Epoxide hydrolase cytosolic

The existence of a cytosolic epoxide hydrolase was first indicated by its ability to hydrolyze analogs of insect juvenile hormone not readily hydrolyzed by microsomal epoxide hydrolase. Subsequent studies demonstrated a unique cytosolic enzyme catalytically and structurally distinct from the microsomal enzyme. It appears probable that the cytosolic enzyme is peroxisomal in origin. Both enzymes are broadly nonspecific and have many substrates in common. It is clear, however, that many substrates hydrolyzed well by cytosolic epoxide hydrolase are hydrolyzed poorly by microsomal epoxide hydrolase and vice versa. For example, l-(4 -ethylphenoxy)-3,7-dimethy I -6,7-epoxy-//7//i,v-2-octene, a substituted geranyl epoxide insect juvenile hormone mimic, is hydrolyzed 10 times more rapidly by the cytosolic enzyme than by the microsomal one. In any series, such as the substituted styrene oxides, the trans configuration is hydrolyzed more rapidly by the cytosolic epoxide hydrolase than is the cis isomer. At the same time, it should remembered that in this and other series, 

---

It should be noted that as early as 1993, Kurth and coworkers investigated the enzymatic transformation of bis-epoxides of type 8-51 using cytosolic epoxide hydrolase from rat liver. However, at that time the regio- and stereochemistry of the obtained THFs had not been investigated. 

According to biochemical separation, location, and substrate specificity, epoxide hydrolases (EH) have been divided into a number of groups. In mammals, the insoluble microsomal epoxide hydrolases and the soluble cytosolic epoxide hydrolases are enzymes of broad and complementary substrate specificity. 

The human cytosolic epoxide hydrolase (cytosolic EH, cEH, also known as soluble EH) has 554 amino acids (Mr 62.3 kDa) and is the product of the EPHX2 gene [49]. Its specific substrate is trans-stilbene oxide, and it appears... 

Fig. 10.6. Simplified representation of the postulated catalytic cycle of microsomal and cytosolic epoxide hydrolases, showing the roles played by the catalytic triad (i.e., nucleophile, general base, and charge relay acid) and some other residues, a) Nucleophilic attack of the substrate to form a /3-hydroxyalkyl ester intermediate, b) Nucleophilic attack of the /Thydroxyal-kyl ester by an activated H20 molecule, c) Tetrahedral transition state in the hydrolysis of the /f-hydroxyalkyl ester, d) Product liberation, with the enzyme poised for a further catalytic... 

G. M. Pacifici, A. Temellini, L. Giuliani, A. Rane, H. Thomas, F. Oesch, Cytosolic Epoxide Hydrolase in Humans Development and Tissue Distribution , Arch. Toxicol. 1988, 62, 254 - 257. 

L. Schladt, W. Worner, F. Setiabudi, F. Oesch, Distribution and Inducibility of Cytosolic Epoxide Hydrolase in Male Sprague-Dawley Rats , Biochem. Pharmacol. 1986, 35, 3309 - 3316. 

E. C. Dietze, J. Stephens, J. Magdalou, D. M. Bender, M. Moyer, B. Fowler, B. D. Hammock, Inhibition of Human and Murine Cytosolic Epoxide Hydrolase by Group-Selective Reagents , Comp. Biochem. Physiol., B 1993, 104, 299 - 308. 

G. Bellucci, C. Chiappe, F. Marioni, M. Benetti, Regio- and Enantioselectivity of the Cytosolic Epoxide Hydrolase-Catalysed Hydrolysis of Racemic Monosubstituted Alkyloxiranes ,./. Chem. Soc., Perkin Trans. 1 1991, 361 - 363 G. Bellucci, C. Chiappe, L. Conti, F. Marioni, G. Pierini, Substrate Enantioselection in the Microsomal Epoxide Hydrolase Catalyzed Hydrolysis of Monosubstituted Oxiranes. Effects of Branching of Alkyl Chains ,./. Org. Chem. 1989, 54, 5978 - 5983. 

N. Chacos, J. Capdevilla, J. R. Falck, S. Manna, C. Martin-Wixtrom, S. S. Gill, B. D. Hammock, R. W. Estabrook, The Reaction of Arachidonic Acid Epoxides (Epoxyeico-satrienoic Acids) with a Cytosolic Epoxide Hydrolase , Arch. Biochem. Biophys. 1983, 223, 639 - 648. 

J. Meijer, J. W. DePierre, Properties of Cytosolic Epoxide Hydrolase Purified from the Liver of Untreated and Clofibrate-Treated Mice , Eur. J. Biochem. 1985, 150,1 - 16. 

J. Magdalou, B. D. Hammock, 1,2-Epoxycycloalkanes Substrates and Inhibiors of Microsomal and Cytosolic Epoxide Hydrolases in Mouse Liver , Biochem. Pharmacol. 1988, 37, 2717 - 2722. 

G. Bellucci, C. Chiappe, F. Marioni, Enantioselectivity of the Enzymatic Hydrolysis of Cyclohexene Oxide and ( )-l-Methylcyclohexene Oxide A Comparison between Microsomal and Cytosolic Epoxide Hydrolases , J. Chem. Soc., Perkin Trans. 1 1989, 2369 -2373. 

