3.3.2.9: microsomal epoxide hydrolase
This is an abbreviated version!
For detailed information about microsomal epoxide hydrolase, go to the full flat file.
Word Map on EC 3.3.2.9
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3.3.2.9
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phenobarbital
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cholesterol
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phospholipid
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hepatocytes
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monooxygenase
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hydroxylase
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triglyceride
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xenobiotics
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steroid
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nadph-cytochrome
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thyroid
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isozymes
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lipoprotein
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s-transferase
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testosterone
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aniline
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benzoapyrene
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phosphatidylcholine
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glucuronidation
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3-methylcholanthrene
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bile
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drug-metabolizing
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arachidonic
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prostaglandin
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acyltransferase
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heme
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hepatotoxicity
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nadph-dependent
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cyp2e1
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gsh
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autoimmune
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apolipoprotein
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cyp1a2
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autoantibody
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biphenyls
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polycyclic
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udp-glucuronosyltransferase
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monoxide
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glucose-6-phosphatase
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tetrachloride
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polychlorinated
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thyroglobulin
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ketoconazole
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demethylase
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ccl4
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desaturation
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n-oxide
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androstenedione
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beta-hydroxysteroid
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21-hydroxylase
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synthesis
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medicine
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drug development
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analysis
- 3.3.2.9
- phenobarbital
- cholesterol
- phospholipid
- hepatocytes
- monooxygenase
- hydroxylase
- triglyceride
- xenobiotics
- steroid
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nadph-cytochrome
- thyroid
- isozymes
- lipoprotein
- s-transferase
- testosterone
- aniline
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benzoapyrene
- phosphatidylcholine
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glucuronidation
- 3-methylcholanthrene
- bile
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drug-metabolizing
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arachidonic
- prostaglandin
- acyltransferase
- heme
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hepatotoxicity
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nadph-dependent
- cyp2e1
- gsh
- autoimmune
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apolipoprotein
- cyp1a2
- autoantibody
- biphenyls
-
polycyclic
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udp-glucuronosyltransferase
- monoxide
- glucose-6-phosphatase
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tetrachloride
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polychlorinated
- thyroglobulin
- ketoconazole
- demethylase
- ccl4
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desaturation
- n-oxide
- androstenedione
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beta-hydroxysteroid
- 21-hydroxylase
- synthesis
- medicine
- drug development
- analysis
Reaction
Synonyms
alpha,beta fold epoxide hydrolase, alpha,beta-fold type EH, E1-b', EC 3.3.2.3, EC 4.2.1.63, EC 4.2.1.64, EH1, EH2, Eha, EHb, EPHX, EPHX 1, EPHX1, EPOX, epoxide hydrolase, HYL1, JH epoxide hydrolase, JHEH, juvenile hormone epoxide hydrolase, mEH, mEH-like protein, mEH1, mEPHX, microsomal, microsomal EH, microsomal EPHX1, Microsomal epoxide hydrolase, microsomal epoxide hydrolase 1, microsomal epoxide hydrolase-like protein, microsomal xenobiotic epoxide hydrolase, More, PNSO hydrolase, SEH, styrene-epoxide hydrolase, Tcjheh-r1, Tcjheh-r3, XEHase, xenobiotic epoxide hydrolase
