Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificitiess⃞s⃞ The online version of this article (available at http://www.jlr.org) contains…
By D. Draganov, J. Teiber, A. Speelman, Y. Osawa, R. Sunahara, B. La Du. Journal of Lipid Research, 2005
699 citations recorded by the source corpus.
The paraoxonase (PON) gene family in humans has three members, PON1, PON2, and PON3. Their physiological role(s) and natural substrates are uncertain. We developed a baculovirus-mediated expression system, suitable for all three human PONs, and optimized procedures for their purification. The recombinant PONs are glycosylated with high-mannose-type sugars, which are important for protein stability but are not essential for their enzymatic activities. Enzymatic characterization of the purified PONs has revealed them to be lactonases/lactonizing enzymes, with some overlapping substrates (e.g., aromatic lactones), but also to have distinctive substrate specificities. All three PONs metabolized very efficiently 5-hydroxy-eicosatetraenoic acid 1,5-lactone and 4-hydroxy-docosahexaenoic acid, which are products of both enzymatic and nonenzymatic oxidation of arachidonic acid and docosahexaenoic acid, respectively, and may represent the PONs' endogenous substrates. Organophosphates are hydrolyzed almost exclusively by PON1, whereas bulky drug substrates such as lovastatin and spironolactone are hydrolyzed only by PON3. Of special interest is the ability of the human PONs, especially PON2, to hydrolyze and thereby inactivate N-acyl-homoserine lactones, which are quorum-sensing signals of pathogenic bacteria. None of the recombinant PONs protected low density lipoprotein against copper-induced oxidation in vitro.
Subfields: Clinical Biochemistry, Plant Science
View Paper: https://www.semanticscholar.org/paper/4427bb1ba80d04a86e21b757e925ebad4a563ae8
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Citations in the corpus
- Latent evolutionary potentials under the neutral mutational drift of an enzyme (2007, background): “Because all three PON paralogs are lactonases (Draganov et al., 2005), the variability in these residues primarily affects the various man-made promiscuous substrates.”
- Vascular oxidative stress, nitric oxide and atherosclerosis. (2014, background): “enzymes with overlapping and discrete esterase and lactonase activities [93].”
- Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis (2006, background): “Interestingly, PON1 has been reported to catalyze the hydrolysis of a variety of lactones, including homocysteine thiolactone, suggesting that its native activity is as a lactonase (Jakubowski, 2000; Draganov et al., 2005; Khersonsky and Tawfik, 2005).”
- Targeting virulence: a new paradigm for antimicrobial therapy (2007, background): “, which themselves have lactonase activi-ty against AHLs in vitro”
- Enzyme promiscuity: evolutionary and mechanistic aspects. (2006, background): “b Since the publication of [33 ], it has been established that serum paraoxonase (PON1) is a lipo-lactonase, and its preferred substrates are 5- and 6-mebered ring lactones, typically with aliphatic side chains [59,68,69].”
- Enzyme promiscuity: a mechanistic and evolutionary perspective. (2010, background): “Indeed, the consistency of the lactonase function in all PON paralogs and orthologs and the haphazardness of others’ activities (phosphotriesterase and aryl esterase; Table 1, entry 1) prompted the identification of the lactonase as the native function of PONs (101, 109).”
- Exploiting Quorum Sensing To Confuse Bacterial Pathogens (2013, background): “Evolutionary relationship analysis of PONs and studies of PON1 reactivity with more than 50 different substrates demonstrated that PON1 can hydrolyze lactones, esters, and phosphotriesters using the same active site, but its primary activity appears to be as a lactonase (76, 77).”