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epoxide hydrolase 2

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Target id: 2970

Nomenclature: epoxide hydrolase 2

Family: Hydrolases & Lipases

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 555 8p21.2-p21.1 EPHX2 epoxide hydrolase 2
Mouse - 554 14 34.36 cM Ephx2 epoxide hydrolase 2, cytoplasmic
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 Click here for help
epoxide hydrolase 2, cytoplasmic | sEH | soluble epoxide hydrolase | bifunctional epoxide hydrolase 2
Database Links Click here for help
Alphafold P34913 (Hs), P34914 (Mm), P80299 (Rn)
BRENDA 3.1.3.76, 3.3.2.10
ChEMBL Target CHEMBL2409 (Hs), CHEMBL4140 (Mm), CHEMBL5669 (Rn)
Ensembl Gene ENSG00000120915 (Hs), ENSMUSG00000022040 (Mm), ENSRNOG00000017286 (Rn)
Entrez Gene 2053 (Hs), 13850 (Mm), 65030 (Rn)
Human Protein Atlas ENSG00000120915 (Hs)
KEGG Enzyme 3.1.3.76, 3.3.2.10
KEGG Gene hsa:2053 (Hs), mmu:13850 (Mm), rno:65030 (Rn)
OMIM 132811 (Hs)
Pharos P34913 (Hs)
RefSeq Nucleotide NM_001979 (Hs), NM_007940 (Mm), NM_022936 (Rn)
RefSeq Protein NP_001970 (Hs), NP_031966 (Mm), NP_075225 (Rn)
UniProtKB P34913 (Hs), P34914 (Mm), P80299 (Rn)
Wikipedia EPHX2 (Hs)
Enzyme Reaction Click here for help
EC Number: 3.1.3.76
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: 3.3.2.10
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 go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SWE101 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.5 pKd 16
⤷ pKd 6.5 (Kd 3x10-7 M) [16]
Description: Binding affinity for the N-terminal domain of sEH by isothermal titration calorimetry.
EC5026 Small molecule or natural product Hs Inhibition >10.3 pKi 11
⤷ pKi >10.3 (Ki <5x10-11 M) [11]
compound G1 [PMID: 36689364] Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 10.3 pIC50 4
⤷ pIC50 10.3 (IC50 5x10-11 M) [4]
Description: Inhibition of recombinant human sEH in vitro
compound G1 [PMID: 36689364] Small molecule or natural product Immunopharmacology Ligand Mm Inhibition 9.9 pIC50 4
⤷ pIC50 9.9 (IC50 1.4x10-10 M) [4]
Description: Inhibition of recombinant mouse sEH in vitro
inhibitor M9 [PMID: 38236416] Small molecule or natural product Immunopharmacology Ligand Mm Inhibition 9.1 pIC50 5
⤷ pIC50 9.1 (IC50 7.2x10-10 M) [5]
AR-9281 Small molecule or natural product Immunopharmacology Ligand Mm Inhibition 8.8 pIC50 7
⤷ pIC50 8.8 (IC50 1.7x10-9 M) [7]
inhibitor M9 [PMID: 38236416] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.7 pIC50 5
⤷ pIC50 8.7 (IC50 2x10-9 M) [5]
MPPA Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 8.7 pIC50 3
⤷ pIC50 8.7 (IC50 2.1x10-9 M) [3]
Description: In vitro assay measuring inhibition of recombinant human sEH enzymatic activity.
dual sEH/FAAH inhibitor 11 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.3 pIC50 10
⤷ pIC50 8.3 (IC50 5x10-9 M) [10]
BI-1935 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 8.1 pIC50 21
⤷ pIC50 8.1 (IC50 7x10-9 M) [21]
Description: In a biochemical h-sEH binding assay.
AR-9281 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 8.1 – 8.1 pIC50 6,13
⤷ pIC50 8.1 (IC50 7x10-9 M) [13]
pIC50 8.1 (IC50 8x10-9 M) [6]
dual sEH/FAAH inhibitor 11 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Rn Inhibition 7.7 pIC50 15
⤷ pIC50 7.7 (IC50 1.8x10-8 M) [15]
diflapolin Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 7.7 pIC50 9
⤷ pIC50 7.7 (IC50 2x10-8 M) [9]
Description: Inhibition of isolated sEH activity in vitro.
dual sEH/FAAH inhibitor 11 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Mm Inhibition 7.6 pIC50 15
⤷ pIC50 7.6 (IC50 2.7x10-8 M) [15]
triple modulator 10 [PMID: 29878767] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.4 pIC50 20
⤷ pIC50 7.4 (IC50 4.3x10-8 M) [20]
SWE101 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.2 pIC50 16
⤷ pIC50 7.2 (IC50 5.8x10-8 M) [16]
Description: Inhibition of sEH's phosphatase activity.
GSK2256294 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 7.0 pIC50 2
⤷ pIC50 7.0 (IC50 1.1x10-7 M) [2]
Description: In a biochemical enzyme assay.
MPPA Small molecule or natural product Immunopharmacology Ligand Rn Inhibition 6.8 pIC50 3
⤷ pIC50 6.8 (IC50 1.5x10-7 M) [3]
Description: In vitro assay measuring inhibition of recombinant rat sEH enzymatic activity.
PF750 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.2 – 6.4 pIC50 15
⤷ pIC50 6.4 (IC50 3.6x10-7 M) [15]
Description: Following a 5 min preincubation with inhibitor.
pIC50 6.2 (IC50 6.4x10-7 M) [15]
zafirlukast Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 5.7 pIC50 20
⤷ pIC50 5.7 (IC50 2x10-6 M) [20]
oxaprozin Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 5.3 pIC50 14
⤷ pIC50 5.3 (IC50 5x10-6 M) [14]
Description: Inhibition of sEH's phosphatase activity in vitro using bacterially-expressed recombinant N-terminal domain of sEH.
SMTP-7 Small molecule or natural product Hs Inhibition - - 1
⤷ [1]
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 [18].
Immuno Process Associations
Immuno Process:  Inflammation
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphism
Species:  Human
Description:  A nonsynonymous SNP associated wih coronary artery calcification in African American patients.
Amino acid change:  R287Q
References:  8
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:  17
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 [19]. 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 [12]. 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.

