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Papers In Press, published online ahead of print November 1, 2006
J. Lipid Res., doi:10.1194/jlr.M600297-JLR200
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Journal of Lipid Research, Vol. 47, 2492-2502, November 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology
The 192R/Q polymorphs of serum paraoxonase PON1 differ in HDL binding, lipolactonase stimulation, and cholesterol efflux
* Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel
Technion Faculty of Medicine, Rappaport Family Institute for Research in the Medical Sciences, Rambam Medical Center, Haifa 31096, Israel
Published, JLR Papers in Press, August 16, 2006.
The online version of this article (available at http://www.jlr.org) contains an additional figure.
1 To whom correspondence should be addressed. e-mail: tawfik{at}weizmann.ac.il
Serum paraoxonase (PON1) is a HDL-associated enzyme exhibiting potentially antiatherogenic properties. Here, we examined the common PON1-192R/Q human polymorphism. Despite numerous studies, the effect of this polymorphism on the antiatherogenic potential of PON1 is yet unresolved. Our structural model suggests that amino acid 192 constitutes part of the HDL-anchoring surface and active site of PON1. Based on our findings that PON1 is an interfacially activated lipolactonase that selectively binds HDL carrying apolipoprotein A-I (apoA-I) and is thereby greatly stabilized and catalytically activated, we examined the interaction of the PON1-192 isozymes with reconstituted HDL-apoA-I particles. We found that PON1 position 192 is indeed involved in HDL binding. The PON1-192Q binds HDL with a 3-fold lower affinity than the R isozyme and consequently exhibits significantly reduced stability, lipolactonase activity, and macrophage cholesterol efflux. We also observed the lower affinity and stability of the 192Q versus the 192R isozyme in sera of individuals belonging to the corresponding genotypes. The observed differences in the properties of PON1-192R/Q isozymes provide a basis for further analysis of the contribution of the 192R/Q polymorphism to the susceptibility to atherosclerosis, although other factors, such as the overall levels of PON1, may play a more significant role.
Supplementary key words paraoxonase isozymes • polymorphism • atherosclerosis • lactones • sera tests • lipoproteins • low density lipoprotein oxidation • enzyme stability • high density lipoprotein
Abbreviations: apoA-I, apolipoprotein A-I; HSL, homoserine lactone; NTA, nitrilotriacetic acid; PON1, serum paraoxonase; rePON1, recombinant serum paraoxonase; rHDL, reconstituted high density lipoprotein
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