The 192R/Q polymorphs of serum paraoxonase PON1 differ in HDL binding, lipolactonase stimulation, and cholesterol efflux.
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.
Gaidukov
Leonid
L
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Rosenblat
Mira
M
Aviram
Michael
M
Tawfik
Dan S
DS
D043303:Aryldialkylphosphatase / Q000235:genetics*; D002384:Catalysis; D002784:Cholesterol / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D007700:Kinetics; D007783:Lactones / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000235:genetics* / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008956:Models, Chemical; D011110:Polymorphism, Genetic; D020033:Protein Isoforms; D020349:Surface Plasmon Resonance
D007783:Lactones; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D020033:Protein Isoforms; D002784:Cholesterol; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human