickel|Ni]] (n=2).
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"/>
In this reaction the [[oxidation state]] of the metal cation oscillates between n and n+1.
=== Bacteria ===
==Types==
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 | title = Superoxide dismutase C is required for intracellular survival and virulence of Burkholderia pseudomallei | journal = Microbiology | volume = 157 | issue = Pt 8 | pages = 2392–400 | date = Aug 2011 | pmid = 21659326 | doi = 10.1099/mic.0.050823-0 }}</ref>
===General===
SOD was discovered by Irwin Fridovich and Joe McCord, which prior were known as several metalloproteins with unknown function (for example, CuZnSOD was known as erythrocuprein). Several common forms of SOD exist: they are proteins cofactored with [[copper proteins|copper]] and [[zinc]], or [[manganese]], [[iron]], or [[nickel]].
* The [[cytosol]]s of virtually all [[eukaryote|eukaryotic]] cells contain an SOD enzyme with [[copper]] and [[zinc]] (Cu-Zn-SOD). (For example, Cu-Zn-SOD available commercially is normally purified from the bovine erythrocytes: [[Protein Data Bank|PDB]] [http://www.rcsb.org/pdb/cgi/explore.cgi?pid=26081034364676&page=0&pdbId=1SXA 1SXA], EC 1.15.1.1). The Cu-Zn enzyme is a homodimer of molecular weight 32,500. The two subunits are joined primarily by hydrophobic and electrostatic interactions. The ligands of copper and zinc are [[histidine]] side chains.
* Chicken liver (and nearly all other) [[mitochondria]], and many [[bacteria]] (such as ''[[E. coli]]'') contain a form with [[manganese]] (Mn-SOD). (For example, the Mn-SOD found in a human mitochondrion: [[Protein Data Bank|PDB]] [http://www.rcsb.org/pdb/navbarsearch.do?inputQuickSearch=1N0J 1N0J], EC 1.15.1.1). 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).
* ''E. coli'' and many other bacteria also contain a form of the enzyme with [[iron]] (Fe-SOD); some bacteria contain Fe-SOD, others Mn-SOD, and some contain both. (For the ''E. coli'' Fe-SOD: [[Protein Data Bank|PDB]] [http://www.rcsb.org/pdb/cgi/explore.cgi?pid=28071034364826&page=0&pdbId=1ISA 1ISA], EC 1.15.1.1). The active sites of Mn and Fe superoxide dismutases contain the same type of amino acids side chains.
[[Image:SODsite.gif||left|thumb|Structure of the active site of human superoxide dismutase 2]]
----
== Biochemistry ==
===Human===
SOD out-competes damaging reactions of superoxide, thus protecting the cell from superoxide toxicity.
In humans, three forms of superoxide dismutase are present. [[SOD1]] is located in the [[cytoplasm]], [[SOD2]] in the [[mitochondrion|mitochondria]] and SOD3 is [[extracellular]]. The first is a [[dimer]] (consists of two units), while the others are tetramers (four subunits). [[SOD1]] and SOD3 contain copper and zinc, while SOD2 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).
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 (O<sub>2</sub><sup>−</sup>) spontaneously dismutes to O<sub>2</sub> and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) 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]].
A microtiter plate assay for SOD is available<ref>{{cite journal | author = A.V. Peskin, C.C. Winterbourn | title = A microtiter plate assay for superoxide dismutase using a water-soluble tetrazolium salt (WST-1) | journal = Clinica Chimica Acta | year = 2000 | volume = 293 | pages = 157–166 }}</ref>.
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 x 10<sup>9</sup> M<sup>−1</sup>s<sup>−1</sup>),<ref name="isbn3-540-32680-4">{{cite book | last1 = Heinrich | first1 = Peter C. | first2 = Georg | last2 = Löffler | first3 = Petro E. | last3 = Petrifies | name-list-format = vanc | title = Biochemie und Pathobiochemie (Springer-Lehrbuch) (German Edition) | edition = | publisher = Springer | location = Berlin | year = 2006 | origyear = | pages = 123 | quote = | isbn = 3-540-32680-4 }}</ref> this reaction being limited only by the frequency of collision between itself and superoxide. That is, the reaction rate is "diffusion-limited".
