TY  - JOUR
A1  - Barbosa Sicard, Eduardo
A1  - Frömel, Timo
A1  - Keserü, Benjamin
A1  - Brandes, Ralf
A1  - Morisseau, Christophe
A1  - Hammock, Bruce D.
A1  - Braun, Thomas
A1  - Krüger, Marcus
A1  - Fleming, Ingrid
T1  - Inhibition of the soluble epoxide hydrolase by tyrosine nitration
T2  - Journal of biological chemistry
N2  - 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.
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/76464
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-764644
SN  - 0021-9258
VL  - 284.2009
IS  - 41
SP  - 28156
EP  - 28163
PB  - American Society for Biochemistry and Molecular Biology Publications
CY  - Bethesda, Md
ER  -