Superoxide dismutase

Superoxide dismutase is a key antioxidant enzyme responsible for catalysing the dismutation of the superoxide anion radical into molecular oxygen and hydrogen peroxide. Superoxide is a reactive oxygen species generated continuously as a by-product of aerobic metabolism. Without effective control, it damages lipids, proteins and nucleic acids. Hydrogen peroxide produced by the SOD reaction is further detoxified by enzymes such as catalase and peroxidases. Nearly all oxygen-exposed organisms rely on SOD for redox balance, with the notable exception of Lactobacillus plantarum and related species which depend on high intracellular manganese concentrations for protection against oxidative stress.

Chemical Properties and Catalytic Mechanism

Superoxide dismutases catalyse the conversion of two molecules of superoxide into one molecule each of oxygen and hydrogen peroxide. The overall dismutation reaction proceeds via alternate reduction and oxidation steps occurring at the metal centre of the enzyme. A generalised scheme applicable to all SOD forms can be expressed as the oscillation of the metal ion between two oxidation states—Cu(I)/Cu(II) in copper-containing enzymes and Mn(II)/Mn(III), Fe(II)/Fe(III) or Ni(II)/Ni(III) in the respective manganese, iron or nickel forms.
In copper–zinc SOD, for example, copper accepts and donates electrons during catalytic cycling, whilst zinc plays a structural role stabilising the active site. The catalytic rate approaches the diffusion limit, with a kcat_\text{cat}cat​/KM_\text{M}M​ of approximately 7×1097 \times 10^97×109 M−1^{-1}−1 s−1^{-1}−1. Such efficiency is essential because superoxide, although spontaneously dismuting, can persist for relatively long periods at low concentrations and rapidly inactivates vulnerable enzymes such as aconitase.

Types and Structural Families

Superoxide dismutases fall into several major classes distinguished by their metal cofactors, protein folds and evolutionary distributions.

1. Copper–Zinc SOD (CuZnSOD): This family occurs primarily in the cytosol of eukaryotic cells, including animals and plants. The typical enzyme is a homodimer with a Greek-key β-barrel structure. The copper and zinc ions are coordinated by histidine and aspartate residues. Human CuZnSOD (SOD1) is well characterised and has served as a model system in structural enzymology.
2. Iron and Manganese SOD (FeSOD and MnSOD): Both types share a conserved fold consisting of α-helices surrounding a metal-containing active site. The ligand environment includes histidine and aspartate residues and, depending on the oxidation state, a water or hydroxyl ligand. FeSOD occurs widely in bacteria and in the chloroplasts of plants, whereas MnSOD is prominent in mitochondria and certain bacteria. Human mitochondrial MnSOD (SOD2) is a homotetramer essential for detoxifying superoxide generated by oxidative phosphorylation.
3. Nickel SOD (NiSOD): This form, found only in prokaryotes, consists of hexameric assemblies built around right-handed four-helix bundles. The characteristic N-terminal “Ni-hook” motif provides key metal-binding residues, making it a reliable marker for identifying NiSOD genes.

Cellular and Organismal Distribution

Superoxide dismutase isoenzymes are compartmentalised in both animals and plants to counteract localised sources of reactive oxygen species.

• Humans and other mammals possess three major isoforms:
  • SOD1 (cytosolic, Cu/Zn) encoded on chromosome 21
  • SOD2 (mitochondrial, Mn) encoded on chromosome 6
  • SOD3 (extracellular, Cu/Zn) encoded on chromosome 4

  These enzymes differ in subunit composition: SOD1 is a dimer, whereas SOD2 and SOD3 are tetramers.

• Higher plants express multiple forms across chloroplasts, mitochondria, peroxisomes, cytosol and apoplast.
  • FeSODs are abundant in chloroplasts, where they are believed to represent one of the earliest antioxidant systems.
  • MnSODs are prevalent in mitochondria and peroxisomes.
  • CuZnSODs occur in the cytosol, chloroplasts, peroxisomes and extracellular spaces, although they provide less protection in chloroplasts compared with FeSODs.

Plants increase SOD concentrations under abiotic stresses such as drought, ozone exposure, heavy metals, herbicides, photoinhibition and ultraviolet radiation, mitigating oxidative injury to membranes, enzymes and nucleic acids.

• Bacteria often express FeSOD or MnSOD, with some species harbouring both forms. In pathogenic bacteria, SOD can defend against host immune responses; for example, Burkholderia pseudomallei produces SOD to resist oxidative killing by phagocytes.

Biochemical Roles and Kinetics

Superoxide readily reacts with other radicals such as nitric oxide to form highly reactive peroxynitrite. Because spontaneous dismutation requires two superoxide molecules, it follows second-order kinetics, resulting in a relatively long half-life at nanomolar concentrations. In contrast, SOD-mediated dismutation proceeds with first-order kinetics with respect to superoxide and is sufficiently efficient to prevent its interaction with crucial cellular components.
The need for rapid turnover is evident from the sensitivity of iron–sulphur enzymes to superoxide-mediated damage. Aconitase, a citric acid cycle enzyme, is rapidly inactivated by superoxide, releasing free iron and impairing metabolism. High intracellular SOD levels protect such delicate metabolic pathways.

Evolution and Phylogeny

The major SOD families show deep evolutionary roots, likely emerging soon after the rise of oxygenic photosynthesis and the associated increase in atmospheric oxygen levels. Structural conservation among FeSOD and MnSOD suggests divergence from a common ancestral enzyme, whereas CuZnSOD and NiSOD represent independent adaptations to oxidative stress in different lineages. The widespread distribution of SODs across bacteria, archaea and eukaryotes highlights their central role in aerobic life.
As molecular evolution continued, gene duplication and compartmental specialisation enabled multicellular organisms to fine-tune oxidative stress responses. In plants and animals, the diversification of isoenzymes supports the compartment-specific management of reactive oxygen species, ensuring that oxidative by-products of respiration, photosynthesis and metabolic turnover remain under tight control.