PON3 Gene – Paraoxonase 3: Function, Expression, Mutations & Disease

PON3 (paraoxonase 3) is a member of the paraoxonase gene family, which also includes PON1 and PON2. It encodes a calcium-dependent lactonase enzyme that hydrolyzes a wide range of substrates, including aromatic lactones, lipid peroxides, and certain organophosphates. PON3 is primarily expressed in the liver and kidney, and its protein is secreted into the bloodstream where it associates with high-density lipoprotein (HDL). It plays a key role in protecting against oxidative stress, detoxifying xenobiotics, and modulating lipid metabolism. PON3 has been implicated in cardiovascular disease, diabetes, and cancer.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Reactome: R-HSA-6806667 – Metabolism of xenobiotics by cytochrome P450

• Reactome: R-HSA-8957322 – Metabolism of lipids

• WikiPathways: WP2879 – Paraoxonase pathway

• KEGG: hsa00980 – Metabolism of xenobiotics by cytochrome P450

PON3 is a 354-amino-acid glycoprotein (40 kDa) that belongs to the paraoxonase family. It contains a conserved calcium-binding site essential for lactonase activity. The protein is synthesized with a signal peptide (residues 1–19) and is secreted. PON3 is primarily associated with HDL in plasma and exhibits broad substrate specificity, including hydrolysis of aromatic lactones (e.g., dihydrocoumarin), lipid peroxides, and certain organophosphates. Its antioxidant function protects LDL and HDL from oxidation. PON3 is less studied than PON1 but is increasingly recognized for its role in metabolic and inflammatory diseases.