The 192R/Q polymorphs of serum paraoxonase PON1 differ in HDL binding, stimulation of lipo-lactonase, and macrophage cholesterol efflux

Leonid Gaidukov, Mira Rosenblat, Michael Aviram, and Dan S. Tawfik

Biochemistry, Weizmann Institute of Science, Rehovot 76100

Corresponding Author: leonid.gaydukov{at}weizmann.ac.il

Serum paraoxonase (PON1) is a high-density lipoprotein (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 comprises part of the HDL-anchoring surface and active site of PON1. Based on our findings that PON1 is an interfacially activated lipo-lactonase 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, lipo-lactonase activity and macrophage cholesterol efflux. We also observed the lower affinity and stability of the 192Q versus the 192R isozymes 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.

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