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General Information
General Information on EC 3.3.2.9 - microsomal epoxide hydrolase
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evolution
malfunction
metabolism
physiological function
additional information
enzymatic activity of mEH can be greatly increased by a point mutation E404D in the catalytic triad. But this variant is not found in any vertebrate species, despite the obvious advantage of accelerated detoxification. This evolutionary avoidance might be due to the fact that the mEH plays a dualistic role in detoxification and control of endogenous vascular signaling molecules. The critical role for mEH E404D in vasodynamics suggests that deregulation of endogenous signaling pathways is the undesirable gain of function associated with the E404D variant
evolution
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epoxide hydrolases of the alpha,beta-hydrolase type share significant homologies with other hydrolases, including esterases. The two Karenia brevis EHs are similar in that each has two active site Tyrs as well as a Glu located after beta7. Both of the alpha,beta fold type EHs identified in Karenia brevis belong to the mEH class. The lengths of the NC loops of the EHs are 36 and 43 residues, whereas both cap-loops are 14 residues. mEHs are characterized by having long to very long NC-loops (33 or more residues) and short to medium cap-loops. The Karenia brevis NC-loops and cap-loops are considered very long and medium in length, respectively. The length of these domains is believed to govern substrate selectivity of the EH and this combination of long/med NC-loop/cap-loop would suggest selectivity for aromatic epoxides. The EH1 appears to deviate from this generalization as selectivity is observed for aliphatic over aromatic substituted epoxides
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
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association of GSTT1 and GSTM1 null genotypes and mEPHX polymorphisms with hepatitis virus-related HCC risk in an Indian population
malfunction
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genetically reduced EPHX1 activity is not a major risk factor for COPD and asthma, overview
malfunction
95% decrease in microsomal epoxide hydrolase expression levels is associated with a decrease in bile acid transport and severe hypercholanemia. EPHX1 transcription is significantly inhibited by two heterozygous mutations observed in the Old Order Amish population that present numerous hypercholanemic subjects in the absence of liver damage suggesting a defect in bile acid transport into the hepatocyte. High frequency of the H1.2 site polymorphism in the Amish population results in a potential genetic predisposition to hypercholanemia
malfunction
EPHX1 intron-1 heterozygous polymorphism in the human mEH gene (EPHX1) resulting in a 95% decrease in mEH expression. A patient exhibits a 100fold increase in serum bile acids in the absence of liver damage, suggesting a defect in transport while NTCP mRNA and protein expression levels are normal. EPHX1 intron-1 heterozygous polymorphism are previously described in a high percentage of the Lancaster County Old Order Amish population that present numerous hypercholanemic subjects without liver injury, suggesting the loss of transport capacity. No mutations have been detected in the NTCP gene from this population. The mEH intron-1 polymorphism results in a genetic predisposition for hypercholanemia and further supports the significant role of mEH in mediating hepatic sodium-dependent bile acid transport in concert with other transport mechanisms
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
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
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epoxide hydrolases comprise a family of enzymes important in detoxification and conversion of lipid signaling molecules, namely epoxyeicosatrienoic acids. Microsomal epoxide hydrolase is involved in the cerebral epoxyeicosatrienoic acid metabolism
metabolism
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the enzyme plays a role in the endocannabinoid signaling and a new arachidonic acid biosynthetic pathway
metabolism
role of microsomal epoxide hydrolase, Na+-taurocholate cotransporting polypeptide, and organic anion transporting polypeptide in hepatic sodium-dependent bile acid transport
metabolism
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epoxide hydrolases comprise a family of enzymes important in detoxification and conversion of lipid signaling molecules, namely epoxyeicosatrienoic acids. Microsomal epoxide hydrolase is involved in the cerebral epoxyeicosatrienoic acid metabolism
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microsomal epoxide hydrolase and cytochrome P-450 ensure the rapid detoxification of epoxides generated during the oxidative metabolism of xenobiotics
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
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
physiological function
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epoxide hydrolases are the key enzymes in the biosynthesis of polyether ladder compounds such as the brevetoxins which are produced by the dinoflagellate Karenia brevis, which is the principal HAB organism in the Gulf of Mexico also known as the Florida red tide dinoflagellate. Microsomal epoxide hydrolases, mEHs, are involved in the metabolism of xenobiotics
physiological function
in human liver fractions and hepatocytes, oxetane hydrolysis by mEH is the only oxetane ring-opening metabolic route, with no contribution from soluble epoxide hydrolase (sEH, EC 3.3.2.10) or from cytochrome P450-catalyzed oxidation
