文章基本信息

标题：Effect of soluble epoxide hydrolase polymorphism on substrate and inhibitor selectivity and dimer formation
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作者：Christophe Morisseau ; Aaron T. Wecksler ; Catherine Deng 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2014
卷号：55
期号：6
页码：1131-1138
DOI：10.1194/jlr.M049718
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：Epoxy FAs (EpFAs) are important lipid mediators that are mainly metabolized by soluble epoxide hydrolase (sEH). Thus, sEH inhibition is a promising therapeutic target to treat numerous ailments. Several sEH polymorphisms result in amino acid substitutions and alter enzyme activity. K55R and R287Q are associated with inflammatory, cardiovascular, and metabolic diseases. R287Q seems to affect sEH activity through reducing formation of a catalytically active dimer. Thus, understanding how these SNPs affect the selectivity of sEH for substrates and inhibitors is of potential clinical importance. We investigated the selectivity of four sEH SNPs toward a series of EpFAs and inhibitors. We found that the SNPs alter the catalytic activity of the enzyme but do not alter the relative substrate and inhibitor selectivity. We also determined their dimer/monomer constants ( K_D/M ). The WT sEH formed a very tight dimer, with a K_D/M in the low picomolar range. Only R287Q resulted in a large change of the K_D/M . However, human tissue concentrations of sEH suggest that it is always in its dimer form independently of the SNP. These results suggest that the different biologies associated with K55R and R287Q are not explained by alteration in dimer formation or substrate selectivity.
关键词：epoxy-fatty acids ; inflammation ; pain