Epoxide hydrolase 2
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| Location (UCSC) | Chr 8: 27.49 – 27.55 Mb | Chr 14: 66.32 – 66.36 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that in humans is encoded by the EPHX2 gene.[5][6][7] sEH is a member of the epoxide hydrolase family. This enzyme, found in both the cytosol and peroxisomes, binds to specific epoxides and converts them to the corresponding diols. A different region of this protein also has lipid-phosphate phosphatase activity. Mutations in the EPHX2 gene have been associated with familial hypercholesterolemia.[5]
Tissue distribution
While most highly expressed in the liver, sEH is also expressed in other tissues including vascular
Catalyzed reactions
The form of sEH in the intracellular environment is a
The C-term-EH catalyzes the addition of water to an epoxide to yield a vicinal diol (reaction 1).[6] The Nterm-phos hydrolyzes phosphate monoesters, such as lipid phosphates, to yield alcohols and phosphoric acid (reaction 2).[6] The C-term-EH hydrolyzes one important class of lipid signaling molecules that includes many epoxyeicosatrienoic acids (EETs) that have vasoactive, anti-inflammatory and analgesic properties.[9]
sEH also appears to be the hepoxilin hydrolase that is responsible for inactivating the epoxyalcohol metabolites of arachidonic acid, hepoxilin A3 and hepoxiin B3.[10][11]
Discovery
The sEH was first identified in the cytosolic fraction of mouse liver through its activity on epoxide containing substrates such as juvenile hormone and lipid epoxides such as epoxystearate.[12] The soluble EH activity was shown to be distinct from that of the microsomal epoxide hydrolase (mEH) previously discovered with a different substrate selectivity and cellular localization than the mEH. Studies using a lipid epoxide as a substrate detected this activity in the soluble fraction of multiple organs, though at a lesser amount than in liver and kidney.[13] The enzyme activity was detected in rabbits, mice and rats, and humans, and it is now believed to be ubiquitous in vertebrates.[14] The proposed enzyme was first named cytosolic epoxide hydrolase; however, after its discovery inside the peroxisomes of some organs, it was renamed soluble epoxide hydrolase or sEH.[14]
Function
sEH has a restricted substrate selectivity, and has not been shown to hydrolyze any toxic or mutagenic
The proposed role of sEH in the regulation of hypertension can be used as a simple model of sEH function in the kidney.
This simplified model is complicated by a number of factors in vivo. The EETs display different properties in different vascular beds.[15] The DHETs are more readily excreted, but they have yet to be fully characterized, and may possess biological properties themselves, complicating the balance of signals described in the simplified model.[6] There are epoxides of other lipids besides arachidonic acid such as the omega three docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) epoxides.[19] These lipid epoxides have been shown to have biological effects in vitro in which they inhibit platelet aggregation.[20] In fact, in some assays they are more potent than the EETs.[21] Other epoxidized lipids include the 18-carbon leukotoxin and isoleukotoxin.[22] The diepoxide of linoleic acid can form tetrahydrofuran diols,[23]
sEH metabolizes the biologically active epoxyalcohol metabolites of arachidnoic acid, hepoxilin A3 (8-hydroxy-11S,12Sepoxy-(5Z,8Z,14Z)-eicosatrienoic acid) to trioxilin A3 (8,11,12-trihydroxy-(5Z,9E,14Z)-eicosatrienoic acid) and hepoxilin B3 (10-hydroxy-11S,12Sepoxy-(5Z,9E,14Z)-eicosatrienoic acid) to trioxlin B3 (10,11,12-trihydroxy-(5Z,9E,14Z)-eicosatrienoic acid.[24] These trihydroxy products are generally considered to be inactive and the sEH pathway is generally considered to limit the actions of the hepoxilins.[11][24]
The phosphatase activity of sEH has been shown to hydrolyze in vitro lipid phosphates such as terpene pyrophosphates or lysophosphatidic acids.[6] Studies suggest a potential role of sEH in regulating cholesterol biosynthesis and metabolism in the brain. If the N-terminal domain of sEH is regulating cholesterol metabolism, it emplies that higher levels of its phosphatase activity could potentially increase brain cholesterol concentrations.[25] However, its biological role is still unknown.
Clinical significance
Through metabolism of EETs and other lipid mediators, sEH plays a role in several diseases, including
Because of the implications to human health, sEH has been pursued as a pharmaceutical target and several sEH inhibitors have been developed in the private and public sectors.
