Literature summary for 3.3.2.9 extracted from

Marowsky, A.; Haenel, K.; Bockamp, E.; Heck, R.; Rutishauser, S.; Mule, N.; Kindler, D.; Rudin, M.; Arand, M.
Genetic enhancement of microsomal epoxide hydrolase improves metabolic detoxification but impairs cerebral blood flow regulation (2016), Arch. Toxicol., 90, 3017-3027 .

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Protein Variants

Protein Variants	Comment	Organism
E404D	catalytic triad mutation, enzymatic activity of mEH can be greatly increased by a point mutation, leading to an E404D amino acid exchange in its catalytic triad, the mutation improves metabolic detoxification but impairs cerebral blood flow regulation. In liver microsomes from mutant mice, turnover of the xenobiotic compound phenanthrene-9,10-oxide is four times faster compared to wild-type liver microsomes. Hemodynamics are assessed in mEH E404D mutant and WT cerebral cortex and hippocampus using cerebral blood volume (CBV)-based functional magnetic resonance imaging (fMRI). Basal CBV0 levels are similar between mEH E404D and control mice in both brain areas. But vascular reactivity and vasodilation in response to the vasodilatory drug acetazolamide are reduced in mEH E404D forebrain compared to WT controls by factor 3 and 2.6, respectively. Role of mEH E404D in acetazolamide-induced vasodilation in cerebral cortex and hippocampus	Mus musculus

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
microsome	-	Mus musculus	-	-

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
(R)-styrene oxide + H2O	Mus musculus	-	(1R)-1-phenylethane-1,2-diol	-	?

Organism

Organism	UniProt	Comment	Textmining
Mus musculus	Q9D379	-	-

Source Tissue

Source Tissue	Comment	Organism	Textmining
liver	-	Mus musculus	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
(R)-styrene oxide + H2O	-	Mus musculus	(1R)-1-phenylethane-1,2-diol	-	?

Synonyms

Synonyms	Comment	Organism
mEH	-	Mus musculus
Microsomal epoxide hydrolase	-	Mus musculus

General Information

General Information	Comment	Organism
evolution	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	Mus musculus
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	Mus musculus

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Release 2023.1 (January 2023)