Enzyme catalysed hydrolysis of racemic epoxides is interesting from a practical point of view. This reaction is catalysed by epoxide hydrolases (EHs, EC 3.3.2.3) (Archelas and Furstoss, 1998). Mammalian EHs are the most widely studied and they are divided into five groups among which the soluble (cytosolic) epoxide hydrolases (sEH) and microsomal epoxide hydrolases (mEH) are best charactelised. The mechanism of sEH from rat starts with a nucleophilic attack by Asp333 on a carbon of the epoxide (usually the least hindered one) to form a glycol monoester intermediate which is stabilised by an oxyanion hole. A water molecule activated by His523 releases the 1,2-diol product. An... 

Conversion of arene oxides to dihydrodiols by mouse liver cytosol epoxide hydrolase and microsomal epoxide hydrolase has been compared, and it is found that the former is less active than the latter.200... 

Leukotriene A4 hydrolase is a unique cytosolic epoxide hydrolase, structurally dissimilar to the cytosolic enzyme described above. Its substrate specificity is narrow, being restricted to leukotriene A4, (5(S)-trans-5,6-oxido-7,9-cis-ll,l4-trans-eicosatetraenoic acid), and related fatty acids. 

Lipoxygenases Cytosol Epoxide hydrolases Endoplasmic reticulum... 

Oxide A Comparison Between Microsomal and Cytosolic Epoxide Hydrolases, /. Chem. Soc, Perkin Trans. / 2369-2373. 

Hammock, B., Ratcliff, M., and Schooley, D. A. (1980). Hydration of an 180 Epoxide by a Cytosolic Epoxide Hydrolase from Mouse Liver, Life ScL, 27 1635-1641. 

There are two distinct types of epoxide hydrolases, both widely distributed in mammalian tissues. One type is localized primarily in the endoplasmic reticulum, the second in the cytosol. The microsomal and cytosolic enzymes have different properties, including substrate selectivities. Several inducers of xenobiotic metabolizing enzymes, including pheno-barbital, planar PCB congeners, and ra s-stilbene oxide, selectively increase (induce) microsomal, but not cytosolic, epoxide hydrolase activity. 

Oesch F, Golan M. 1980. Specificity of mouse liver cytosolic epoxide hydrolase for K-region epoxides derived from polycyclic aromatic hydrocarbons. Cancer Lett 9 169-175. 

Meijer, J., Depierre, J. W. (1988). Cytosolic epoxide hydrolase. Chemico-Biological Interactions, 64, 207-249. 

B.D. Hammock, J.R. Snapper et al. (1993). Regio- and enantiofacial selectivity of epoxyeicosatrienoic acid hydration by cytosolic epoxide hydrolase. J. Biol. Chem. 268, 6402-6407. 

Meijer J, DePierre JW (1988) Cytosolic epoxide hydrolase. Chem Biol Interact 64 207-249... 

CEH Cytosolic epoxide hydrolase nadV Nicotinamide adenine... 

Epoxidation by the introduction of an oxygen atom into flunarizine produced l-[bis(4-fluoro-phenyl)methyl] - 4 - [(3-phenyloxiran - 2 - yl)methyl] piperazine (metabolite 2) and epoxide hydration to a diol, 3-[4-[bis(4-fluorophenyl)methyl]-l-piper-azinyl]-l-phenyl-l,2-propanediol (metabolite 10). Lavrijsen et al. (1992) found metabolites formed by epoxidation at the double bond (metabolite 2) and epoxide hydration (metabolite 10) in incubates with subcellular hepatocyte fractions of male and female rats. Metabolites formed by epoxidation and epoxide hydration were not detected in vivo (Meuldermans et al. 1983), probably because the resulting metabolites were metabolised in vivo, much more quickly than in vitro, into secondary metabolites. A diol metabolite, however, was described for the metabolism of l-butyl-4-dimamyl-piperazine in guinea pigs (Morishita et al. 1978). With supernatant fractions a rapid disappearance of the epoxide intermediate from incubate was observed. This seems to indicate that, for the epoxide hydrolysis, besides microsomal epoxide hydrolase, cytosolic epoxide hydrolase might also be involved. 

Chacos N, Capdevila J, Falck JR, Manna S, Martin-Wixtrom C, Gill SS, Hammock BD, Estabrook, RW (1983) The reaction of arachidonic acid epoxides (epoxyeicosatrienoic acids) with a cytosolic epoxide hydrolase. Arch Biochem Biophys 223 639-648... 

So far five different types of epoxide hydrolases have been characterized in mammals, and they have been grouped depending on their enzymatic activity and biochemical characteristics. These groups include the soluble epoxide hydrolases (sEHs, also referred to as cytosolic epoxide hydrolases) [50], microsomal epoxide hydrolases (mEHs) [34], leukotriene A4 hydrolase (LTA44H) [51], cholesterol epoxide hydrolase [52], and hepoxilin hydrolase [53]. Several reviews have focused on these enzymes of medical importance [34,54]. 

---