Structure of a human Mn superoxide dismutase 2 tetramer[1]
EC no.
CAS no.9054-89-1
IntEnzIntEnz view
ExPASyNiceZyme view
MetaCycmetabolic pathway
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

Superoxide dismutase (SOD, EC is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide (O
) radical into ordinary molecular oxygen (O2) and hydrogen peroxide (H
). 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 O

Chemical reaction

SODs catalyze the disproportionation of superoxide:

+ 2O
+ H

In this way, O
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:

The reactions by which SOD−catalyzed dismutation of superoxide for Cu,Zn SOD can be written as follows:

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 information: Nickel superoxide dismutase and Iron superoxide dismutase

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).

Ribbon diagram of bovine Cu-Zn SOD subunit[6]
Active site of Human Manganese SOD, manganese shown in purple[7]
Mn-SOD vs Fe-SOD dimers
Copper/zinc superoxide dismutase
Yeast Cu,Zn superoxide dismutase dimer[13]
Available protein structures:
Pfam  structures / ECOD  
PDBsumstructure summary
Iron/manganese superoxide dismutases, alpha-hairpin domain
Structure of domain1 (color), human mitochondrial Mn superoxide dismutase[10]
Available protein structures:
Pfam  structures / ECOD  
PDBsumstructure summary
Iron/manganese superoxide dismutases, C-terminal domain
Structure of domain2 (color), human mitochondrial Mn superoxide dismutase[10]
Available protein structures:
Pfam  structures / ECOD  
PDBsumstructure summary
Nickel superoxide dismutase
Structure of Streptomyces Ni superoxide dismutase hexamer[12]
Available protein structures:
Pfam  structures / ECOD  
PDBsumstructure summary

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]


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).

SOD1, soluble
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]
Alt. symbolsALS, ALS1
NCBI gene6647
Other data
EC number1.15.1.1
LocusChr. 21 q22.1
Search for
SOD2, mitochondrial
Active site of human mitochondrial Mn superoxide dismutase (SOD2)[1]
Alt. symbolsMn-SOD; IPO-B; MVCD6
NCBI gene6648
Other data
EC number1.15.1.1
LocusChr. 6 q25
Search for
SOD3, extracellular
Crystallographic structure of the tetrameric human SOD3 enzyme (cartoon diagram) complexed with copper and zinc cations (orange and grey spheres respectively)[17]
Alt. symbolsEC-SOD; MGC20077
NCBI gene6649
Other data
EC number1.15.1.1
LocusChr. 4 pter-q21
Search for


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 O
(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 H
from superoxide (O
), 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]


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]


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 (O
) spontaneously dismutes to O2 and hydrogen peroxide (H
) 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]


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. Depletion of SOD1 and SOD2 in the nervous system and muscles of Drosophila is associated with reduced lifespan.[30] 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.[31]

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.[32] 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.[32]

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.[33]

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.[34] 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.[35]

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).[36][37][38][39] The most common mutation in the U.S. is A4V, while the most intensely studied is G93A. Inactivation of SOD1 causes hepatocellular carcinoma.[27] Diminished SOD3 activity has been linked to lung diseases such as acute respiratory distress syndrome (ARDS) or chronic obstructive pulmonary disease (COPD).[40][41][42] 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]

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.),[43] 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.[44] 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.[45]

In mice, the extracellular superoxide dismutase (SOD3, ecSOD) contributes to the development of hypertension.[46][47] Inactivation of SOD2 in mice causes perinatal lethality.[26]

Medical uses

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.[48]


SOD has been used in experimental treatment of chronic inflammation in inflammatory bowel conditions.[49][50] SOD may ameliorate cis-platinum-induced nephrotoxicity (rodent studies).[51] 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.[52] 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.[53] TEMPOL and similar SOD-mimetic nitroxides exhibit a multiplicity of actions in diseases involving oxidative stress.[54]

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.[55] Superoxide dismutase is known to reverse fibrosis, possibly through de-differentiation of myofibroblasts back to fibroblasts.[56][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.[57]

See also


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