Inhibition of epoxide metabolism by α,β-epoxyketones and isosteric analogs

Glenn D. Prestwich, Jing Wen Kuo, Sang Kyu Park, Dana N. Loury, Bruce D. Hammock

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Abstract

Chalcone oxides and several isosteric compounds have been prepared to examine the importance of the α,β-epoxyketone moiety in the inhibition of the hydrolysis of [3H]-trans-stilbene oxide to its meso-diol by mouse liver cytosolic epoxide hydrolase (cEH). Inhibition of microsomal EH and glutathione S-transferase were also examined. For cEH, replacement of the carbonyl by methylidene reduces inhibitor potency by a factor of 44, while replacement of the epoxide ring with a cyclopropyl ring reduces inhibition by a factor of 450. A 2′-hydroxyl also reduces cEH inhibition by 100 times. These observations are consistent with a model of the active site in which the carbonyl is hyhydrogen-bonded to an acidic site presumed to be involved in initiating epoxide hydrolysis. The chalcone oxides thus bind tightly but are not readily turned over as substrates.

Original languageEnglish (US)
Pages (from-to)11-15
Number of pages5
JournalArchives of Biochemistry and Biophysics
Volume242
Issue number1
DOIs
StatePublished - 1985

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ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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