==Biochemistry==
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 = 13399–405 | date = Jun 1995 | pmid = 7768942 | doi = 10.1074/jbc.270.22.13399 }}</ref>
Simply-stated, SOD outcompetes 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 its main reactions are with itself (dismutation) or with another biological radical such as [[nitric oxide]] (NO). The superoxide anion radical (O<sub>2</sub><sup>-</sup>) spontaneously dismutes to O<sub>2</sub> and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) quite rapidly (~10<sup>5</sup> M<sup>-1</sup> s<sup>-1</sup> at pH 7). SOD is biologically necessary because superoxide reacts even faster with certain targets such as NO radical, which makes peroxynitrite. Similarly, 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 has the fastest [[turnover number]] (reaction rate with its substrate) of any known enzyme (~10<sup>9</sup> M<sup>-1</sup> s<sup>-1</sup>), this reaction being only limited by the frequency of collision between itself and superoxide. That is, the reaction rate is "diffusion limited".
==Physiology==
== Stability and folding mechanism ==
Superoxide is one of the main [[reactive oxygen species]] in the cell and as such, 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, amidst massive [[oxidative stress]]<ref name="ref3">[[Image:Free_text.png]] {{cite journal | first = Y. | last = Li, et al. | title = Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. | journal = Nat. Genet. | year = 1995 | volume = 11 | issue = | pages = 376-381 }}</ref>. Mice lacking SOD1 develop a wide range of pathologies, including hepatocellular carcinoma<ref name="ref4">[[Image:Free_text.png]] {{cite journal | first = S. | last = Elchuri, et al. | title = CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. | journal = Oncogene | year = 2005 | volume = 24 | issue = | pages = 367-380 }}</ref>, an acceleration of age-related muscle mass loss<ref>[[Image:Free_text.png]] {{cite journal | first = F. L.| last = Muller, et al. | title = Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy. | journal = Free Radic. Biol. Med | year = 2006 | volume = 40 | issue = | pages = 1993-2004 }}</ref>, an earlier incidence of cataracts and a reduced lifespan. Mice lacking SOD3 do not show any obvious defects and exhibit a normal lifespan<ref>[[Image:Free_text.png]] {{cite journal | first = M. L.| last = Sentman, et al. | title = Phenotypes of mice lacking extracellular superoxide dismutase and copper- and zinc-containing superoxide dismutase | journal = J. Biol. Chem. | year = 2006 | volume = 281 | issue = | pages = 6904-6909 | doi = 10.1074/jbc.M510764200 }}</ref>.
==Role in disease==
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.<ref name=":0">{{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 = 6184–93 | date = March 2006 | pmid = 16407238 | doi = 10.1074/jbc.M509496200 }}</ref> By [[differential scanning calorimetry]] (DSC), holo SOD1 [[Protein folding|unfolds]] by a two-state mechanism: from dimer to two unfolded monomers.<ref name=":0" /> 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 = 106–23 | date = January 2006 | pmid = 16307756 | doi = 10.1016/j.jmb.2005.10.042 }}</ref>
Mutations in the first SOD enzyme ([[SOD1]]) have been linked to familial [[amyotrophic lateral sclerosis]] (ALS, a form of [[motor neuron disease]]). The other two types have not been linked to any human diseases, however, in mice inactivation of SOD2 causes perinatal lethality<ref name="ref3" /> and inactivation of SOD1 causes [[hepatocellular carcinoma]]<ref name="ref4" />. Mutations in [[SOD1 ]] can cause familial ALS, by a mechanism that is presently not understood, but not due to loss of enzymatic activity. Overexpression of SOD1 has been linked to [[Down's syndrome]]<ref>[[Image:Free_text.png]] {{cite journal | first = Y. et al.| last = Groner | title = Cell damage by excess CuZnSOD and Down's syndrome. | journal = Biomed Pharmacother. | year = 1994 | volume = 48 | issue = | pages = 231-40 | pmid = 7999984 }}</ref>. The veterinary antiinflammatory drug "Orgotein" is purified bovine liver superoxide dismutase.
==Delivery systems==
== Physiology ==
Superoxide dismutase is effective as a [[nutritional supplement]] when bound to the polymeric films of wheat matrix [[gliadin]] (a delivery method also known as [[glisodin]]). Gliadin is an ideal carrier because it protects SOD from stomach acid and [[enzymes]] found in the [[digestive system]] which break down its molecular structure. This has been established in a variety of animal studies and human clinical trials, in which SOD's generally high [[antioxidant]] capacity is kept intact under a variety of conditions.
