epoxide hydrolase 2 | Hydrolases | IUPHAR/BPS Guide to PHARMACOLOGY

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epoxide hydrolase 2

target has curated data in GtoImmuPdb

Target id: 2970

Nomenclature: epoxide hydrolase 2

Family: Hydrolases

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 555 8p21.2-p21.1 EPHX2 epoxide hydrolase 2
Mouse - 554 14 D1; 14 34.36 cM Ephx2 epoxide hydrolase 2
Rat - 554 15p12 Ephx2 epoxide hydrolase 2
Gene and Protein Information Comments
Three protein isoforms are reported from the human gene, with isoform a (555 amino acids) being the longest. The mouse gene produces 4 transcripts and protein isoforms, isoform a being the longest at 554 amino acids.
Previous and Unofficial Names
epoxide hydrolase 2, cytoplasmic | sEH | soluble epoxide hydrolase | bifunctional epoxide hydrolase 2
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
RefSeq Nucleotide
RefSeq Protein
Enzyme Reaction
EC Number:
Description Reaction Reference
Lipid-phosphate phosphatase activity (9S,10S)-10-hydroxy-9-(phosphonooxy)octadecanoate + H(2)O <=> (9S,10S)-9,10-dihydroxyoctadecanoate + phosphate
EC Number:
Description Reaction Reference
Epoxide hydrase activity An epoxide + H(2)O <=> a glycol

Download all structure-activity data for this target as a CSV file

Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SWE101 Hs Inhibition 6.5 pKd 9
pKd 6.5 (Kd 3x10-7 M) [9]
Description: Binding affinity for the N-terminal domain of sEH by isothermal titration calorimetry.
MPPA Hs Inhibition 8.7 pIC50 2
pIC50 8.7 (IC50 2.1x10-9 M) [2]
Description: In vitro assay measuring inhibition of recombinant human sEH enzymatic activity.
dual sEH/FAAH inhibitor 11 Hs Inhibition 8.3 pIC50 5
pIC50 8.3 (IC50 5x10-9 M) [5]
BI-1935 Hs Inhibition 8.1 pIC50 14
pIC50 8.1 (IC50 7x10-9 M) [14]
Description: In a biochemical h-sEH binding assay.
dual sEH/FAAH inhibitor 11 Rn Inhibition 7.7 pIC50 8
pIC50 7.7 (IC50 1.8x10-8 M) [8]
diflapolin Hs Inhibition 7.7 pIC50 4
pIC50 7.7 (IC50 2x10-8 M) [4]
Description: Inhibition of isolated sEH activity in vitro.
dual sEH/FAAH inhibitor 11 Mm Inhibition 7.6 pIC50 8
pIC50 7.6 (IC50 2.7x10-8 M) [8]
triple modulator 10 [PMID: 29878767] Hs Inhibition 7.4 pIC50 13
pIC50 7.4 (IC50 4.3x10-8 M) [13]
SWE101 Hs Inhibition 7.2 pIC50 9
pIC50 7.2 (IC50 5.8x10-8 M) [9]
Description: Inhibition of sEH's phosphatase activity.
GSK2256294 Hs Inhibition 7.0 pIC50 1
pIC50 7.0 (IC50 1.1x10-7 M) [1]
Description: In a biochemical enzyme assay.
MPPA Rn Inhibition 6.8 pIC50 2
pIC50 6.8 (IC50 1.5x10-7 M) [2]
Description: In vitro assay measuring inhibition of recombinant rat sEH enzymatic activity.
PF750 Hs Inhibition 6.2 – 6.4 pIC50 8
pIC50 6.4 (IC50 3.6x10-7 M) [8]
Description: Following a 5 min preincubation with inhibitor.
pIC50 6.2 (IC50 6.4x10-7 M) [8]
zafirlukast Hs Inhibition 5.7 pIC50 13
pIC50 5.7 (IC50 2x10-6 M) [13]
oxaprozin Hs Inhibition 5.3 pIC50 7
pIC50 5.3 (IC50 5x10-6 M) [7]
Description: Inhibition of sEH's phosphatase activity in vitro using bacterially-expressed recombinant N-terminal domain of sEH.
View species-specific inhibitor tables
Immunopharmacology Comments
Its role in metabolism of arachadonic acid EET metabolites, means that sEH participates in the regulation of prostaglandin and leukotriene production and therefore in immune homeostasis. Small molecule sEH inhibitors can be used as chemical probes to investigate EET (immuno)biology [11].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes
GO:0002539 prostaglandin production involved in inflammatory response ISO
GO:0006954 inflammatory response NAS
Biologically Significant Variants
Type:  Single nucleotide polymorphism
Species:  Human
Description:  A nonsynonymous SNP associated wih coronary artery calcification in African American patients.
Amino acid change:  R287Q
References:  3
Type:  Single nucleotide polymorphism
Species:  Human
Description:  A nonsynonymous SNP associated wih the risk of developing coronary heart disease in Caucasian patients, and with a higher risk of hypertension and ischemic stroke in male homozygotes
Amino acid change:  K55R
References:  10
General Comments
Epoxide hydrolase 2 (sEH) performs two enzymatic functions. The C terminal contains an epoxide hydrolase domain and the N terminal has a lipid phosphatase domain [12]. sEH plays a major role in the metabolism of endogenous chemical mediators originated from arachidonic acid, including epoxyeicosatrienoic acids (EETs, which are arachidonic acid metabolites produced by certain Cyp450 enzymes) and squalene oxide (a key intermediate in cholesterol biosynthesis). Through metabolism of EETs and other lipid mediators, sEH plays a role in several pathologies, including hypertension, cardiac hypertrophy, and arteriosclerosis [6]. It also appears to be involved in pain mechanisms. Inhibition of sEH is expected to increase EETs levels, thereby potentiating their in vivo anti-inflammatory and vasodilatory effects. Novel drugs targeting sEH have progressed to clinical trial for inflammatory and cardiovascular diseases.