physiological function
microsomal epoxide hydrolase (mEH) is a bifunctional protein that plays a central role in the metabolism of numerous xenobiotics as well as mediating the sodium-dependent transport of bile acids into hepatocytes. These compounds are involved in cholesterol homeostasis, lipid digestion, excretion of xenobiotics and the regulation of several nuclear receptors and signaling transduction pathways. The type I form of microsomal epoxide hydrolase (mEH) is expressed on the hepatocyte endoplasmic reticulum membrane plays a central role in the metabolism of numerous xenobiotics. The type II form is targeted to the plasma membrane where it can mediate the sodium-dependent transport of bile acids in parallel with the sodium-taurocholate cotransporting protein (Ntcp)
physiological function
microsomal epoxide hydrolase (mEH) plays a significant role in the hepatic transport of conjugated bile acids
physiological function
Microsomal epoxide hydrolase is a xenobiotic-metabolizing enzyme, which hydrolyzes potentially genotoxic epoxides to less reactive dihydrodiols. Key features of mEH comprise a broad substrate spectrum and almost ubiquitous expression in all body tissues, with particularly high expression in liver and kidney,consistent with a central role in detoxification. Enzyme mEH is also capable of metabolizing endogenous compounds including epoxy steroids and arachidonic acid-derived lipid signaling molecules, so-called epoxyeicosatrienoic acids (EETs). Genetic enhancement of microsomal epoxide hydrolase through mutation E404D improves metabolic detoxification but impairs cerebral blood flow regulation. mEH E404D animals also show faster metabolization of a specific class of endogenous eicosanoids, arachidonic acid-derived epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs). Significantly higher DHETs/EETs ratios are found in mEH E404D liver, urine, plasma, brain and cerebral endothelial cells compared to WT controls, suggesting a broad impact of the mEH mutant on endogenous EETs metabolism
physiological function
soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) in the metabolic pathway of arachidonic acid
physiological function
the microsomal epoxide hydrolase plays a role in detoxification of 4-vinylcyclohexene diepoxide and is regulated by phosphatidylinositol-3 kinase signaling (PI3K). 4-Vinylcyclohexene diepoxide (VCD) is a metabolite of 4-vinylcyclohexene (VCH) which has the potential to be formed in the ovary through CYP2E1 activity. Functional role for mEH in the rat ovary involvement of PI3K signaling in regulation of ovarian xenobiotic metabolism by mEH
physiological function
the microsomal epoxide hydrolase plays a role in detoxification of 4-vinylcyclohexene diepoxide and is regulated by phosphatidylinositol-3 kinase signaling. 4-Vinylcyclohexene diepoxide (VCD) is a metabolite of 4-vinylcyclohexene (VCH) which has the potential to be formed in the ovary through CYP2E1 activity. The inactive tetrol metabolite (4-(1,2-dihydroxy)ethyl-1,2-dihydroxycyclohexane) can be formed in mouse ovarian follicles, potentially through detoxification action of mEH. mEH can bioactivate the ovotoxic chemical 7,12-dimethylbenz[a]anthracene (DMBA) to the more toxic compound, DMBA-3,4-diol-1,2-epoxide
physiological function
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the microsomal epoxide hydrolase plays a role in detoxification of 4-vinylcyclohexene diepoxide and is regulated by phosphatidylinositol-3 kinase signaling (PI3K). 4-Vinylcyclohexene diepoxide (VCD) is a metabolite of 4-vinylcyclohexene (VCH) which has the potential to be formed in the ovary through CYP2E1 activity. Functional role for mEH in the rat ovary involvement of PI3K signaling in regulation of ovarian xenobiotic metabolism by mEH
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evaluation of different epoxide hydrolase (EH) enzymes in the hydrolysis of skin-relevant fatty acid epoxides and comparison to the products to those of acid-catalyzed hydrolysis
additional information
homology structure modeling of human microsomal epoxide hydrolase using multiple templates, catalytic triad consits of Asp-His-Glu, and role of the oxyanion hole and the conserved motif (HGXP) in epoxide hydrolases, overview. Proposed mechanism for the ring-opening reaction catalyzed by mEH, analysis of substrate-enzyme interactions, docking and molecular dynamic simulation
additional information
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homology structure modeling of human microsomal epoxide hydrolase using multiple templates, catalytic triad consits of Asp-His-Glu, and role of the oxyanion hole and the conserved motif (HGXP) in epoxide hydrolases, overview. Proposed mechanism for the ring-opening reaction catalyzed by mEH, analysis of substrate-enzyme interactions, docking and molecular dynamic simulation
additional information
mEH phenotyping of wild-type and naturally occuring mutants Y113H and H139R
additional information
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mEH phenotyping of wild-type and naturally occuring mutants Y113H and H139R
additional information
quantitative structure-activity relationship (QSAR) modeling. The enzyme structure is used for predictions of small molecule binding
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
additional information
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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
additional information
transition state of epoxide ring opening catalyzed by sEH, and binding mode of urea which mimic the transition state
additional information
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two step mechanism of the alpha,beta-hydrolase fold type and endo-tet and exo-tet cyclization mechanisms