Theoretical Studies on Mechanism of Inactivation of Kanamycin A by 4′-O-Nucleotidyltransferase
comunitat-uji-handle:10234/9
comunitat-uji-handle2:10234/7013
comunitat-uji-handle3:10234/8638
comunitat-uji-handle4:
INVESTIGACIONMetadades
Títol
Theoretical Studies on Mechanism of Inactivation of Kanamycin A by 4′-O-NucleotidyltransferaseData de publicació
2019-01-29Editor
Frontiers MediaCita bibliogràfica
MARTÍ FORÉS, Sergio; BASTIDA, Agatha; ŚWIDEREK, Katarzyna (2019). Theoretical Studies on Mechanism of Inactivation of Kanamycin A by 4′-O-Nucleotidyltransferase. Frontiers in Chemistry, v. 6Tipus de document
info:eu-repo/semantics/articleVersió
info:eu-repo/semantics/publishedVersionParaules clau / Matèries
Resum
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 ... [+]
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 kanamycin A (KAN) catalyzed by 4′-O-Nucleotidyltransferase [ANT(4′)], an
active enzyme against almost all aminoglycoside antibiotics. Free energy surfaces,
obtained with Free Energy Perturbation methods at the 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 1◦-KIE of 1.2% and 2◦-KIE of 0.07% for the Glu145-assisted mechanism are
in very good agreement with experimentally measured data. Additionally, based on the
obtained results, the role of electrostatic and compression effects in enzymatic catalysis
is discussed. [-]
Publicat a
Frontiers in Chemistry (2019), v. 6Drets d'accés
info:eu-repo/semantics/openAccess
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