Superoxide dismutase

For other senses of the term SOD/Sod, see Sod (disambiguation).

Superoxide dismutase
Structure of a human Mn superoxide dismutase 2 tetramer.[1]
Identifiers
EC number	1.15.1.1
CAS number	9054-89-1
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles

Superoxide dismutases (SOD, EC 1.15.1.1) are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen. One of the exceedingly rare exceptions is Lactobacillus plantarum and related lactobacilli, which use a different mechanism.

Reaction

The SOD-catalysed dismutation of superoxide may be written with the following half-reactions :

• 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 this reaction the oxidation state of the metal cation oscillates between n and n+1.

Types

General

Discovered by Irwin Fridovich and Joe McCord, SOD enzymes were previously thought to be several metalloproteins with unknown function (for example, CuZnSOD was known as erythrocuprein).^[2] Several common forms of SOD exist: they are proteins cofactored with copper and zinc, or manganese, iron, or nickel. For example, Brewer (1967) identified a protein that became known as superoxide dismutase as an indophenol oxidase by protein analysis of starch gels using the phenazine-tetrazolium technique.^[3]

Bovine Cu-Zn SOD subunit.^[4]

There are three major families of superoxide dismutase, depending on the metal cofactor: Cu/Zn (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. 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 the bovine erythrocytes: The Cu-Zn enzyme is a homodimer of molecular weight 32,500. The bovine Cu-Zn protein was the first SOD structure to be solved, in 1975.^[5] 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, primarily by hydrophobic and some electrostatic interactions. The ligands of the copper and zinc are six histidine and one aspartate side-chains; one histidine is shared between the two metals.^[6]
• Iron or manganese – used by prokaryotes and protists, and in mitochondria
  • Iron – 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: . Fe-SOD can be found in the plastids 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.
  • Manganese – 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 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).^[7]
• nickel – prokaryotic. A hexameric 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.^[8][9]

Copper/zinc superoxide dismutase Structure of the yeast Cu,Zn enzyme superoxide dismutase.[10] Identifiers Symbol Sod_Cu Pfam PF00080 InterPro IPR001424 PROSITE PDOC00082 SCOP 1sdy Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

Iron/manganese superoxide dismutases, alpha-hairpin domain The structure of human mitochondrial manganese superoxide dismutase, which reveals a novel tetrameric interface of two 4-helix bundles.[7] Identifiers Symbol Sod_Fe_N Pfam PF00081 InterPro IPR001189 PROSITE PDOC00083 SCOP 1n0j Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

Iron/manganese superoxide dismutases, C-terminal domain The structure of human mitochondrial manganese superoxide dismutase, which reveals a novel tetrameric interface of two 4-helix bundles.[7] Identifiers Symbol Sod_Fe_C Pfam PF02777 InterPro IPR001189 PROSITE PDOC00083 SCOP 1n0j Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

Nickel-containing superoxide dismutase Structure of nickel-containing superoxide dismutase.[9] Identifiers Symbol Sod_Ni Pfam PF09055 InterPro IPR014123 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure 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.^[11][12]

Human

In humans (as in all other mammals and most chordates), three forms of superoxide dismutase are present. 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 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 Crystallographic structure of the human SOD1 enzyme (rainbow colored N-terminus = blue, C-terminus = red) complexed with copper (blue-green sphere) and zinc (grey spheres).[13] Identifiers Symbol SOD1 Alt. symbols ALS, ALS1 Entrez 6647 HUGO 11179 OMIM 147450 RefSeq NM_000454 UniProt P00441 Other data EC number 1.15.1.1 Locus Chr. 21 q22.1

SOD2, mitochondrial Structure of the active site of human superoxide dismutase 2.[1] Identifiers Symbol SOD2 Alt. symbols Mn-SOD; IPO-B; MVCD6 Entrez 6648 HUGO 11180 OMIM 147460 RefSeq NM_000636 UniProt P04179 Other data EC number 1.15.1.1 Locus Chr. 6 q25

