Inhibition of the soluble epoxide hydrolase by tyrosine nitration

  • Inhibition of the soluble epoxide hydrolase (sEH) has beneficial effects on vascular inflammation and hypertension indicating that the enzyme may be a promising target for drug development. As the enzymatic core of the hydrolase domain of the human sEH contains two tyrosine residues (Tyr383 and Tyr466) that are theoretically crucial for enzymatic activity, we addressed the hypothesis that the activity of the sEH may be affected by nitrosative stress. Epoxide hydrolase activity was detected in human and murine endothelial cells as well in HEK293 cells and could be inhibited by either authentic peroxynitrite (ONOO−) or the ONOO− generator 3-morpholino-sydnonimine (SIN-1). Protection of the enzymatic core with 1-adamantyl-3-cyclohexylurea in vitro decreased sensitivity to SIN-1. Both ONOO− and SIN-1 elicited the tyrosine nitration of the sEH protein and mass spectrometry analysis of tryptic fragments revealed nitration on several tyrosine residues including Tyr383 and Tyr466. Mutation of the latter residues to phenylalanine was sufficient to abrogate epoxide hydrolase activity. In vivo, streptozotocin-induced diabetes resulted in the tyrosine nitration of the sEH in murine lungs and a significant decrease in its activity. Taken together, these data indicate that the activity of the sEH can be regulated by the tyrosine nitration of the protein. Moreover, nitrosative stress would be expected to potentiate the physiological actions of arachidonic acid epoxides by preventing their metabolism to the corresponding diols.

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Author:Eduardo Barbosa SicardGND, Timo FrömelGND, Benjamin KeserüGND, Ralf BrandesORCiDGND, Christophe MorisseauORCiD, Bruce D. HammockORCiD, Thomas BraunORCiDGND, Marcus KrügerORCiDGND, Ingrid FlemingORCiDGND
URN:urn:nbn:de:hebis:30:3-764644
DOI:https://doi.org/10.1074/jbc.M109.054759
ISSN:0021-9258
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/19704161
Parent Title (English):Journal of biological chemistry
Publisher:American Society for Biochemistry and Molecular Biology Publications
Place of publication:Bethesda, Md
Document Type:Article
Language:English
Date of Publication (online):2021/01/04
Year of first Publication:2009
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/04/16
Volume:284.2009
Issue:41
Page Number:8
First Page:28156
Last Page:28163
Institutes:Medizin
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International