Lewis electron configuration of superoxide. The six outer shell electrons of each oxygen atom are shown in black; one electron pair is shared (middle); the unpaired electron is shown in the upper left and the additional electron conferring a negative charge is shown in red.

Superoxide is the anion O₂⁻. It is important as the product of the one-electron reduction of dioxygen, which occurs widely in nature.^[1] With one unpaired electron, the superoxide ion is a free radical, and, like dioxygen, it is paramagnetic.

Synthesis, basic reactions, and structure

Superoxides are compounds in which the oxidation number of oxygen is ?½. The O-O bond distance in O₂⁻ is 1.33 Å, vs. 1.21 Å in O₂ and 1.49 Å in O₂²⁻.

The salts CsO₂, RbO₂, KO₂, and NaO₂ are prepared by the direct reaction of O₂ with the respective alkali metal.^[2] The overall trend corresponds to a reduction in the bond order from 2 (O₂), to 1.5 (O₂⁻), to 1 (O₂²⁻).

The alkali salts of O₂⁻ are orange-yellow in color and quite stable, provided they are kept dry. Upon dissolution of these salts in water, however, the dissolved O₂⁻ undergoes disproportionation (dismutation) extremely rapidly:

2 O₂⁻ + 2 H₂O ? O₂ + H₂O₂ + 2 OH⁻

In this process O₂⁻ acts as a strong Brønsted base, initially forming HO₂. The pKa of its conjugate acid, hydrogen superoxide (HO₂, also known as "hydroperoxyl" or "perhydroxy radical"), is 4.88 so that at neutral pH 7 the vast majority of superoxide is in the anionic form, O₂⁻.

Salts also decompose in the solid state, but this process requires heating:

2NaO₂ ? Na₂O₂ + O₂

This reaction is the basis of the use of potassium superoxide as an oxygen source in chemical oxygen generators, such as those used on the space shuttle and on submarines.

Superoxide in biology

Superoxide is biologically quite toxic and is deployed by the immune system to kill invading microorganisms. In phagocytes, superoxide is produced in large quantities by the enzyme NADPH oxidase for use in oxygen-dependent killing mechanisms of invading pathogens. Mutations in the gene coding for the NADPH oxidase cause an immunodeficiency syndrome called chronic granulomatous disease, characterized by extreme susceptibility to infection. In turn, micro-organisms genetically engineered to lack superoxide dismutase (SOD), lose virulence. Superoxide is also deleteriously produced as a byproduct of mitochondrial respiration (most notably by Complex I and Complex III), as well as several other enzymes, for example xanthine oxidase.

Despite being chemically rather benign, superoxide is so toxic that intracellular levels above 1nM are lethal. The biological toxicity of superoxide is not entirely understood, but derives in part from its capacity to inactivate iron-sulfur cluster containing enzymes (which are critical in a wide variety of metabolic pathways), thereby liberating free iron in the cell, which can undergo Fenton chemistry and generate the highly reactive hydroxyl radical. In its HO₂ form (hydroperoxyl radical), superoxide can also initiate lipid peroxidation of polyunsaturated fatty acids. It also reacts with carbonyl compounds and halogenated carbons to create toxic peroxy radicals. Superoxide can also react with nitric oxide (NO) to form ONOO⁻. Superoxide can also form tyrosine peroxides as a result of reaction with enzymes containing tyrosyl radicals (such as ribonucleotide reductase). Superoxide can also oxidize hemoglobin (forming the non-oxygen carrying met-hemoglobin), and possibly other low-potential heme proteins. Finally, superoxide can oxidize low potential thiols. As such, superoxide is one of the main causes of oxidative stress.

Because superoxide is toxic, nearly all organisms living in the presence of oxygen contain isoforms of the superoxide scavenging enzyme, superoxide dismutase, or SOD. SOD is an extremely efficient enzyme; it catalyzes the neutralization of superoxide nearly as fast as the two can diffuse together spontaneously in solution. Other proteins, which can be both oxidized and reduced by superoxide, have weak SOD-like activity (e.g. hemoglobin). Genetic inactivation ("knockout") of SOD produces deleterious phenotypes in organisms ranging from bacteria to mice and have provided important clues as to the mechanisms of toxicity of superoxide in vivo.

Yeast lacking both mitochondrial and cytosolic SOD grow very poorly in air, but quite well under anaerobic conditions. Absence of cytosolic SOD causes a dramatic increase in mutagenesis and genomic instability. Mice lacking mitochondrial SOD (MnSOD) die around 21 days after birth due to neurodegeneration, cardiomyopathy and lactic acidosis. Mice lacking cytosolic SOD (CuZnSOD) are viable but suffer from multiple pathologies, including reduced lifespan, liver cancer, muscle atrophy, cataracts, thymic involution, haemolytic anemia and a very rapid age-dependent decline in female fertility.

Superoxide may contribute to the pathogenesis of many diseases (the evidence is particularly strong for radiation poisoning and hyperoxic injury), and perhaps also to aging via the oxidative damage that it inflicts on cells. While the action of superoxide in the pathogenesis of some conditions is strong, for instance, mice and rats overexpressing CuZnSOD or MnSOD are more resistant to strokes and heart attacks, the role of superoxide in aging, must be regarded as unproven for now. In model organisms (yeast, the fruit fly Drosophila and mice), genetically knocking out CuZnSOD shortens lifespan and accelerates certain features of aging (cataracts, muscle atrophy, macular degeneration, thymic involution), but the converse, increasing the levels of CuZnSOD, does not seem (except perhaps in Drosophila), to consistently increase lifespan. The most widely accepted view is that oxidative damage (derived amongst other factors, from superoxide) is but one of several factors limiting lifespan.

References

Further reading

• McCord, J. M.; Fridovich, I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J. Biol. Chem. 244:6049-6055.; 1969.
• Li, Y. et al. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat. Genet. 11:376-381; 1995.
• Elchuri, S. et al. CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24:367-380; 2005.
• Muller, F. L.; et al. Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy. Free Radic. Biol. Med. 40:1993-2004; 2006.
• Muller, F. L., Lustgarten, M. S., Jang, Y., Richardson, A. and Van Remmen, H. (2007) Trends in oxidative aging theories. Free Radic. Biol. Med. 43, 477-503

See also

• ozonide, O₃⁻
• superoxide, O₂⁻
• peroxide, O₂²⁻
• oxide, O²⁻
• dioxygenyl, O₂⁺
• Antimycin A - used in fishery management, this compound produces large quantities of this free radical.

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