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1. Blocher R, Lamers C, Wittmann SK, Diehl O, Hanke T, Merk D, Steinhilber D, Schubert-Zsilavecz M, Kahnt AS, Proschak E. (2016) Design and synthesis of fused soluble epoxide hydrolase/peroxisome proliferator-activated receptor modulators. Medchemcomm, 7: 1209-1216. DOI: 10.1039/C6MD00042H

2. Blöcher R, Wagner KM, Gopireddy RR, Harris TR, Wu H, Barnych B, Hwang SH, Xiang YK, Proschak E, Morisseau C et al.. (2018) Orally Available Soluble Epoxide Hydrolase/Phosphodiesterase 4 Dual Inhibitor Treats Inflammatory Pain. J. Med. Chem., 61 (8): 3541-3550. [PMID:29614224]

3. Fornage M, Boerwinkle E, Doris PA, Jacobs D, Liu K, Wong ND. (2004) Polymorphism of the soluble epoxide hydrolase is associated with coronary artery calcification in African-American subjects: The Coronary Artery Risk Development in Young Adults (CARDIA) study. Circulation, 109 (3): 335-9. [PMID:14732757]

4. Garscha U, Romp E, Pace S, Rossi A, Temml V, Schuster D, König S, Gerstmeier J, Liening S, Werner M et al.. (2017) Pharmacological profile and efficiency in vivo of diflapolin, the first dual inhibitor of 5-lipoxygenase-activating protein and soluble epoxide hydrolase. Sci Rep, 7 (1): 9398. [PMID:28839250]

5. Hammock B, Kodani S. (2017) Inhibitors for soluble epoxide hydrolase (seh) and fatty acid amide hydrolase (faah). Patent number: WO2017160861A1. Assignee: The Regents Of The University Of California. Priority date: 15/03/2016. Publication date: 21/09/2017.

6. Imig JD, Hammock BD. (2009) Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. Nat Rev Drug Discov, 8 (10): 794-805. [PMID:19794443]

7. Klingler FM, Wolf M, Wittmann S, Gribbon P, Proschak E. (2016) Bacterial Expression and HTS Assessment of Soluble Epoxide Hydrolase Phosphatase. J Biomol Screen, 21 (7): 689-94. [PMID:27009944]

8. Kodani SD, Wan D, Wagner KM, Hwang SH, Morisseau C, Hammock BD. (2018) Design and Potency of Dual Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase Inhibitors. ACS Omega, 3 (10): 14076-14086. DOI: 10.1021/acsomega.8b01625 [PMID:30411058]

9. Kramer JS, Woltersdorf S, Duflot T, Hiesinger K, Lillich FF, Knöll F, Wittmann SK, Klingler FM, Brunst S, Chaikuad A et al.. (2019) Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain. J. Med. Chem., 62 (18): 8443-8460. [PMID:31436984]

10. Lee CR, North KE, Bray MS, Fornage M, Seubert JM, Newman JW, Hammock BD, Couper DJ, Heiss G, Zeldin DC. (2006) Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study. Hum. Mol. Genet., 15 (10): 1640-9. [PMID:16595607]

11. Morisseau C, Hammock BD. (2013) Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health. Annu. Rev. Pharmacol. Toxicol., 53: 37-58. [PMID:23020295]

12. Newman JW, Morisseau C, Harris TR, Hammock BD. (2003) The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity. Proc. Natl. Acad. Sci. U.S.A., 100 (4): 1558-63. [PMID:12574510]

13. Schierle S, Flauaus C, Heitel P, Willems S, Schmidt J, Kaiser A, Weizel L, Goebel T, Kahnt AS, Geisslinger G et al.. (2018) Boosting Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology. J. Med. Chem., 61 (13): 5758-5764. [PMID:29878767]

14. Taylor SJ, Soleymanzadeh F, Eldrup AB, Farrow NA, Muegge I, Kukulka A, Kabcenell AK, De Lombaert S. (2009) Design and synthesis of substituted nicotinamides as inhibitors of soluble epoxide hydrolase. Bioorg. Med. Chem. Lett., 19 (20): 5864-8. [PMID:19758802]

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