Phosphylated oxime , AChE reactivation

Experiments using site-directed mutagenesis and computational modelling have shown that oximes appear to have preferred entry routes for attack of the phosphyl moiety and that side-chain substitutions of the active site gorge of AChE may significantly alter the reactivity (Radic and Taylor, 1999 Taylor el. al., 1999 Wong et al., 2000 Kovarik el. al., 2004). Hence, marked species differences in reactivatability of phosphylated AChE towards oximes are to be expected. In fact, experimental data support the assumption of substantial species differences in reactivation of OP-inhibited AChE... 

The classic studies of Wilson and Ginsburg (1955a,b) established that reactivation of phosphylated AChE could be accelerated by certain compounds more nucleophilic than water, such as A -methylhydroxylamine. Since that time, a variety of reactivators, termed oximes, have been synthesized for use in the treatment of subjects poisoned by OP anticholinesterases. In the United States, the oxime pralidoxime [iV-niethyi-(2-hydroxyaminoformyl-pyridinium)chlorlde] is the only reactivator approved for use (Fig. 7), whereas obidoxime (Ai,t[4-hydroxyamino-... 

Certain ChE mutants sensitive to OPs do not "age" after phosphylation they are fully reactivatable (Figure 75.1, reaction 3). Such ChE mutants, such as the human AChE mutant Y337A/F338A (Cochran et al., 2011) when associated with oximes (e.g., 2-PAM, HI-6), act as pseudocatalysts in displacing the OP moiety bound to the enzyme. These enzyme reactivator-coupled systems could lead to a new family of pseudocatalytic bioscavengers (Taylor et al., 2007 Kovarik et al., 2007, 2013 ... 

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