==Cosmetic uses==
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 | title = Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase | journal = Nature Genetics | volume = 11 | issue = 4 | pages = 376–81 | date = Dec 1995 | pmid = 7493016 | doi = 10.1038/ng1295-376 }}</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 | title = CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life | journal = Oncogene | volume = 24 | issue = 3 | pages = 367–80 | date = Jan 2005 | pmid = 15531919 | doi = 10.1038/sj.onc.1208207 }}</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 | 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 = Jun 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 = 6904–9 | date = Mar 2006 | pmid = 16377630 | doi = 10.1074/jbc.M510764200 }}</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).
SOD is used in cosmetic products to reduce free radical damage to skin, for example to reduce fibrosis following radiation for breast cancer. Studies of this 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>[[Image:Free_text.png]] {{cite journal | first = F. | last = Campana | title = Topical superoxide dismutase reduces post-irradiation breast cancer fibrosis | journal = J. Cell. Mol. Med. | year = 2004 | volume = 8 | issue = 1 | pages = 109–116 | format = available free | pmid = 15090266 | url = http://www.jcmm.org/en/pdf/8/1/jcmm008.001.11.pdf }}</ref> Superoxide dismutase is known to reverse fibrosis, perhaps through reversion of [[myofibroblasts]] back to [[fibroblasts]].<ref>{{cite journal |title=Antifibrotic action of Cu/Zn SOD is mediated by TGF-beta1 repression and phenotypic reversion of myofibroblasts |accessdate=2007-11-28 |author= Vozenin-Brotons MC |coauthors= Sivan V, Gault N, Renard C, Geffrotin C, Delanian S, Lefaix JL, Martin M |date=[[January 1]] [[2001]] |journal=Free Radic Biol Med |publisher=Elsevier |volume=30 |issue=1 |pages=30-42 |pmid=11134893}}</ref>
==References==
''[[Drosophila]]'' lacking SOD1 have a dramatically shortened lifespan, whereas flies lacking SOD2 die before birth.
<div class="references-small">{{reflist|2}}</div>
==See also==
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 |title=Extension of life-span with superoxide dismutase/catalase mimetics |journal=Science |volume=289 |issue=5484 |pages=1567–9 |date=September 2000 |pmid=10968795 |doi= |url=}}</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=Biochem. Biophys. Res. Commun. |volume=444 |issue=2 |pages=260–3 |date=February 2014 |pmid=24462872 |doi=10.1016/j.bbrc.2014.01.056 |url=}}</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 Biol. Int. |volume=40 |issue=1 |pages=100–6 |date=January 2016 |pmid=26507459 |doi=10.1002/cbin.10556 |url=}}</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 | issue = | pages = 458427 | year = 2011 | pmid = 21603028 | pmc = 3096450 | doi = 10.1155/2011/458427 }}</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 | title = Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase | journal = Science | volume = 261 | issue = 5124 | pages = 1047–51 | date = Aug 1993 | pmid = 8351519 | doi = 10.1126/science.8351519 }}</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 = Dec 2006 | pmid = 17070848 | doi = 10.1016/j.jns.2006.07.009 }}</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 = Aug 2000 | pmid = 10970056 | doi = 10.1097/00019052-200008000-00006 | url = http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1350-7540&volume=13&issue=4&spage=397 }}</ref> The most common mutation in the U.S. is [[SOD1#A4V|A4V]], while the most intensely studied is [[SOD1#G93A|G93A]]. The other two isoforms of SOD have not been linked to any human diseases, however, in mice inactivation of SOD2 causes perinatal lethality<ref name="pmid7493016"/> and inactivation of SOD1 causes [[hepatocellular carcinoma]].<ref name="pmid15531919"/> 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 | title = SOD1 mRNA expression in sporadic amyotrophic lateral sclerosis | journal = Neurobiology of Disease | volume = 39 | issue = 2 | pages = 198–203 | date = Aug 2010 | pmid = 20399857 | doi = 10.1016/j.nbd.2010.04.008 }}</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 | title = Cell damage by excess CuZnSOD and Down's syndrome | journal = Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie | volume = 48 | issue = 5–6 | pages = 231–40 | 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 = 194–8 | date = May 2015 | pmid = 26110130 | doi = 10.4103/1947-2714.157480 | url = http://www.najms.org/text.asp?2015/7/5/194/157480 | pmc=4462814}}</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 | title = Role of extracellular superoxide dismutase in hypertension | journal = Hypertension | volume = 48 | issue = 3 | pages = 473–81 | date = Sep 2006 | pmid = 16864745 | doi = 10.1161/01.HYP.0000235682.47673.ab }}</ref><ref name="pmid20008675">{{cite journal | vauthors = Lob HE, Marvar PJ, Guzik TJ, Sharma S, McCann LA, Weyand C, Gordon FJ, Harrison DG | 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 = Feb 2010 | pmid = 20008675 | pmc = 2813894 | doi = 10.1161/HYPERTENSIONAHA.109.142646 }}</ref> 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 | title = Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function | journal = Thorax | volume = 61 | issue = 5 | pages = 394–9 | 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 | title = Superoxide dismutase 3, extracellular (SOD3) variants and lung function | journal = Physiological Genomics | volume = 37 | issue = 3 | pages = 260–7 | 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 | 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 = 915–26 | date = Oct 2008 | pmid = 18787098 | pmc = 2543061 | doi = 10.2353/ajpath.2008.080119 }}</ref>
Superoxide dismutase is also not expressed in neural crest cells in the developing [[fetus]]. Hence, high levels of free radicals can cause damage to them and induce dysraphic anomalies (neural tube defects).
