Any feedback?
Please rate this page
(literature.php)
(0/150)

BRENDA support

Literature summary extracted from

  • Vaclavikova, R.; Hughes, D.J.; Soucek, P.
    Microsomal epoxide hydrolase 1 (EPHX1) Gene, structure, function, and role in human disease (2015), Gene, 571, 1-8 .
    View publication on PubMedView publication on EuropePMC

Activating Compound

EC Number Activating Compound Comment Organism Structure
3.3.2.9 additional information substituted imidazole, metyrapone, and ethanol activate EPHX1 in vitro Homo sapiens

Cloned(Commentary)

EC Number Cloned (Comment) Organism
3.3.2.9 gene EPHX1, located on chromosome 1 (1q42.12) consists of nine exons, and spans about 35 kb, exons 2-9 of EPHX1 encode three transcription variants differing in the 5'-untranslated region, while each translated protein product has 455 amino acids. Human EPHX1 expression in the liver is selectively driven by the proximal E1 promoter, but an alternative promoter region (E1-b promoter) drives expression in other tissues from both adult and fetal sources, e.g. an EPHX1 transcript (E1-b') generated from the upstream promoter is reported to be expressed in a tissue-selective manner with the highest level in human ovary. The E1-b promoter region harbors several functionally important polymorphisms including a double Alu insertion, which may influence interindividual susceptibility to toxicity of xenobiotics Homo sapiens

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
3.3.2.9 crystal structure determination Aspergillus niger

Protein Variants

EC Number Protein Variants Comment Organism
3.3.2.9 H139R rs2234922, A416>G, naturally occuring mutation, used as marker to predict EPHX1 activity Homo sapiens
3.3.2.9 Y113H rs1051740, T337>C, naturally occuring mutation, used as marker to predict EPHX1 activity Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
3.3.2.9 1,1,1-trichloropropene-2,3-oxide
-
 Agrobacterium tumefaciens
3.3.2.9 1,1,1-trichloropropene-2,3-oxide
-
 Homo sapiens
3.3.2.9 1,1,1-trichloropropene-2,3-oxide
-
 Mus musculus
3.3.2.9 2-nonylsulfanyl-propionamide
-
 Agrobacterium tumefaciens
3.3.2.9 2-nonylsulfanyl-propionamide
-
 Homo sapiens
3.3.2.9 2-nonylsulfanyl-propionamide
-
 Mus musculus
3.3.2.9 Cyclohexene oxide
-
 Agrobacterium tumefaciens
3.3.2.9 Cyclohexene oxide
-
 Homo sapiens
3.3.2.9 Cyclohexene oxide
-
 Mus musculus
3.3.2.9 elaidamide
-
 Agrobacterium tumefaciens
3.3.2.9 elaidamide
-
 Homo sapiens
3.3.2.9 elaidamide
-
 Mus musculus

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
3.3.2.9 endoplasmic reticulum
-
 Homo sapiens 5783
-
3.3.2.9 microsome
-
 Homo sapiens
-
-
3.3.2.9 additional information the topology of EPHX1 on the cell surface greatly varies between different cell types Homo sapiens
-
-
3.3.2.9 plasma membrane sinusoidal plasma membrane Homo sapiens 5886
-

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
3.3.2.9 androstene oxide + H2O Homo sapiens
-
 ?
-
 ?
3.3.2.9 epoxyestratrienol + H2O Homo sapiens
-
 ?
-
 ?
3.3.2.9 additional information Homo sapiens the enzyme converts epoxides to diols and is able to either detoxify or bioactivate a wide range of substrates. The prototypical EPHX1 reaction involves conversion of epoxides to trans-dihydrodiols. EPHX1 more readily converts xenobiotics than endogenous substrates ?
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
3.3.2.9 Agrobacterium tumefaciens O31243
-
-
3.3.2.9 Aspergillus niger Q5EC68
-
-
3.3.2.9 Homo sapiens P07099
-
-
3.3.2.9 Mus musculus Q9D379
-
-

