Cholinesterase-like organocatalysis by imidazole and imidazole-bearing molecules

Paola Nieri,Sara Carpi,Adriano Podestà,Stefano Fogli,Beatrice Polini,Maria Cristina Breschi

doi:10.1038/srep45760

Abstract

Organocatalysis, which is mostly explored for its new potential industrial applications, also represents a chemical event involved in endogenous processes. In the present study, we provide the first evidence that imidazole and imidazole derivatives have cholinesterase-like properties since they can accelerate the hydrolysis of acetylthiocholine and propionylthiocholine in a concentration-dependent manner. The natural imidazole-containing molecules as L-histidine and histamine show a catalytic activity, comparable to that of imidazole itself, whereas synthetic molecules, as cimetidine and clonidine, were less active. In the experimental conditions used, the reaction progress curves were sigmoidal and the rational of such unexpected behavior as well as the mechanism of catalysis is discussed. Although indirectly, findings of the present study suggests that imidazolic compounds may interfere with the homeostasis of the cholinergic system in vivo.

Highlights

Binding specificity is the cornerstone event that characterizes the vast majority of structural and kinetic properties of the living state of matter
Ellman’s assay is used to estimate free thiol groups. This reaction is based on the ability of the reagent 5,5′-dithiobis-(2-nitrobenzoic acid) (DTNB) to react with the thiol to give the mixed disulfide and 2-nitro-5-thiobenzoate (TNB)
For the correct assessment of the catalytic activity of imidazole and imidazole derivatives, we measured the extent of thioester hydrolysis that spontaneously occurs when thioesters are dissolved in water

Summary

Introduction

Binding specificity is the cornerstone event that characterizes the vast majority of structural and kinetic properties of the living state of matter. More than one hundred of reaction types have been described in which monomeric organic molecules were able to promote enantioselective catalysis in vitro[5,6,7,8,9], even in an aqueous environment[10,11] This evidence suggests that, under appropriate circumstances, some small molecules may act as catalysts in vivo influencing specific biological processes. Experimental confirmation of such a hypothesis may represent the rational base to synthesize new drug candidates[12] to be used in pathological conditions characterized by the loss of endogenous enzyme activity. We provide the first evidence that imidazole and other endogenous or synthetic imidazole-containing molecules have a concentration-dependent cholinesterase-like activity and discuss possible physiological and pharmacological implications

Methods

Results

Conclusion