Superoxide dismutase

Superoxide dismutase
Structure of the monomeric unit of human superoxide dismutase 2.
Identifiers
EC number	1.15.1.1
CAS number	9054-89-1
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB	structures
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).^[1] 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 which became known as superoxide dismutase as an indophenol oxidase by protein analysis of starch gels using the phenazine-tetrazolium technique.^[2]

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 finally 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 two subunits are joined primarily by hydrophobic and electrostatic interactions. The ligands of copper and zinc are histidine side chains.^[3]
• Iron or manganese – used by prokaryotes and protists
  • 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 active sites of Mn and Fe superoxide dismutases contain the same type 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 a human mitochondrion: 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).^[4]
• 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.^{[5] [6]}

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.^[7][8]

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), while the others are tetramers (four subunits). SOD1 and SOD3 contain copper and zinc, while 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).

superoxide dismutase 1, 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).[9] 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

superoxide dismutase 2, mitochondrial Structure of the active site of human superoxide dismutase 2. Identifiers Symbol SOD2 Entrez 6648 HUGO 11180 OMIM 147460 RefSeq NM_000636 UniProt P04179 Other data EC number 1.15.1.1 Locus Chr. 6 q25

superoxide dismutase 3, extracellular Identifiers Symbol SOD3 Entrez 6649 HUGO 11181 OMIM 185490 RefSeq NM_003102 UniProt P08294 Other data EC number 1.15.1.1 Locus Chr. 4 pter-q21

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). The superoxide anion radical (O₂⁻) spontaneously dismutes to O₂ and hydrogen peroxide (H₂O₂) quite rapidly (~10⁵ M⁻¹s⁻¹ at pH 7). SOD is biologically necessary because superoxide reacts even faster with certain targets such as the 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 dismutase has the fastest turnover number (reaction rate with its substrate) of any known enzyme (~7 x 10⁹ M⁻¹s⁻¹),^[10] this reaction being only limited by the frequency of collision between itself and superoxide. That is, the reaction rate is "diffusion limited".

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, amidst massive oxidative stress.^[11] Mice lacking SOD1 develop a wide range of pathologies, including hepatocellular carcinoma,^[12] an acceleration of age-related muscle mass loss,^[13] 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.^[14] 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 while 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).^[15][16][17] The most common mutation in the U.S. is A4V while the most intensely studied is G93A. The other two types have not been linked to any human diseases, however, in mice inactivation of SOD2 causes perinatal lethality^[11] and inactivation of SOD1 causes hepatocellular carcinoma.^[12] 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 Down's syndrome.^[18]

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, such as antioxidants, may be important, new tools for the treatment of inflammatory bowel disease.^[19]

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.^[20] Superoxide dismutase is known to reverse fibrosis, perhaps through reversion of myofibroblasts back to fibroblasts.^[21]

References

See also

• Catalase
• Peroxidase
• Jiaogulan

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