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Challenges in Computational Enzymology

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Front. Chem. | doi: 10.3389/fchem.2018.00660

Theoretical Studies on Mechanism of Inactivation of Kanamycin A by 4’-O-Nucleotidyltransferase.

  • 1Department de Quimica Fisica i Analitica, Universitat Jaume I, Spain
  • 2Instituto de Química Orgánica General (IQOG), Spain
  • 3Department de Química Física i Analítica,, Universitat Jaume I, Spain

This work is focused on mechanistic studies of the transfer of an adenylyl group (Adenoside-5’-monophosfate) from adenosine 5’-triphosphate (ATP) to a OH-4’ hydroxyl group of an antibiotic. Using hybrid quantum mechanics / molecular mechanics (QM/MM) techniques, we study the substrate and base-assisted mechanisms of the inactivation process of the kanamycin A (KAN) catalyzed by 4’-O-Nucleotidyltransferase(ANT(4’)), an active enzyme against almost all aminoglycosides antibiotics. Free energy surfaces, obtained with Free Energy Perturbation methods at M06-2X/MM level of theory, show that the most favorable reaction path presents a barrier of 12.2 kcal∙mol-1 that corresponds to the concerted activation of O4’ from KAN by Glu145. In addition, the primary and secondary 18O kinetic isotope effects (KIEs) have been computed for bridge O3α, and non-bridge O1α, O2α and O5’ atoms of ATP. The observed normal 1º-KIE of 1.2% and 2º-KIE of 0.07% for the Glu145-assisted mechanism are in very good agreement with experimentally measured data. Additionally, based on obtained results the role of an electrostatic and compression effects in enzymatic catalysis is discussed.

Keywords: Kanamycin, antibiotic, QM/MM (quantum mechanics/molecular mechanics), Aminoglycosides, kinetic isotope effects, SEMIEMPIRICAL METHODS, O-Nucleotidyltransferase , electrostatic effects

Received: 23 Nov 2018; Accepted: 18 Dec 2018.

Edited by:

Fahmi Himo, Stockholm University, Sweden

Reviewed by:

Tiziana Marino, Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Italy
Rongzhen Liao, Huazhong University of Science and Technology, China  

Copyright: © 2018 Marti, Bastida and Świderek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Katarzyna Świderek, Universitat Jaume I, Department de Química Física i Analítica,, Castelló de La Plana, Spain, swiderek@uji.es