Superoxide dismutase Totally Explained

Everything about Superoxide Dismutase totally explained

The enzyme superoxide dismutase (SOD, ), catalyzes the dismutation of superoxide into oxygen and hydrogen peroxide. As such, it's 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

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're proteins cofactored with copper and zinc, or manganese, iron, or nickel.
Brewer (1967) identifed superoxide dismutase as an indophenol oxidase by protein analysis of starch gels using the phenazine-tetrazolium technique. Brewer detected this enzyme in several human tissues an indophenol oxidase A(IPO-A). After that Brewer observed an electrophoretic variant of IPO-A, which he called 'Morenci,' in 3 generations of a family with presumed male-to-male transmission. Using a RT-PCR analysis Brewer has identified 5 splice variants of SOD1. The variants were expressed in brain, a region involved in amynotrophic lateral sclerosis.

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: PDB 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: PDB 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: PDB 1ISA

, EC 1.15.1.1). 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.

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.,

Human

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.

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^-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 (for example 0.05 seconds at 0.1mM) is actually quite long at low concentrations (for example 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 (~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".

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. 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 don't 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 The veterinary antiinflammatory drug "Orgotein" is purified bovine liver superoxide dismutase.

Delivery systems

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

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.

Further Information

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