Complex stereoselectivity of human butyrylcholinesterase for the neurotoxic V-agents (Poster)

Human butyrylcholinesterase (BChE ; 3.1.1.8) functions as a bioscavenger, protecting the cholinergic system against organophosphate compounds (OPs). The stereoselectivity of BChE is an important parameter for its efficiency at scavenging the most toxic OPs enantiomer for AChE.
Crystals of BChE inhibited with racemic V-agents systematically show the formation of the PS adduct. In this configuration, no catalysis of aging seems possible. These results are in agreement with mass spectrometry data, showing that no aging was detectable for BChE inhibited by VX and VR in solution under similar conditions. Crystals of BChE soaked in optically pure VXR-(+) and VXS-(-) solutions lead to the formation of the PS and PR adduct, respectively. Additionally, they show that BChE reacts with VXR-(+) in the presence of racemic mixture of V-agents, at odds with kinetic results showing a moderate higher inhibition rate for VXS-(-).
Multiple hypotheses could explain this discrepancy such as a bias in crystallography method due to the preparation of crystals or a switch in selectivity originates from the ability of BChE to bind multiple molecules or related to the different orders of concentration in enzyme and OP used for the various method of analysis.
Since BChE scavenges the PR enantiomer before the PS, it follows that the amount of BChE required to achieve full protection must be at least as high as the amount of the racemic V-agent. Only half of that amount would be required if AChE is used as the bioscavenger. This represents an important advantage for AChE considering that recombinant enzymes are expensive.