Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 515, Issue 1, Pages 248-253Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2019.05.088
Keywords
Soluble epoxide hydrolase; Phosphatase; Inhibitor
Categories
Funding
- Japan Society for the Promotion of Science [17H02201, ES002710]
- National Institute of Environmental Health Sciences (NIEHS)
- Grants-in-Aid for Scientific Research [17H02201] Funding Source: KAKEN
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The soluble epoxide hydrolase (sEH) is a bifunctional enzyme implicated in the regulation of inflammation. The N-terminal domain harbors a phosphatase activity (N-phos) with an affinity to lipid phosphomonoesters, and the C-terminal domain has an activity to hydrolyze anti-inflammatory lipid epoxides (C-EH). Although many potent inhibitors of C-EH have been discovered, little is known about inhibitors of N-phos. Here, we identify N-substituted amino acids as selective inhibitors of N-phos. Many of the N-substituted amino acids inhibited differently mouse and human N-phos; phenylalanine derivatives are relatively selective for mouse N-phos, whereas tyrosine derivatives are more selective for human N-phos. The best inhibitors, Fmoc-L-Phe(4-CN) (67) and Boc-L-Tyr(Bzl) (23), inhibited mouse and human N-phos competitively with K-I in the low micromolar range. These compounds inhibit the N-phos activity 37- (67) and 137-folds (23) more potently than the C-EH. The differences in inhibitor structure activity suggest different active site structure between species, and thus, probably a divergent substrate preference between mouse and human N-phos. (C) 2019 Elsevier Inc. All rights reserved.
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