Source Tissue

EC Number Source Tissue Comment Organism Textmining
3.3.2.9 astrocyte
-
 Homo sapiens
-
3.3.2.9 blood vessel synovial blood vessels and lining cells Homo sapiens
-
3.3.2.9 brain
-
 Homo sapiens
-
3.3.2.9 brain
-
 Mus musculus
-
3.3.2.9 brain cancer cell
-
 Homo sapiens
-
3.3.2.9 cerebellum
-
 Homo sapiens
-
3.3.2.9 frontal lobe
-
 Homo sapiens
-
3.3.2.9 hepatocyte
-
 Homo sapiens
-
3.3.2.9 liver
-
 Homo sapiens
-
3.3.2.9 liver
-
 Mus musculus
-
3.3.2.9 macrophage alveolar Homo sapiens
-
3.3.2.9 additional information gene expression of EPHX1 in most tissues and anatomical compartments, by microarray, SAGE, and RNASeq, highest EPHX1 transcript and protein levels in liver and skin, high inter-individual variation among humans. Immunohistochemical EPHX1 protein staining Homo sapiens
-
3.3.2.9 neuron
-
 Homo sapiens
-
3.3.2.9 occipital lobe
-
 Homo sapiens
-
3.3.2.9 ovary
-
 Homo sapiens
-
3.3.2.9 pons
-
 Homo sapiens
-
3.3.2.9 red nucleus
-
 Homo sapiens
-
3.3.2.9 skin
-
 Homo sapiens
-
3.3.2.9 substantia nigra
-
 Homo sapiens
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
3.3.2.9 1-methyl-1-phenyloxirane + H2O
-
 Homo sapiens ?
-
 ?
3.3.2.9 11,12-epoxyeicosatrienoate + H2O
-
 Homo sapiens 11,12-hydroxyeicosatrienoate
-
 ?
3.3.2.9 7,12-dimethylbenz[a]anthracene + 3 H2O
-
 Mus musculus 7,12-dimethylbenz[a]anthracene-3,4-diol-1,2-epoxide
-
 ?
3.3.2.9 androstene oxide + H2O
-
 Homo sapiens ?
-
 ?
3.3.2.9 androstene oxide + H2O
-
 Homo sapiens androstene diol
-
 ?
3.3.2.9 benzene + H2O
-
 Homo sapiens ?
-
 ?
3.3.2.9 benzo[a]pyrene 7,8-oxide + H2O
-
 Homo sapiens benzo[a]pyrene 7,8-diol
-
 ?
3.3.2.9 butadiene + H2O
-
 Homo sapiens butadienol
-
 ?
3.3.2.9 cyclohexene + H2O
-
 Homo sapiens cyclohexadiol
-
 ?
3.3.2.9 epoxyestratrienol + H2O
-
 Homo sapiens ?
-
 ?
3.3.2.9 epoxyestratrienol + H2O
-
 Homo sapiens dihydroxyestratrienol
-
 ?
3.3.2.9 ethylene oxide + H2O
-
 Homo sapiens ethylene glycol
-
 ?
3.3.2.9 indene 1,2-oxide + H2O
-
 Homo sapiens ?
-
 ?
3.3.2.9 additional information the enzyme converts epoxides to diols and is able to either detoxify or bioactivate a wide range of substrates. The prototypical EPHX1 reaction involves conversion of epoxides to trans-dihydrodiols. EPHX1 more readily converts xenobiotics than endogenous substrates Homo sapiens ?
-
 ?
3.3.2.9 additional information EPHX1 has a broad substrate specificity. It also metabolizes endocannabinoid 2-arachidonoylglycerol to free arachidonic acid and glycerol Homo sapiens ?
-
 ?
3.3.2.9 styrene + H2O
-
 Homo sapiens ?
-
 ?
3.3.2.9 styrene oxide + H2O
-
 Homo sapiens styrene glycol
-
 ?

