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Papers In Press, published online ahead of print June 1, 2005
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Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109
The online version of this article (available at http://www.jlr.org) contains additional text, figures, and references.
Published, JLR Papers in Press, March 16, 2005. DOI 10.1194/jlr.M400511-JLR200
1 To whom correspondence should be addressed. e-mail: draganov{at}umich.edu
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.
Abbreviations: ACN, acetonitrile; AHL, acylhomoserine lactone; DDM, n-dodecyl-ß-D-maltoside; 5,6-DHTL, 5,6-dihydroxytrienoic acid 1,5-lactone; 5,6-EET, 5,6-epoxyeicosatrienoic acid; EndoH, endoglycosidase H; 4-HDoHE, (±)4-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid; 5-HETEL, (±)5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid 1,5-lactone; PLA2, phospholipase A2; PON, paraoxonase; thio-PAF, 2-thio platelet-activating factor
Supplementary key words N-acyl-homoserine lactones • protein expression and purification • arylesterase • low density lipoprotein oxidation
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