Probing the orientation of inhibitor and epoxy-eicosatrienoic acid binding in the active site of soluble epoxide hydrolase

Kin Sing Stephen Lee, Niel M. Henriksen, Connie J. Ng, Jun Yang, Weitao Jia, Christophe Morisseau, Armann Andaya, Michael K. Gilson, Bruce D. Hammock

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Soluble epoxide hydrolase (sEH) is an important therapeutic target of many diseases, such as chronic obstructive pulmonary disease (COPD) and diabetic neuropathic pain. It acts by hydrolyzing and thus regulating specific bioactive long chain polyunsaturated fatty acid epoxides (lcPUFA), like epoxyeicosatrienoic acids (EETs). To better predict which epoxides could be hydrolyzed by sEH, one needs to dissect the important factors and structural requirements that govern the binding of the substrates to sEH. This knowledge allows further exploration of the physiological role played by sEH. Unfortunately, a crystal structure of sEH with a substrate bound has not yet been reported. In this report, new photoaffinity mimics of a sEH inhibitor and EET regioisomers were prepared and used in combination with peptide sequencing and computational modeling, to identify the binding orientation of different regioisomers and enantiomers of EETs into the catalytic cavity of sEH. Results indicate that the stereochemistry of the epoxide plays a crucial role in dictating the binding orientation of the substrate.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalArchives of Biochemistry and Biophysics
Volume613
DOIs
StatePublished - Jan 1 2017

Keywords

  • Computational simulation
  • Epoxyeicosatrienoic acid
  • Peptide sequencing
  • Photoaffinity tag
  • Photolabel
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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    Lee, K. S. S., Henriksen, N. M., Ng, C. J., Yang, J., Jia, W., Morisseau, C., Andaya, A., Gilson, M. K., & Hammock, B. D. (2017). Probing the orientation of inhibitor and epoxy-eicosatrienoic acid binding in the active site of soluble epoxide hydrolase. Archives of Biochemistry and Biophysics, 613, 1-11. https://doi.org/10.1016/j.abb.2016.10.017