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A more recent version of this article appeared on June 1, 2005

Papers In Press, published online ahead of print March 16, 2005
J. Lipid Res., doi:10.1194/jlr.M400511-JLR200
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Submitted on December 23, 2004
Revised on February 23, 2005
Accepted on March 3, 2005

Enzymatic characterization of recombinant human paraoxonases (PON1, PON2 and PON3) - lactonases with overlapping and distinct substrate specificities

Dragomir I. Draganov, John F. Teiber, Audrey Speelman, Yoichi Osawa, Roger Sunahara, and Bert N. La Du

Pharmacology Dept., University of Michigan, Ann Arbor, MI 48019-0632

Corresponding Author: 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 having 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 non-enzymatic oxidation of arachidonic and docosahexaenoic acid, respectively, and may represent 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.


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