A cross-sectional study in humans suggests that serum SOD could be a marker of cardiovascular alterations in hypertensive and diabetic patients, since changes in its serum levels are correlated with alterations in vascular structure and function.<ref name="pmid26635913">{{cite journal | vauthors = Gómez-Marcos MA, Blázquez-Medela AM, Gamella-Pozuelo L, Recio-Rodriguez JI, García-Ortiz L, Martínez-Salgado | title = Serum Superoxide Dismutase Is Associated with Vascular Structure and Function in Hypertensive and Diabetic Patients | journal = Oxidative Medicine and Cellular Longevity | volume = 2016 | issue = 9124676 | pages = 1–8| date = Nov 2016 | pmid = 26635913 | pmc = 4655282 | doi = 10.1155/2016/9124676 }}</ref>
== Pharmacological activity ==
SOD has powerful antinflammatory activity. For example, SOD is a highly effective experimental treatment of chronic inflammation in [[colitis]].{{Citation needed|date=April 2013}} Treatment with SOD decreases [[reactive oxygen species]] generation and [[oxidative stress]] and, thus, inhibits endothelial activation. Therefore, such antioxidants may be important new therapies for the treatment of [[inflammatory bowel disease]].<ref name="pmid15197232">{{cite journal | vauthors = Seguí J, Gironella M, Sans M, Granell S, Gil F, Gimeno M, Coronel P, Piqué JM, Panés J | 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 = 537–44 | date = Sep 2004 | pmid = 15197232 | doi = 10.1189/jlb.0304196 }}</ref>
Likewise, SOD has multiple pharmacological activities. E.g., it ameliorates [[Cisplatin|cis-platinum]]-induced [[nephrotoxicity]] in rodents.<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 = 267–77 | 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 anti-inflammatory 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 }}</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 = 119–45 | date = May 2010 | pmid = 20153367 | pmc = 2854323 | doi = 10.1016/j.pharmthera.2010.01.003 }}</ref>
== 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 | title = Topical superoxide dismutase reduces post-irradiation breast cancer fibrosis | journal = Journal of Cellular and Molecular Medicine | volume = 8 | issue = 1 | pages = 109–16 | year = 2004 | pmid = 15090266 | doi = 10.1111/j.1582-4934.2004.tb00265.x }}</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 | 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 = Jan 2001 | pmid = 11134893 | doi = 10.1016/S0891-5849(00)00431-7 }}</ref>{{elucidate| 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 = 430–6 | date = Mar 2015 | pmid = 25701330 | doi = 10.1016/j.nut.2014.10.006 }}</ref>
== See also ==
* [[Catalase]]
* [[Catalase]]
* [[Glutathione peroxidase]]
* [[Jiaogulan]]
* [[NADPH oxidase]], an enzyme which ''produces'' superoxide
* [[Peroxidase]]
* [[Peroxidase]]
* [[Jiaogulan]]
==External links==
== References ==
{{reflist|33em}}
== External links ==
* {{OMIM|105400}} (ALS)
* {{OMIM|105400}} (ALS)
* [http://www.alsod.org/ The ALS Online Database]
* [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.worthington-biochem.com/SODBE/default.html A short but substantive overview of SOD and its literature.]
* [http://www.senescence.info/causes.html Damage-Based Theories of Aging] Includes a discussion of the roles of SOD1 and SOD2 in aging.