References

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1. Bellien J, Djerada Z. (2022) Use of inhibitors of phosphatase activity of soluble epoxide for the treatment of cardiometabolic diseases. Patent number: US20220023265A1. Assignee: Universitaire De Reims. Priority date: 16/09/2019. Publication date: 27/01/2022.

2. 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

3. 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]

4. Chen Y, Chen L, Xu H, Cao R, Morisseau C, Zhang M, Shi Y, Hammock BD, Wang J, Zhuang J et al.. (2023) Structure-Directed Discovery of Potent Soluble Epoxide Hydrolase Inhibitors for the Treatment of Inflammatory Diseases. J Med Chem, 66 (4): 2979-3009. [PMID:36689364]

5. Chen Y, Sun J, Tong H, Wang J, Cao R, Xu H, Chen L, Morisseau C, Zhang M, Shi Y et al.. (2024) Design and Synthesis of Dual-Targeting Inhibitors of sEH and HDAC6 for the Treatment of Neuropathic Pain and Lipopolysaccharide-Induced Mortality. J Med Chem, 67 (3): 2095-2117. [PMID:38236416]

6. Codony S, Pujol E, Pizarro J, Feixas F, Valverde E, Loza MI, Brea JM, Saez E, Oyarzabal J, Pineda-Lucena A et al.. (2020) 2-Oxaadamant-1-yl Ureas as Soluble Epoxide Hydrolase Inhibitors: In Vivo Evaluation in a Murine Model of Acute Pancreatitis. J Med Chem, 63 (17): 9237-9257. [PMID:32787085]

7. Du F, Sun W, Morisseau C, Hammock BD, Bao X, Liu Q, Wang C, Zhang T, Yang H, Zhou J et al.. (2021) Discovery of memantyl urea derivatives as potent soluble epoxide hydrolase inhibitors against lipopolysaccharide-induced sepsis. Eur J Med Chem, 223: 113678. [PMID:34218083]

8. 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]

9. 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]

10. 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.

11. Hammock BD, McReynolds CB, Wagner K, Buckpitt A, Cortes-Puch I, Croston G, Lee KSS, Yang J, Schmidt WK, Hwang SH. (2021) Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative. J Med Chem, 64 (4): 1856-1872. [PMID:33550801]

12. 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]

13. Jones PD, Tsai HJ, Do ZN, Morisseau C, Hammock BD. (2006) Synthesis and SAR of conformationally restricted inhibitors of soluble epoxide hydrolase. Bioorg Med Chem Lett, 16 (19): 5212-6. [PMID:16870439]

14. 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]

15. 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]

16. 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]

17. 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]

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

19. 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 USA, 100 (4): 1558-63. [PMID:12574510]

20. 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]

21. 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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