The Mechanism of Cholinesterase Reactions with Organo-Phosphorus Quasisubstrates and Ester Substrates |
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Authors: | J Järv A Sepp |
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Institution: | Tartu State University , Tartu , 202400 , Estonian , SSR |
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Abstract: | Abstract The leaving groups of organophosphorus compounds and carbo-xylic esters are differently located in the active centers of cholinesterases that is connected with the stereochemi-cal regularities of the nucleophilic displacement reactions occurring at the carboxyl and phosphoryl groups of these reagents. This different spatial location of quasisubstrates in the enzyme active center also reveals in the mechanism of the bond-breaking steps leading to the formation of the covalent enzymereagent intermediate. In the present coinmunication the mechanism of these reaction steps is discussed with the implication of the putative structures of the transition states. The analysis is based on the results of QSAR for the leaving group effects of ester substrates and organophosphorus quasisubstrates in their reactions with acetylcholinesterase and butyrylcholinesterase. It has been found that the sensitivity of the enzyme phosphorylat-ion rate against the inductive effect of the quasisubstrate leaving group was remarkably nigh pointing to the complete separation of charges in the transition state. On the other hand, the transition state of the butyrylcholinesterase acylation reaction has been found to be similar to the structure of the appropriate acyl-enzyme. aesides these two enzymes the reactions of ester substrates and organophosphorus quasisubstrates have been studied with a covalently modified derivative of acetylcholinesterase, synthesized by affinity labelling of the native enzyme with N,N-dimethyl-2-phenylaziridinium ions, The data obtained allow to discuss the role of the putative “anionic point” of acetylcholinesterase in the enzyme reactions with organophosphorus quasisubstrates and ester substrates. |
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