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J. Biol. Chem., Vol. 282, Issue 1, 100-108, January 5, 2007

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Phospholipase Action of Platelet-activating Factor Acetylhydrolase, but Not Paraoxonase-1, on Long Fatty Acyl Chain Phospholipid Hydroperoxides^*

Tamas Kriska, Gopal K. Marathe, Jacob C. Schmidt, Thomas M. McIntyre¹, and Albert W. Girotti²

From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and the Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, Ohio 44195

Phospholipid hydroperoxide (PLOOH) degrading activity of high density lipoprotein (HDL)-derived paraoxonase-1 (PON1) was investigated, using peroxidized 1-palmitoyl-2-oleoyl phosphatidylcholine (PCOOH) as substrate and high performance thin layer chromatography for quantitative peroxide analysis. Incubation of PCOOH with PON1 resulted in decay of the latter and reciprocal buildup of oleic acid hydroperoxide (OAOOH) at rates unaffected by GSH or other reductants. A serine esterase inhibitor blocked this activity and a recombinant PON1 was devoid of it, raising the possibility that the activity represents platelet-activating factor acetylhydrolase (PAF-AH), an esterase that co-purifies with PON1 from HDL. This was verified by showing that a recombinant PAF-AH recapitulates the ability of natural PON1 to hydrolyze PCOOH and release OAOOH while having essentially no effect on parental PC. Furthermore, recombinant PAF-AH and natural PON1 were shown to have similar K_m values for PCOOH hydrolysis. Finally, we found that recombinant PAF-AH, but not PON1, catalyzes PLOOH hydrolysis in peroxidized low density lipoprotein. We conclude from this study that PON1 is neither a PLOOH peroxidase nor hydrolase and that the phospholipase A₂-like activity previously attributed to PON1 in natural enzyme preparations was actually due to novel PLOOH hydrolytic activity of contaminating PAF-AH.

Received for publication, August 24, 2006 , and in revised form, November 6, 2006.

^* This work was supported by National Institutes of Health Grants HL44513 (to T. M. M.) and CA72630 (to A. W. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Dept. of Cell Biology, NE-10, Lerner Research Institute, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-444-1048; Fax: 216-444-9404; E-mail: mcintyt{at}ccf.org. ² To whom correspondence may be addressed: Dept. of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226. Tel.: 414-456-8432; Fax: 414-456-6510; E-mail: agirotti{at}mcw.edu.

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