SOD3, extracellular Crystallographic structure of the tetrameric human SOD3 enzyme (cartoon diagram) complexed with copper and zinc cations (orange and grey spheres respectively).[14] Identifiers Symbol SOD3 Alt. symbols EC-SOD; MGC20077 Entrez 6649 HUGO 11181 OMIM 185490 RefSeq NM_003102 UniProt P08294 Other data EC number 1.15.1.1 Locus Chr. 4 pter-q21

Plants

In higher plants, superoxide dismutase enzymes (SODs) act as antioxidants and protect cellular components from being oxidized by reactive oxygen species (ROS).^[15] 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.^[16][17] Specifically, molecular O2 is reduced to O2- (an 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.^[16] 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 are they are indigenous. Second, Mn SODs consist of a homodimer and homotetramer species each containing a single Mn(III) atom per subunit. They are predominantly found in mitochondrion and peroxisomes. Third, Cu-Zn SODs have electrical properties very different from 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.^[15][16][17]

Bacteria

Human white blood cells 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.^[18]

Biochemistry

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) or a metal. The superoxide anion radical (O₂⁻) spontaneously dismutes to O₂ and hydrogen peroxide (H₂O₂) quite rapidly (~10⁵ M⁻¹s⁻¹ at pH 7). SOD is necessary because superoxide reacts with sensitive and critical cellular targets. For example, it reacts the NO radical, and makes toxic peroxynitrite. 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 x 10⁹ M⁻¹s⁻¹),^[19] this reaction being only limited by the frequency of collision between itself and superoxide. That is, the reaction rate is "diffusion limited". 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.^[20]

Physiology

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, amid massive oxidative stress.^[21] Mice lacking SOD1 develop a wide range of pathologies, including hepatocellular carcinoma,^[22] an acceleration of age-related muscle mass loss,^[23] 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.^[24] Knockout mice of any SOD enzyme are more sensitive to the lethal effects of superoxide generating drugs, such as paraquat and diquat.

Drosophila lacking SOD1 have a dramatically shortened lifespan, whereas flies lacking SOD2 die before birth. SOD knockdowns in C. elegans do not cause major physiological disruptions. Knockout or null mutations in SOD1 are highly detrimental to aerobic growth in the yeast Sacchormyces cerevisiae and result in a dramatic reduction in post-diauxic lifespan. SOD2 knockout or null mutations cause growth inhibition on respiratory carbon sources in addition to decreased post-diauxic lifespan.

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).^[25][26][27] 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^[21] and inactivation of SOD1 causes hepatocellular carcinoma.^[22] Mutations in SOD1 can cause familial ALS, 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.^[28] Genetic polymorphisms in SOD enzymes and their altered expressions and activities are associated with oxidative DNA damage and subsequently the individual’s risk of cancer susceptibility.^[29]

SOD has proved to be highly effective in treatment of colonic inflammation in experimental colitis. Treatment with SOD decreases reactive oxygen species generation and oxidative stress and, thus, inhibits endothelial activation and indicate that modulation of factors that govern adhesion molecule expression and leukocyte-endothelial interactions. Therefore, such as antioxidants may be important new therapies for the treatment of inflammatory bowel disease.^[30]

In recent years it has become more apparent that in mice the extracellular superoxide dismutase (SOD3, ecSOD) is critical in the development of hypertension.^[31][32] In other studies, diminished SOD3 activity was linked to lung diseases such as Acute Respiratory Distress Syndrome (ARDS) or Chronic obstructive pulmonary disease (COPD).^{[33] [34] [35]}

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).

Cosmetic uses

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 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.^[36] Superoxide dismutase is known to reverse fibrosis, perhaps through reversion of myofibroblasts back to fibroblasts.^[37]

See also

• Catalase
• Peroxidase
• Jiaogulan

References

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External links

• Online 'Mendelian Inheritance in Man' (OMIM) 105400 (ALS)
• The ALS Online Database
• A short but substantive overview of SOD and its literature.
• Damage-Based Theories of Aging Includes a discussion of the roles of SOD1 and SOD2 in aging.
• Physicians' Comm. For Responsible Med.
• SOD and Oxidative Stress Pathway Image
• 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"
• JM McCord discusses the discovery of SOD