Paraoxonases are a family of enzymes that is found in mammals. These enzymes were originally discovered when analysing the hydrolysis of organophosphates. There are 3 types of paraoxonase isozymes, known as paraoxonase 1, paraoxonase 2, and paraoxonase 3.
There are three known forms of paraoxonase enzymes. Paraoxonase 1, this enzyme is expressed most commonly by the liver, but can also be found in tissue in the colon and kidneys. Paraoxonase 1 that is produced by the liver is distributed through the bloodstream, where it comes into contact with high-density lipoprotein, also known as HDL. Paraoxonase 1 is compatible with multiple substrates, and it is proven to have antioxidant properties when preventing the oxidation of low-density lipoproteins (LDL). This can help to lower the risk of atherosclerosis, a major risk factor for heart disease. Paraoxonase 2, this is an intracellular protein, which is expressed throughout the body. Its main function is to protect against oxidative damage. Although it has antioxidant capabilities, it cannot hydrolyze some types of organophosphate metabolites, unlike paraoxonase 1 and 3. Paraoxonase 3 is similar to paraoxonase 1, but there are differences in substrate interaction. Research suggests that PON3 activity is up to 100 times lower than that of PON1. As PON3 also binds to HDL, it can play a role in preventing the oxidation of LDL and HDL.
Atherosclerosis is one of the most common and potent risk factors for coronary heart disease. As paraoxonases, most notably PON1 and PON3, have an association with HDL and LDL, they can play a significant role in reducing the risk of heart attacks and strokes.
The function of paraoxonases can be inhibited by lipid peroxides, which may be present in the blood. It is possible for lipid peroxides to hamper the antioxidant role of paraoxonases. If PON1 and PON3 activity are reduced, this can increase the risk of LDL oxidation.
Paraoxonase 1 consists of 354 amino acids, which are arranged in a propeller-like structure, which has a central channel that contains two calcium ions. The location of the calcium ions has a significant impact on the function and activity of PON1. The calcium ion that lies deepest in the tunnel has a structural role, while the other calcium ion is involved in catalysing reactions and positioning the substrate.
Researchers have been studying this family of enzymes for many years now, but a lack of information related to natural substrates and the diversity of roles the enzymes play has made it difficult to pinpoint the specific mechanisms involved in reactions that are catalysed by this enzyme group. All paraoxonase enzymes use catalytic calcium ions as an oxy-anion to secure substrates and stabilise reactions. The active site of serum paraoxonase-1 may also utilise 2 histidine residues, glutamic acid and asparagine to stabilise transitional sites.