A long and winding road: defining the biological role and clinical importance of paraoxonases

Abstract

Paraoxonase-1 (PON1) is an enzyme belonging to a three-member gene family, each of which is highly conserved in mammalian evolution. Whilst there is consensus that the paraoxonase family members have a general protective influence, their precise biological role has remained elusive. A toxicological role, protecting from environmental poisoning by organophosphate derivatives, drove much of the earlier work on the enzymes. More recently, clinical interest has focused on a protective role in vascular disease via a hypothesised impact on lipoprotein lipid oxidation. Recent confirmation that the primary activity of the paraoxonases is that of a lactonase considerably expands the potential sources of biological substrates for the enzyme. Studies on such substrates may shed further light on different mechanisms by which paraoxonases beneficially influence atherosclerosis, as well as defining possible roles in limiting bacterial infection and in innate immunity.