ISSN:
1573-904X
Keywords:
carboxylesterases
;
mammalian liver
;
thioester substrates
;
trifluoromethylketone inhibitors
;
structure-activity relationships
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Purpose. Carboxylesterases are important in the detoxification of drugs, pesticides and other xenobiotics. This study was to evaluate a series of substrates and inhibitors for characterizing these enzymes. Methods. A series of novel aliphatic esters and thioesters were used in spectral assays to monitor human, murine and porcine esterases. A series of transition state mimics were evaluated as selective esterase inhibitors. Results. Several α-alkyl thioacetothioates were found to be ~2 to 11-fold superior to commonly used substrates for monitoring carboxylesterase activity. Insertion of a heteroatom in the acid portion of these esters in the β or γ position relative to the carbonyl had a dramatic effect on enzyme activity with S or O substituents often improving the kCAT/K M ratio of the substrate and N decreasing it. Several α,α′-bis(2-oxo-3,3,3-trifluoropropylthio)alkanes proved to be potent selective transition state mimics of the esterase activity with IC50's from 10−5 to 10−9M. Conclusions. This library of substrates and inhibitors are useful research tools for characterizing the numerous isozymes of carboxylesterases present in mammalian tissues.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1016071311190
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