Original scientific paper

Structural Basis for Selectivity of Butyrylcholinesterase towards Enantiomeric Quinuclidin-3-yl Benzoates: a Quantum Chemical Study

Ines Primožič orcid.org/0000-0003-1154-4735 ; University of Zagreb, Faculty of Science, Department of Chemistry, Strossmayerov trg 14, HR-10000 Zagreb, Croatia
Tomica Hrenar ; University of Zagreb, Faculty of Science, Department of Chemistry, Strossmayerov trg 14, HR-10000 Zagreb, Croatia
Srđanka Tomić ; University of Zagreb, Faculty of Science, Department of Chemistry, Strossmayerov trg 14, HR-10000 Zagreb, Croatia
Zlatko Meić ; University of Zagreb, Faculty of Science, Department of Chemistry, Strossmayerov trg 14, HR-10000 Zagreb, Croatia

Abstract

In order to explain different rates of hydrolysis of (R)- and (S)-quinuclidin-3-yl benzoates and benzoylcholine catalyzed with butyrylcholinesterase, semiempirical PM3 calculations were performed with an assumed active site model of human BChE (20 amino acids). Contributions of different protein residues to the stabilization of Michaelis complexes and tetrahedral intermediates were analyzed. It was shown that the hydrolysis rates of quinuclidinium enantiomers were to an appreciable extent affected by the existence or absence of the hydrogen bond between the quinuclidinium N+–H group and the protein residues. Calculations indicated that the better stabilization of quinuclidinium moiety in the Michaelis complex than in the tetrahedral intermediate was the main reason for a greater barrier and a slower reaction rate of the (R)-enantiomer of quinuclidinium esters compared to benzoylcholine. In the case of (S)-enantiomer, the calculation indicated that the barrier to the substrate reorientation from a favourable, but non-productive binding to a productive one significantly influenced the rate of hydrolysis.

Keywords

butyrylcholinesterase; benzoylcholine; (R)- and (S)-quinuclidin-3-yl benzoates; semiempirical calculations; Michaelis complexes; tetrahedral intermediates; mechanism of hydrolysis

Hrčak ID:

103077

URI

https://hrcak.srce.hr/103077

Publication date:

30.4.2003.

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