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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28 Scopus citations


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 (US)
Pages (from-to)2587-2596
Number of pages10
JournalBiochemical Pharmacology
Issue number12
StatePublished - Dec 15 1990

ASJC Scopus subject areas

  • Pharmacology


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