Disease relevance of PON3

• While the physiological function of these proteins is unknown, studies currently underway using PON2 and PON3 knockout and transgenic mice should enable us to tease out the apparently redundant functions of these three proteins and yield clues as to their physiological function as well as their role in atherogenesis [1].
• In the present study, human PON3 gene was cloned from Human Fetal Liver Marathon-Ready cDNA and expressed in insect cells using baculovirus vector [2].
• These changes included the statistically significant upregulation of several genes associated with inflammation and acute-phase response, including selectin-E (ELAM-I), as well as the downregulation of the antioxidants paraoxonase 3 and ceruloplasmin [3].
• Cloning, purification, and refolding of human paraoxonase-3 expressed in Escherichia coli and its characterization [4].

High impact information on PON3

• Directed evolution of mammalian paraoxonases PON1 and PON3 for bacterial expression and catalytic specialization [5].
• Cellular PON2 and PON3 were also shown to reduce oxidative stress [6].
• The role of PON2 and PON3 in atherosclerosis and their antioxidant properties with respect to LDL and macrophages also merit further investigation [7].
• PON2 and PON3 protect against oxidative stress, with PON2 acting mainly at the cellular level [8].
• Organophosphates are hydrolyzed almost exclusively by PON1, whereas bulky drug substrates such as lovastatin and spironolactone are hydrolyzed only by PON3 [9].

Biological context of PON3

• Identification of paraoxonase 3 gene (PON3) missense mutations in a population of southern Italy [10].
• Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities [9].
• However, we could not exclude the possibility that these polymorphisms may have linkage disequilibrium with a tightly linked PON3 locus or significant atherosclerotic alleles of nearby genes [11].
• We tested the association of 29 SNPs in PON1, PON2 and PON3 with AD in 730 Caucasian and 467 African American participants of the MIRAGE Study, an ongoing multi-center family-based genetic epidemiology study of AD [12].
• Results from these investigations are conflicting, and recent data suggest a complex pattern with influences from other polymorphisms in either the PON1 and/or the PON2 and PON3 genes, or even another region of the gene cluster [13].

Anatomical context of PON3

• Pretreatment of cultured human aortic endothelial cells with supernatants from HeLa Tet On cell lines overexpressing PON3 prevents the formation of mildly oxidized LDL and inactivates preformed mildly oxidized LDL [14].
• In the present study, we have identified the presence of PON3 in rat liver microsomes and a method for the purification to homogeneity is presented [15].
• Precision and accuracy of PON3 statinase activity determination in human blood serum with SV as substrate were satisfactory and acceptable for bioanalytical methods [16].

Associations of PON3 with chemical compounds

• PON1 and PON3 were also inhibited by EDTA and both enzyme activities were restored by the addition of free calcium [17].
• The supplementation of E0 mice with dietary antioxidants (vitamin E, pomegranate juice) significantly increased macrophage PON3 activity (by 23% to 40%), suggesting that oxidative stress was the cause for the reduced macrophage PON3 activity [18].
• PON1 and PON3 reside on high-density lipoprotein (HDL, 'good cholesterol') and are involved in the prevention of atherosclerosis [19].
• Human paraoxonase (hPON3) is a high density lipoprotein-related glycoprotein with multi-enzymatic properties and antioxidant activity which is proposed to participate in the prevention of low density lipoprotein (LDL) oxidation [4].

Other interactions of PON3

• PON1 and PON2 genes have missense polymorphisms, but, to date, no missense variants are reported in PON3 gene [10].

Analytical, diagnostic and therapeutic context of PON3

• Furthermore, PON3 expression is not regulated in HepG2 cells by oxidized phospholipids and is not regulated in the livers of mice fed a high-fat atherogenic diet [14].
• We present a kinetic and site-directed mutagenesis study aimed at deciphering the lactonase mechanism of PON1 and PON3 [20].

References