* [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.pcrm.org Physicians' Comm. For Responsible Med. ]
* [http://www.sigmaaldrich.com/Area_of_Interest/Biochemicals/Enzyme_Explorer/Cell_Signaling_Enzymes/Superoxide_Dismutase.html SOD and Oxidative Stress Pathway Image]
* [http://www.sigmaaldrich.com/life-science/metabolomics/enzyme-explorer/cell-signaling-enzymes/superoxide-dismutase.html SOD and Oxidative Stress Pathway Image]
* [http://www.sfrbm.org/pdf/FRBM20year.pdf Historical information on SOD research]"The evolution of <i>Free Radical Biology & Medicine</i>: A 20-year history" and "<i>Free Radical Biology & Medicine</i> The last 20 years: The most highly cited papers"
* [https://web.archive.org/web/20070313213535/http://www.sfrbm.org/pdf/FRBM20year.pdf Historical information on SOD research]"The evolution of ''Free Radical Biology & Medicine'': A 20-year history" and "''Free Radical Biology & Medicine'' The last 20 years: The most highly cited papers"
* [http://www.garfield.library.upenn.edu/classics1981/A1981LK85800002.pdf JM McCord discusses the discovery of SOD]
* [http://www.garfield.library.upenn.edu/classics1981/A1981LK85800002.pdf JM McCord discusses the discovery of SOD]
{{Anti-inflammatory and antirheumatic products}}
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Superoxide dismutase (SOD, EC1.15.1.1) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide (O2−) radical into either ordinary molecular oxygen (O2) or hydrogen peroxide (H2O2). Superoxide is produced as a by-product of oxygen metabolism and, if not regulated, causes many types of cell damage.[2] 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 lactobacilli, which use a different mechanism to prevent damage from reactive (O2−).
In this way, O2− is converted into two less damaging species.
The pathway by which SOD-catalyzed dismutation of superoxide may be written, for Cu,Zn SOD, with the following reactions :
Cu2+-SOD + O2− → Cu+-SOD + O2 (reduction of copper; oxidation of superoxide)
Cu+-SOD + O2− + 2H+ → Cu2+-SOD + H2O2 (oxidation of copper; reduction of superoxide)
The general form, applicable to all the different metal-coordinated forms of SOD, can be written as follows:
M(n+1)+-SOD + O2− → Mn+-SOD + O2
Mn+-SOD + O2− + 2H+ → M(n+1)+-SOD + H2O2.
where M = Cu (n=1) ; Mn (n=2) ; Fe (n=2) ; Ni (n=2).
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
Irwin Fridovich and Joe McCord at Duke University discovered the enzymatic activity of superoxide dismutase in 1968.[3] 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".[4] 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.[5]
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 an SOD enzyme with copper and zinc (Cu-Zn-SOD). For example, Cu-Zn-SOD available commercially is normally purified from bovine red blood cells. The bovine Cu-Zn enzyme is a homodimer of molecular weight 32,500. It was the first SOD whose atomic-detail crystal structure was solved, in 1975.[8] 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.[9]
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 hydroxyligand, depending on the Mn oxidation state (respectively II and III).[10]
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.[11][12]
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.[14][15]
Human
Three forms of superoxide dismutase are present in humans, in all other mammals, and most chordates. SOD1 is located in the cytoplasm, SOD2 in the mitochondria, and SOD3 is extracellular. The first is a dimer (consists of two units), whereas the others are tetramers (four subunits). SOD1 and SOD3 contain copper and zinc, whereas SOD2, the mitochondrial enzyme, has manganese in its reactive centre. The genes are located on chromosomes 21, 6, and 4, respectively (21q22.1, 6q25.3 and 4p15.3-p15.1).
Crystal structure of the human SOD1 enzyme (rainbow-color N-terminus = blue, C-terminus = red) complexed with copper (orange sphere) and zinc (grey sphere).[16]
Crystallographic structure of the tetrameric human SOD3 enzyme (cartoon diagram) complexed with copper and zinc cations (orange and grey spheres respectively).[17]
In higher plants, superoxide dismutase enzymes (SODs) act as antioxidants and protect cellular components from being oxidized by reactive oxygen species (ROS).[18] 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.[19][20] To be specific, molecular O2 is reduced to O2− (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.[19] SODs catalyze the production of O2 and H2O2 from superoxide (O2−), 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.[18][19][20]
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.[21]
Biochemistry
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 (O2−) spontaneously dismutes to O2 and hydrogen peroxide (H2O2) quite rapidly (~105 M−1s−1 at pH 7).[citation needed] SOD is necessary because superoxide reacts with sensitive and critical cellular targets. For example, it reacts with the NO radical, and makes toxic peroxynitrite.