Subunits

EC Number Subunits Comment Organism
3.3.2.9 More structure comparison of homologous EPHX enzymes with domains of cytosolic and microsomal EPHX enzymes, overview. N-terminal and C-terminal catalytic domains and caps are highly conserved. The NC-loop has a variable length from 16 to 57 residues and the cap-loop has a variable length from five to 59 residues Mus musculus
3.3.2.9 More structure comparison of homologous EPHX enzymes with domains of cytosolic and microsomal EPHX enzymes, overview. N-terminal and C-terminal catalytic domains and caps are highly conserved. The NC-loop has a variable length from 16 to 57 residues and the cap-loop has a variable length from five to 59 residues Aspergillus niger
3.3.2.9 More structure comparison of homologous EPHX enzymes with domains of cytosolic and microsomal EPHX enzymes, overview. N-terminal and C-terminal catalytic domains and caps are highly conserved. The NC-loop has a variable length from 16 to 57 residues and the cap-loop has a variable length from five to 59 residues Agrobacterium tumefaciens
3.3.2.9 More the N-terminal part anchors the EPHX1 protein into the membrane, while the C-terminus contains catalytic residues Homo sapiens

Synonyms

EC Number Synonyms Comment Organism
3.3.2.9 EPHX
-
 Homo sapiens
3.3.2.9 EPHX1
-
 Homo sapiens
3.3.2.9 EPOX
-
 Homo sapiens
3.3.2.9 HYL1
-
 Homo sapiens
3.3.2.9 mEH
-
 Homo sapiens
3.3.2.9 microsomal EPHX1
-
 Homo sapiens
3.3.2.9 Microsomal epoxide hydrolase
-
 Mus musculus
3.3.2.9 Microsomal epoxide hydrolase
-
 Aspergillus niger
3.3.2.9 Microsomal epoxide hydrolase
-
 Agrobacterium tumefaciens
3.3.2.9 microsomal epoxide hydrolase 1
-
 Homo sapiens

Expression

EC Number Organism Comment Expression
3.3.2.9 Homo sapiens HNF3 (FOXA1, 602294 and FOXB1, 600288) acts as a co-repressor in HepG2 cells down
3.3.2.9 Homo sapiens CEBPA (116897) interacts with DNA-bound NFY (A subunit, 189903, B subunit, 189904, C subunit, 605344) as an additional regulator of EPHX1 expression. Nuclear receptors HNF4A (600281), CAR (NR1I3, 603881), and RXR (RXRA, 180245 and RXRB, 180246) also bind to the proximal EPHX1 promoter region and regulate its expression in human hepatocytes additional information
3.3.2.9 Homo sapiens GATA4 (OMIM: 600576) is the major activator of EPHX1 expression. EPHX1 expression is induced by phenobarbital, beta-naphthoflavone, benzanthracene, and trans-stilbene oxide in human fetal hepatocytes in vitro up
3.3.2.9 Mus musculus methyl-2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate is a potent inducer of transcription factor Nrf2 (nuclear factor, erythroid derived 2) and significantly alters the expression of EPHX1 protein in mice indicating a potential role of redox homeostasis in EPHX1 expression up
3.3.2.9 Agrobacterium tumefaciens methyl-2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate is a potent inducer of transcription factor Nrf2 (nuclear factor, erythroid derived 2) and significantly alters the expression of EPHX1 protein in mice indicating a potential role of redox homeostasis in EPHX1 expression up

