**3. Paraoxonase 2**

The PON2 isoform is highly expressed in several different types of human cells and tissues, mainly in macrophages and hepatocytes, lower lung airways, brain, cardiac and gastrointestinal systems. It is found in association with the endoplasmic reticulum and mitochondria, specifically associating with complex III of the inner mitochondrial membrane. PON2 deficiency alters mitochondrial function by decreasing mitochondrial complex I and III activity and total ATP levels and alters mitochondrial oxidative stress by increasing mitochondrial superoxide production, increasing lipid peroxidation and decreasing reduced glutathione levels. In vascular cells, PON2 has been found to be a cell-based enzyme and appeared in two glycosylated isoforms of approximately 40–43 kDa. PON2 is not detectable in plasma. In brain tissue, PON2 is an antioxidant intracellular enzyme against oxidative stress. In CNS, PON2 expression has been found in nucleus accumbens, striatum and substantia nigra. PON2 is found in astrocytes and neurons in different amounts. However, the loss of PON2 expression in both cells negatively modifies the cellular ability to recover from oxidative damage and subsequently death [67, 68].

PON2 is the oldest yet least studied variant of the paraoxonase family – its intracellular location has made studies challenging. Its three-dimensional structure has not been elucidated, nor has its intracellular compartmental distribution been determined. It has been found in multiple subcellular compartments. PON2 is highly expressed in vital organs such as the heart, brain, and the lungs, and ubiquitously found throughout the body in multiple different tissue types. It is not found in blood/ plasma [69]. At mRNA level, it is enhanced in level in the liver and ubiquitous; at the

protein level its occurrence is ubiquitous. It is found on the endoplasmic reticulum, in the perinuclear region, on the membrane of mitochondria, and on the plasma membrane. It is overexpressed in cancer cells. Expression in the elderly has been shown to be lower [70].

PON2 is degraded by the ubiquitin-proteasome pathway and by ADP-ribosylation. In all cell types, its expression is upregulated by Arachidonic acid, unesterified cholesterol, pomegranate juice, Antioxidants, the licorice phytoestrogen glabidrin, and atorvastatin. Its activity is decreased by glycated compounds. The two common polymorphisms found in PON2 are [71] position 147—an Ala/Gly substitution and position 311—a Ser/Cys substitution.

An apparently benign, heterozygous frameshift mutation in PON2 is present within the general population. This suggests that haploinsufficiency of PON2 is not obviously pathogenic. Thus, only after more profound loss of function than is predicted by eliminating one functional PON2 allele occurs, as in a homozygous defect, will PON2 mutants be pathogenic [72]. Plasma membrane PONs are transmembrane proteins, with the N-terminal region forming a part of the transmembrane anchoring domain on the cytoplasmic side, and C-terminal region as the extracellular catalytic site. Like PON-1, it may counteract lipid peroxidation as well as form the first line of defense for the cell against any microbial invasion [69].

PON2 has multiple enzyme functions as:


It may also hydrolyze arylesters and other esters, however, unlike PON1 and PON3, its paraoxonase and statinase activities have not been detected. As said earlier, PON2 has antioxidative function, which leads to reduce oxidized LDL levels by preventing LDL oxidation and reversing the oxidation of mildly reduced LDL. This leads to inhibition of the monocyte chemotaxis associated with oxidized LDL, and increased efflux of cholesterol. Thus, PON2 is antiatherogenic.