Because the uncatalysed dismutation reaction for superoxide requires two superoxide molecules to react with each other, the dismutation rate is second-order with respect to initial superoxide concentration. Thus, the half-life of superoxide, although very short at high concentrations (e.g., 0.05 seconds at 0.1mM) is actually quite long at low concentrations (e.g., 14 hours at 0.1 nM). In contrast, the reaction of superoxide with SOD is first order with respect to superoxide concentration. Moreover, superoxide dismutase has the largest kcat/KM (an approximation of catalytic efficiency) of any known enzyme (~7 x 109 M−1s−1),[22] 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.[23]
Stability and folding mechanism
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.[24] By differential scanning calorimetry (DSC), holo SOD1 unfolds by a two-state mechanism: from dimer to two unfolded monomers.[24] In chemical denaturation experiments, holo SOD1 unfolds by a three-state mechanism with observation of a folded monomeric intermediate.[25]
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.[26] Mice lacking SOD1 develop a wide range of pathologies, including hepatocellular carcinoma,[27] an acceleration of age-related muscle mass loss,[28] 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.[29]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.
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.[30]
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.[31]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.[32]
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).[33][34][35][36] The most common mutation in the U.S. is A4V, while the most intensely studied is G93A. The other two isoforms of SOD have not been linked to any human diseases, however, in mice inactivation of SOD2 causes perinatal lethality[26] and inactivation of SOD1 causes hepatocellular carcinoma.[27] 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.),[37] 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.[38] 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.[39]
In mice, the extracellular superoxide dismutase (SOD3, ecSOD) contributes to the development of hypertension.[40][41] Diminished SOD3 activity has been linked to lung diseases such as Acute Respiratory Distress Syndrome (ARDS) or Chronic obstructive pulmonary disease (COPD).[42][43][44]
Superoxide dismutase is also not expressed in neural crest cells in the developing fetus. Hence, high levels of free radicals can cause damage to them and induce dysraphic anomalies (neural tube defects).
A cross-sectional study in humans suggests that serum SOD could be a marker of cardiovascular alterations in hypertensive and diabetic patients, since changes in its serum levels are correlated with alterations in vascular structure and function.[45]
Pharmacological activity
SOD has powerful antinflammatory activity. For example, SOD is a highly effective experimental treatment of chronic inflammation in colitis.[citation needed] Treatment with SOD decreases reactive oxygen species generation and oxidative stress and, thus, inhibits endothelial activation. Therefore, such antioxidants may be important new therapies for the treatment of inflammatory bowel disease.[46]
Likewise, SOD has multiple pharmacological activities. E.g., it ameliorates cis-platinum-induced nephrotoxicity in rodents.[47] 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.[48] 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]
An SOD-mimetic agent, TEMPOL, is currently in clinical trials for radioprotection and to prevent radiation-induced dermatitis.[49] TEMPOL and similar SOD-mimetic nitroxides exhibit a multiplicity of actions in diseases involving oxidative stress.[50]
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.[51] Superoxide dismutase is known to reverse fibrosis, possibly through de-differentiation of myofibroblasts back to fibroblasts.[52][further explanation needed]
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 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.[53]
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↑PDB: 2JLP; Antonyuk SV, Strange RW, Marklund SL, Hasnain SS (May 2009). "The structure of human extracellular copper-zinc superoxide dismutase at 1.7 A resolution: insights into heparin and collagen binding". J. Mol. Biol. 388 (2): 310–26. doi:10.1016/j.jmb.2009.03.026. PMID19289127.
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↑McGinness JE, Proctor PH, Demopoulos HB, Hokanson JA, Kirkpatrick DS (1978). "Amelioration of cis-platinum nephrotoxicity by orgotein (superoxide dismutase)". Physiological Chemistry and Physics. 10 (3): 267–77. PMID733940.
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↑Clinical trial number NCT01324141 for "Topical MTS-01 for Dermatitis During Radiation and Chemotherapy for Anal Cancer" at ClinicalTrials.gov
↑Campana F, Zervoudis S, Perdereau B, Gez E, Fourquet A, Badiu C, Tsakiris G, Koulaloglou S (2004). "Topical superoxide dismutase reduces post-irradiation breast cancer fibrosis". Journal of Cellular and Molecular Medicine. 8 (1): 109–16. doi:10.1111/j.1582-4934.2004.tb00265.x. PMID15090266.
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Historical information on SOD research"The evolution of Free Radical Biology & Medicine: A 20-year history" and "Free Radical Biology & Medicine The last 20 years: The most highly cited papers"