General Information

EC Number General Information Comment Organism
3.3.2.9 evolution microsomal epoxide hydrolase (EPHX1) is an evolutionarily highly conserved biotransformation enzyme for converting epoxides to diols. EPHX1 belongs to the family of alpha/beta hydrolases Homo sapiens
3.3.2.9 malfunction gene knockout mice models (Ephx1-null, mEH-/-) are fertile and have no phenotypic abnormalities, but a lack of bioactivation of 7,12-dimethylbenz[a]anthracene to the carcinogenic metabolite 3,4-diol-1,2-oxide. Disappearance of benzene-induced hematotoxicity and myelotoxicity in mEH-/- mice compared with the wild type ones Mus musculus
3.3.2.9 malfunction mutations and polymorphic variants in the EPHX1 gene are associated with susceptibility to several human diseases including cancer. Mutations in EPHX1 may cause preeclampsia, hypercholanemia, and are suspected to contribute to fetal hydantoin syndrome and diphenylhydantoin toxicity. Japanese epilepsy patients carry an EPHX1 diplotype consisting of at least two His alleles in both rs1051740 and rs2234922. These patients show increased plasma carbamazepine-diol/carbamazepine-epoxide ratios. The rs2292566 single-nucleotide polymorphism (SNP) in EPHX1 may affect the maintenance dosage of the widely used anticoagulant warfarin. A significant association of the low EPHX1 activity diplotype harboring the rs1051740 and rs2234922 SNPs with alcohol dependence supports the role of EPHX1 genotype in the risk of alcoholic liver disease. Two non-synonymous EPHX1 SNPs (rs72549341 and rs148240980) are predicted by in silico models as breast cancer susceptibility modifiers. Low activity EPHX1 alleles harboring the rs1051740 SNP increases the risk of localized, but not advanced, prostate carcinoma. The rs1051740 His allele is significantly underrepresented in males with non-Hodgkin's lymphomas compared to healthy control individuals Homo sapiens
3.3.2.9 additional information quantitative structure-activity relationship (QSAR) modeling. The enzyme structure is used for predictions of small molecule binding Aspergillus niger
3.3.2.9 additional information the N-terminal part anchors the EPHX1 protein into the membrane, while the C-terminus contains catalytic residues. The catalytic triad activity consists of fast nucleophilic attack of the substrate by the EPHX1-Asp226 residue forming an enzyme-substrate ester intermediate and subsequent hydrolysis of this complex by activated water. Water activation is fuelled by proton abstraction from the EPHX1-His431-Glu404 charge relay system. Tyr374 of human EPHX1 also performs a significant mechanistic role in substrate activation Homo sapiens
3.3.2.9 physiological function enzyme EPHX1 appears to play an important role in organ-specific human physiology . The enzyme is able to either detoxify or bioactivate a wide range of substrates. An EPHX1 transcription-independent (both cis and trans) regulatory role is suggested for E1-b', a distinct EPHX1 transcript generated from the upstream promoter expressed in a tissue-selective manner in ovaries. Complex EPHX1 gene regulation, overview. EPHX1 more readily converts xenobiotics than endogenous substrates and has mostly a detoxifying function. Microsomal EPHX1 plays a dual role in the biotransformation of xenobiotics. While it detoxifies certain carcinogenic compounds, e.g., butadiene, benzene, styrene etc., it can also activate procarcinogens such as polycyclic aromatic hydrocarbons on the other hand. EPHX1 is also expressed on the sinusoidal plasma membrane where it mediates the sodium-dependent transport of bile acids into hepatocytes. Role of EPHX1 in pathogenesis of neurodegeneration with differential expression in patients with Alzheimer's disease. EPHX1 plays a role in the styrene detoxification pathway with genetic susceptibility to DNA damage in exposed subjects Homo sapiens
3.3.2.9 physiological function EPHX1 is an endogenous modulator of drug dependence in mice. EPHX1 contributes to the cerebral metabolism of epoxyeicosatrienoic acids which might interfere with neuronal signal transmission, vasodilation, cardiovascular homeostasis, and inflammation. Role of mEH in bioactivation of certain polycyclic aromatic hydrocarbons, e.g. 7,12-dimethylbenz[a]anthracene Mus musculus