Effect of soluble epoxide hydrolase polymorphism on substrate and inhibitor selectivity and dimer formation.
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 (KD/M). The WT sEH formed a very tight dimer, with a KD/M in the low picomolar range. Only R287Q resulted in a large change of the KD/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.
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616.
Christophe
C
Morisseau
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616.
Aaron T
AT
Wecksler
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616.
Catherine
C
Deng
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616.
Hua
H
Dong
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616.
Jun
J
Yang
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616.
Kin Sing S
KS
Lee
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616.
Sean D
SD
Kodani
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616.
Bruce D
BD
Hammock
D019943:Amino Acid Substitution; D002384:Catalysis; D004851:Epoxide Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D055503:Protein Multimerization / Q000235:genetics*
D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human
epoxy-fatty acids; inflammation; pain