HGNC Approved Gene Symbol: PON3
Cytogenetic location: 7q21.3 Genomic coordinates (GRCh38): 7:95,359,872-95,396,375 (from NCBI)
Members of the paraoxonase (EC 3.1.1.2) gene family, such as PON3, encode high density lipoprotein (HDL)-related glycoproteins with multienzymatic properties (Lu et al., 2006).
Primo-Parmo et al. (1996) identified 2 human PON1 (168820)-like genes that they designated PON2 (602447) and PON3.
By RT-PCR, Reddy et al. (2001) cloned PON3 from the HepG2 human liver carcinoma cell line. Northern blot analysis detected a transcript of about 1.3 kb primarily in liver, with lower expression in kidney. Western blot analysis of HEK293 human embryonic kidney cells detected endogenous PON3 at an apparent molecular mass of 40 kD. Western blot analysis showed that, like PON1, PON3 localized exclusively to the HDL fraction of human plasma.
Lu et al. (2006) cloned PON3 from a fetal liver cDNA library. The deduced mature protein has 354 amino acids and a calculated molecular mass of 39.6 kD. It contains 3 cysteines that are conserved in PON1 and PON2. Cys41 and cys351 are predicted to form an intramolecular disulfide bond, and cys283 is predicted to be involved in antioxidant activity.
Using nondenaturing PAGE, Draganov et al. (2005) observed native recombinant PON3 at an apparent molecular mass of 94.9 kD, suggesting that it probably forms dimers. Glycosidase treatment of human serum PON3 suggested that the secreted form of PON3 contains complex carbohydrates.
Low density lipoprotein (LDL) can be mildly oxidized by incubation with human aortic endothelial cells (HAECs), and the elevated lipid hydroperoxide content in mildly oxidized LDL induces monocyte chemotactic activity in target HAECs. Reddy et al. (2001) showed that PON3 prevented oxidation of LDL by HAECs. PON3 also lowered the lipid hydroperoxide content of preformed mildly oxidized LDL and attenuated its ability to induce monocyte chemotaxis.
Lu et al. (2006) showed that purified recombinant human PON3 expressed in E. coli had Ca(2+)-dependent arylesterase activity toward phenylacetate and lactonase activity toward dihydrocoumarin. PON3 also protected LDL from Cu(2+)-induced oxidation in vitro.
Draganov et al. (2005) found that glycosylation of recombinant PON3 with high-mannose-type sugars did not alter its enzymatic activity, but it may have affected protein stability. They found that PON1, PON2, and PON3, whether expressed in insect or HEK293 cells, metabolized oxidized forms of arachidonic acid and docosahexaenoic acid. Otherwise, the PONs showed distinctive substrate specificities. PON3, but not the other PONs, hydrolyzed bulky drug substrates, such as lovostatin, spironolactone, and canrenone. About 10% of total lactonase activity of PON3-transfected HEK293 cells was secreted into the culture medium. The recombinant PONs did not protect human LDL against Cu(2+)-induced oxidation in vitro, and no antioxidant activity copurified with any of the PONs.
All 3 PON genes, including PON3, have been mapped to chromosome 7q21-q22 (Primo-Parmo et al. (1996, 1996)). Mochizuki et al. (1998) showed out that PON3 is physically linked to PON1 and PON2 on chromosome 7q21.3.
Shih et al. (2007) generated transgenic mice overexpressing human PON3. RT-PCR detected PON3 expression in a variety of tissues from transgenic mice, including liver, lung, kidney, brain, adipose, and aorta. In transgenic liver, PON3 mRNA was expressed 4- to 7-fold higher than endogenous Pon3. However, like endogenous mouse Pon3, which was cell bound, human PON3 was not detected in plasma or HDL, suggesting species-specific differences in PON3 expression. Atherosclerotic lesion areas were significantly smaller in male transgenic mice fed an atherogenic diet compared with those in nontransgenic mice. In addition to decreased atherosclerotic lesion area, male PON3 transgenic mice bred onto an LDL receptor (LDLR; 606945)-knockout mouse background showed decreased expression of monocyte chemoattractant protein-1 (CCL2; 158105) in aorta, suggesting decreased inflammation, compared with nontransgenic littermates. Male PON3 transgenic mice also showed decreased adiposity and lower circulating leptin (LEP; 164160) levels compared with controls. Transgenic and nontransgenic mice showed no significant differences in triglyceride, glucose, and plasma total, HDL, and VLDL/LDL cholesterol levels. No changes attributed to PON3 overexpression in male transgenic mice were observed in PON3 transgenic females. Overexpression of PON3 did not protect transgenic mice from copper-induced LDL oxidation, consistent the absence of PON3 in mouse circulation. Shih et al. (2007) concluded that PON3 may play a role in protection from obesity and atherosclerosis in males.
Draganov, D. I., Teiber, J. F., Speelman, A., Osawa, Y., Sunahara, R., La Du, B. N. Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J. Lipid Res. 46: 1239-1247, 2005. [PubMed: 15772423] [Full Text: https://doi.org/10.1194/jlr.M400511-JLR200]
Lu, H., Zhu, J., Zang, Y., Ze, Y., Qin, J. Cloning, purification, and refolding of human paraoxonase-3 expressed in Escherichia coli and its characterization. Protein Expr. Purif. 46: 92-99, 2006. [PubMed: 16139510] [Full Text: https://doi.org/10.1016/j.pep.2005.07.021]
Mochizuki, H., Scherer, S. W., Xi, T., Nickle, D. C., Majer, M., Huizenga, J. J., Tsui, L.-C., Prochazka, M. Human PON2 gene at 7q21.3: cloning, multiple mRNA forms, and missense polymorphisms in the coding sequence. Gene 213: 149-157, 1998. [PubMed: 9714608] [Full Text: https://doi.org/10.1016/s0378-1119(98)00193-0]
Primo-Parmo, S. L., Hsu, C., Law, D. J., La Du, B. N. Location and arrangement of three paraoxonase genes: PON1, PON2, and PON3, on human chromosome 7. (Abstract) Am. J. Hum. Genet. 59 (suppl.): A406, 1996.
Primo-Parmo, S. L., Sorenson, R. C., Teiber, L., La Du, B. N. The human serum paraoxonase/arylesterase gene (PON1) is one member of multigene family. Genomics 33: 498-507, 1996. [PubMed: 8661009] [Full Text: https://doi.org/10.1006/geno.1996.0225]
Reddy, S. T., Wadleigh, D. J., Grijalva, V., Ng, C., Hama, S., Gangopadhyay, A., Shih, D. M., Lusis, A. J., Navab, M., Fogelman, A. M. Human paraoxonase-3 is an HDL-associated enzyme with biological activity similar to paraoxonase-1 protein but is not regulated by oxidized lipids. Arterioscler. Thromb. Vasc. Biol. 21: 542-547, 2001. [PubMed: 11304470] [Full Text: https://doi.org/10.1161/01.atv.21.4.542]
Shih, D. M., Xia, Y.-R., Wang, X.-P., Wang, S. S., Bourquard, N., Fogelman, A. M., Lusis, A. J., Reddy, S. T. Decreased obesity and atherosclerosis in human paraoxonase 3 transgenic mice. Circ. Res. 100: 1200-1207, 2007. [PubMed: 17379834] [Full Text: https://doi.org/10.1161/01.RES.0000264499.48737.69]