Product enantioselectivity in the microsomal epoxide hydrolase catalyzed hydrolysis of 10,11-dihydro-10,11-epoxy-5H-dibenzo[a,d]cycloheptene

Bellucci, Giuseppe; Berti, G.; Chiappe, Cinzia; Fabri, Fabio

doi:10.1021/jo00265a044

Cited by 16 publications

(5 citation statements)

References 3 publications

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“…To our knowledge, all previously reported microbial EHs have been observed to predominantly form ( R , R )-diols from meso -epoxides. , We now have found in our EH library the first examples of ( S,S )-selective enzymes for desymmetrization of meso -epoxides. As summarized in Table , these EH-catalyzed reactions exhibited moderate to excellent ee (56−99%), although reaction rates were generally ∼50−200-fold lower relative to those of ( R , R )-diol-producing enzymes.…”

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confidence: 64%

Epoxide Hydrolase-Catalyzed Enantioselective Synthesis of Chiral 1,2-Diols via Desymmetrization of meso-Epoxides

et al. 2004

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The discovery, from nature, of a diverse set of microbial epoxide hydrolases is reported. The utility of a library of epoxide hydrolases in the synthesis of chiral 1,2-diols via desymmetrization of a wide range of meso-epoxides, including cyclic as well as acyclic alkyl- and aryl-substituted substrates, is demonstrated. The chiral (R,R)-diols were furnished with high ee's and yields. The discovery of the first microbial epoxide hydrolases providing access to complementary (S,S)-diols is also described.

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confidence: 64%

Epoxide Hydrolase-Catalyzed Enantioselective Synthesis of Chiral 1,2-Diols via Desymmetrization of meso-Epoxides

et al. 2004

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“…Because of the critical role of sEHs in the metabolism of xenobiotics and their possible involvement in the biosynthesis of metabolites (14)(15)(16)18), 2 a detailed understanding of the catalytic mechanism of sEH is imperative. The anti opening of epoxides has been demonstrated on a select few substrates along with H 2 18 O studies, which have shown that nucleophilic attack occurs on the less hindered carbon (7,19,20). Recently, Hammock et al (21) were able to trap a postulated acylenzyme intermediate, suggesting the possible involvement of a nucleophilic amino acid in the hydration of epoxides by sEH.…”

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confidence: 96%

“…During the past 20 years the mammalian microsomal epoxide hydrolase (mEH) 1 has received a great deal of attention partly due to its higher selectivity for cyclic and arene oxides (4 -6). A great deal of work has provided a clear picture of the regio-, stereo-, and enantiospecificity of mEH (7)(8)(9)(10). Most researchers agree that mEH hydrolyzes the epoxide via an anti (commonly referred to as trans) opening of the oxirane, where attack of the nucleophile usually takes place at the least sterically hindered carbon.…”

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confidence: 99%

Mechanism of Soluble Epoxide Hydrolase

Borhan

Jones

Pinot

et al. 1995

Journal of Biological Chemistry

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18O-Labeled epoxides of trans-1,3-diphenylpropene oxide (tDPPO) and cis-9,10-epoxystearic acid were synthesized and used to determine the regioselectivity of sEH. The nucleophilic nature of sEH catalysis was demonstrated by comparing the enzymatic and nonenzymatic hydrolysis products of tDPPO. The results from single turnover experiments with greater or equal molar equivalents of sEH:substrate were consistent with the existence of a stable intermediate formed by a nucleophilic amino acid attacking the epoxide group. Tryptic digestion of sEH previously subjected to multiple turnovers with tDPPO in H 2 18 O resulted in the isolation and purification of a tryptic fragment containing Asp-333. Electrospray mass spectrometry of this fragment conclusively illustrated the incorporation of 18 O. After complete digestion of the latter peptide it was shown that Asp-333 of sEH exhibited an increased mass. The attack by Asp-333 initiates enzymatic activity, leading to the formation of an ␣-hydroxyacyl-enzyme intermediate. Hydrolysis of the acyl-enzyme occurs by the addition of an activated water to the carbonyl carbon of the ester bond, after which the resultant tetrahedral intermediate collapses, yielding the active enzyme and the diol product.Mammalian epoxide hydrolases (E.C. 3.3.2.3) have been implicated in the metabolism of epoxide containing xenobiotics, many of which are believed to be mutagenic and/or carcinogenic (1-3). During the past 20 years the mammalian microsomal epoxide hydrolase (mEH) 1 has received a great deal of attention partly due to its higher selectivity for cyclic and arene oxides (4 -6). A great deal of work has provided a clear picture of the regio-, stereo-, and enantiospecificity of mEH (7-10). Most researchers agree that mEH hydrolyzes the epoxide via an anti (commonly referred to as trans) opening of the oxirane, where attack of the nucleophile usually takes place at the least sterically hindered carbon. These results are substantiated by substituent effects on the rate of hydrolysis as investigated by Dansette et al. (11) and kinetic solvent isotope studies as reported by Armstrong et al. (12). By the use of single turnover experiments in H 2 18 O (13), Lacourciere and Armstrong have also postulated that the hydrolysis of epoxides by mEH proceeds via the intermediary of a nucleophilic amino acid, yielding an acyl-enzyme intermediate, which is hydrolyzed further to release the diol product and the active enzyme. This is in contrast with the previously more accepted hypothesis in which an activated water molecule was thought to be responsible for direct attack on the epoxide.Much less work has been completed on sEH, but the preliminary data closely parallel those for mEH. Because of the critical role of sEHs in the metabolism of xenobiotics and their possible involvement in the biosynthesis of metabolites (14-16, 18), 2 a detailed understanding of the catalytic mechanism of sEH is imperative. The anti opening of epoxides has been demonstrated on a select few substrates along with H 2 18 O studi...

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“…Bellucci et al reported microsomal epoxide hydrolase catalyzed ring opening of meso-stilbene oxide to furnish (R,R)-1 with 87% enantiomeric excess. 75 They also reported enantioselective ring opening by both the microsomal and the cytosolic epoxides hydrolase of rabbit liver. 76 The former enzyme provided higher enantioselectivity (88% ee).…”

Section: Enantioselective Reductionmentioning

confidence: 97%