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Concentration Dependent Kinetics for Inhibition of Acetylcholinesterase by Paraoxon
Author(s) -
Rosenfeld Clint,
Sultatos Lester
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1134-d
Subject(s) - paraoxon , acetylcholinesterase , oxon , chemistry , kinetics , ic50 , enzyme , reaction rate constant , serine , inhibitory postsynaptic potential , substrate (aquarium) , stereochemistry , biophysics , biochemistry , in vitro , biology , endocrinology , ecology , physics , quantum mechanics , neuroscience
The interaction of the anticholinesterase organophosphorus compounds with acetylcholinesterase has been regularly characterized as a straightforward phosphylation of the active site serine (Ser‐203) which can be described kinetically by the rate inhibitory rate constant k i . However, more recently certain kinetic complexities in the inhibition of acetylcholinesterase by organophosphates such as paraoxon ( O , O ‐diethyl O ‐( p ‐nitrophenyl) phosphate) have raised questions regarding the adequacy of the kinetic scheme on which k i is based. The present report documents conditions in which the inhibitory capacity of paraoxon towards human recombinant acetylcholinesterase appears to change as a function of oxon concentration (as evidenced by a changing k i ), with the inhibitory capacity of individual oxon molecules increasing at lower oxon concentrations. Computer models for the inhibition of acetylcholinesterase based on the k i scheme, as well as an Ordered Uni Bi reaction scheme from which the k i scheme was derived, were unable to accurately simulate inhibition by paraoxon at both high (100 nM) and low (78 pM) concentrations without allowing for changes in the values of certain kinetic parameters. For example, with the Ordered Uni Bi reaction scheme, adjusting the binding constants and/or the phosphorylation constant in a concentration‐dependent manner resulted in accurate simulations of the inhibition of acetylcholinesterase over a wide range of paraoxon concentrations. Conversely, alterations in the reactivation of phosphorylated enzyme had little effect on the simulated inhibition profiles. (Supported in part by grant ES012648 from NIEHS).