Effect of soluble epoxide hydrolase polymorphism on substrate and inhibitor selectivity and dimer formation

Christophe Morisseau, Aaron T. Wecksler, Catherine Deng, Hua Dong, Jun Yang, Kin Sing S Lee, Sean D. Kodani, Bruce D. Hammock

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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 infl ammatory, 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.

Original languageEnglish (US)
Pages (from-to)1131-1138
Number of pages8
JournalJournal of Lipid Research
Volume55
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Epoxide Hydrolases
Polymorphism
Dimers
Substrates
Single Nucleotide Polymorphism
Metabolic Diseases
Enzyme activity
Enzymes
Amino Acid Substitution
Catalyst activity
Substitution reactions
Cardiovascular Diseases
Monomers
Tissue
Lipids
Amino Acids

Keywords

  • Epoxy-fatty acids
  • Infl ammation
  • Pain

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

Cite this

Morisseau, C., Wecksler, A. T., Deng, C., Dong, H., Yang, J., Lee, K. S. S., ... Hammock, B. D. (2014). Effect of soluble epoxide hydrolase polymorphism on substrate and inhibitor selectivity and dimer formation. Journal of Lipid Research, 55(6), 1131-1138. https://doi.org/10.1194/jlr.M049718

Effect of soluble epoxide hydrolase polymorphism on substrate and inhibitor selectivity and dimer formation. / Morisseau, Christophe; Wecksler, Aaron T.; Deng, Catherine; Dong, Hua; Yang, Jun; Lee, Kin Sing S; Kodani, Sean D.; Hammock, Bruce D.

In: Journal of Lipid Research, Vol. 55, No. 6, 2014, p. 1131-1138.

Research output: Contribution to journalArticle

Morisseau, C, Wecksler, AT, Deng, C, Dong, H, Yang, J, Lee, KSS, Kodani, SD & Hammock, BD 2014, 'Effect of soluble epoxide hydrolase polymorphism on substrate and inhibitor selectivity and dimer formation', Journal of Lipid Research, vol. 55, no. 6, pp. 1131-1138. https://doi.org/10.1194/jlr.M049718
Morisseau, Christophe ; Wecksler, Aaron T. ; Deng, Catherine ; Dong, Hua ; Yang, Jun ; Lee, Kin Sing S ; Kodani, Sean D. ; Hammock, Bruce D. / Effect of soluble epoxide hydrolase polymorphism on substrate and inhibitor selectivity and dimer formation. In: Journal of Lipid Research. 2014 ; Vol. 55, No. 6. pp. 1131-1138.
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