Characterization of neuropathy target esterase using trifluoromethyl ketones

Thomas C. Thomas, András Székács, Scott Rojas, Bruce D. Hammock, Barry W. Wilson, Mark G. McNamee

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Neuropathy target esterase (NTE) is a membrane-bound carboxylesterase activity which is proposed as the target site in nerve tissue for initiation of organophosphate-induced delayed neuropathy. This activity is identified as phenyl valerate hydrolysis which is resistant to treatment with paraoxon and sensitive to co-incubation with paraoxon and mipafox. NTE preparations were obtained, which did not contain paraoxon-sensitive or mipafox-resistant hydrolases, by selective reconstitution of detergent-solubilized NTE from chick embryo brain into asolectin vesicles during gel filtration. The topography of the catalytic site of NTE was then examined by investigating the inhibition of NTE by a series of 3-alkylthio- and 3-arylthio-1,1,1-trifluoro-propan-2-ones. These trifluoromethyl ketones were found to be rapidly reversible, competitive inhibitors of NTE with I50 values from 1.3 × 10-4 M to 4.9 × 10-4M. Correlation of I50 values with octanol/water partition coefficients (P), in the range of log P = 1.5 to 5.9, indicated that the optimal lipophilicity for NTE substrates and inhibitors is in the range of log P = 3.0 to 3.4. Electrophilic substitution at the meta position of aromatic rings increased the inhibitory capacity of these inhibitors, whereas substitution at the ortho position reduced inhibitory capacity. These results indicate both that a large hydrophobic pocket is closely associated with the catalytic residue of NTE, and that affinity for the active site is affected by steric and electronic parameters.

Original languageEnglish
Pages (from-to)2587-2596
Number of pages10
JournalBiochemical Pharmacology
Issue number12
Publication statusPublished - Dec 15 1990

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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