One indication of the possible therapeutic value of sEH inhibition comes from studies examining physiologically relevant
Notes
Wikidata Q28291292 . |
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000120915 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022040 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: Epoxide hydrolase 2, cytoplasmic".
- ^ PMID 23020295.
- PMID 23701967.
- PMID 18319271.
- ^ PMID 16987999.
- PMID 21217101.
- ^ PMID 24021977.
- PMID 18383502.
- PMID 7362652.
- ^ PMID 15748653.
- ^ PMID 19794443.
- PMID 21942677.
- ^ PMID 16093425.
- ^ PMID 22168898.
- PMID 21854866.
- S2CID 84732148.
- PMID 18952572.
- S2CID 27194509.
- PMID 8765137.
- ^ PMID 25240838.
- PMID 32063836.
- ^ "NCT00847899". Evaluation of Soluble Epoxide Hydrolase (s-EH) Inhibitor in Patients With Mild to Moderate Hypertension and Impaired Glucose Tolerance. ClinicalTrials.gov. Retrieved 2013-05-04.
- ^ Clinical trial number NCT01762774 for "A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Doses of GSK2256294 in Healthy Volunteers, and Single and Repeat Doses of GSK2256294 in Adult Male Moderately Obese Smokers" at ClinicalTrials.gov
- S2CID 171511522.
- S2CID 25890544.
- PMID 30546909.
- S2CID 17629284.
- ^ PMID 14732757.
- ^ PMID 16595607.
- PMID 16545818.
Further reading
- Sandberg M, Hassett C, Adman ET, Meijer J, Omiecinski CJ (September 2000). "Identification and functional characterization of human soluble epoxide hydrolase genetic polymorphisms". J. Biol. Chem. 275 (37): 28873–81. PMID 10862610.
- Farin FM, Janssen P, Quigley S, Abbott D, Hassett C, Smith-Weller T, Franklin GM, Swanson PD, Longstreth WT, Omiecinski CJ, Checkoway H (November 2001). "Genetic polymorphisms of microsomal and soluble epoxide hydrolase and the risk of Parkinson's disease". Pharmacogenetics. 11 (8): 703–8. PMID 11692079.
- Horti AG, Wang Y, Minn I, Lan X, Wang J, Koehler RC, Alkayed NJ, Dannals RF, Pomper MG (July 2016). "18F-FNDP for PET Imaging of Soluble Epoxide Hydrolase". Journal of Nuclear Medicine. 57 (11): 1817–1822. PMID 27417650.
- Cronin A, Mowbray S, Dürk H, Homburg S, Fleming I, Fisslthaler B, Oesch F, Arand M (February 2003). "The N-terminal domain of mammalian soluble epoxide hydrolase is a phosphatase". Proc. Natl. Acad. Sci. U.S.A. 100 (4): 1552–7. PMID 12574508.
- Petruzzelli S, Franchi M, Gronchi L, Janni A, Oesch F, Pacifici GM, Giuntini C (March 1992). "Cigarette smoke inhibits cytosolic but not microsomal epoxide hydrolase of human lung". Hum Exp Toxicol. 11 (2): 99–103. S2CID 31597447.
- Papadopoulos D, Gröndal S, Rydström J, DePierre JW (May 1992). "Levels of cytochrome P-450, steroidogenesis and microsomal and cytosolic epoxide hydrolases in normal human adrenal tissue and corresponding tumors". Cancer Biochem. Biophys. 12 (4): 283–91. PMID 1423213.
- Yoshimura K, Hanaoka T, Ohnami S, Ohnami S, Kohno T, Liu Y, Yoshida T, Sakamoto H, Tsugane S (2003). "Allele frequencies of single nucleotide polymorphisms (SNPs) in 40 candidate genes for gene-environment studies on cancer: data from population-based Japanese random samples". J. Hum. Genet. 48 (12): 654–8. PMID 14634838.
- Sato K, Emi M, Ezura Y, Fujita Y, Takada D, Ishigami T, Umemura S, Xin Y, Wu LL, Larrinaga-Shum S, Stephenson SH, Hunt SC, Hopkins PN (2004). "Soluble epoxide hydrolase variant (Glu287Arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred". J. Hum. Genet. 49 (1): 29–34. PMID 14673705.
- Gomez GA, Morisseau C, Hammock BD, PMID 15096040.
