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The enzyme superoxide dismutase (SOD, EC 188.8.131.52), 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 lactobacilli, which use a different mechanism.
The SOD-catalysed dismutation of superoxide may be written with the following half-reactions :
In this reaction the oxidation state of the metal cation oscillates between n and n+1.
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 and zinc, or manganese, iron, or nickel.
In humans, 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).
A microtiter plate assay for SOD is available.
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-1 s-1 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 (~109 M-1 s-1), this reaction being only limited by the frequency of collision between itself and superoxide. That is, the reaction rate is "diffusion limited".
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. Mice lacking SOD1 develop a wide range of pathologies, including hepatocellular carcinoma, an acceleration of age-related muscle mass loss, an earlier incidence of cataracts and a reduced lifespan. Mice lacking SOD3 do not show any obvious defects and exhibit a normal lifespan.
Role in disease
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 and inactivation of SOD1 causes hepatocellular carcinoma. 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. The veterinary antiinflammatory drug "Orgotein" is purified bovine liver superoxide dismutase.
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.
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. Superoxide dismutase is known to reverse fibrosis, perhaps through reversion of myofibroblasts back to fibroblasts.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Superoxide_dismutase". A list of authors is available in Wikipedia.|