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@article{1094624,
author = {Tvaroška, Igor and Kozmon, Stanislav and Wimmerová, Michaela and Koča, Jaroslav},
article_location = {Washington},
article_number = {37},
doi = {http://dx.doi.org/10.1021/ja307040m},
keywords = {Glycosyltransferases reaction mechanism qm/mm},
language = {eng},
issn = {0002-7863},
journal = {J. Am. Chem. Soc.},
title = {Substrate Assisted Catalytic Mechanism of O GlcNAc Transferase Discovered by Quantum Mechanics/Molecular Mechanics Investigation},
url = {http://pubs.acs.org/doi/abs/10.1021/ja307040m},
volume = {134},
year = {2012}
}
TY - JOUR
ID - 1094624
AU - Tvaroška, Igor - Kozmon, Stanislav - Wimmerová, Michaela - Koča, Jaroslav
PY - 2012
TI - Substrate Assisted Catalytic Mechanism of O GlcNAc Transferase Discovered by Quantum Mechanics/Molecular Mechanics Investigation
JF - J. Am. Chem. Soc.
VL - 134
IS - 37
SP - 15563-15571
EP - 15563-15571
PB - American Chemical Society
SN - 00027863
KW - Glycosyltransferases reaction mechanism qm/mm
UR - http://pubs.acs.org/doi/abs/10.1021/ja307040m
L2 - http://pubs.acs.org/doi/abs/10.1021/ja307040m
N2 - In higher eukaryotes, a variety of proteins are post-translationally modified by adding O-linked N-acetylglucosamine (GlcNAc) residue to serine or threonine residues. Misregulation of O-GlcNAcylation is linked to a wide variety of diseases, such as diabetes, cancer, and neurodegenerative diseases, including Alzheimer's disease. GlcNAc transfer is catalyzed by an inverting glycosyltransferase O-GlcNAc transferase (uridine diphospho-N-acetylglucosamine:polypeptide beta-N-acetylaminyltransferase, OGT) that belongs to the GT-B superfamily. The catalytic mechanism of this metal-independent glycosyltransferase is of primary importance and is investigated here using QM(DFT)/MM methods. The structural model of the reaction site used in this paper is based on the crystal structures of OGT. The entire enzyme substrate system was partitioned into two different subsystems: the QM subsystem containing 198 atoms, and the MM region containing 11 326 atoms. The catalytic mechanism was monitored by means of three two-dimensional potential energy maps calculated as a function of three predefined reaction coordinates at different levels of theory. These potential energy surfaces revealed the existence of a concerted S(N)2-like mechanism, in which a nucleophilic attack by O-ser, facilitated by proton transfer to the catalytic base, and the dissociation of the leaving group occur almost simultaneously. The transition state for the proposed reaction mechanism at the MPW1K level was located at C1-O-Ser = 1.92 angstrom and C1-O1 = 3.11 angstrom. The activation energy for this passage was estimated to be similar to 20 kcal mol(-1). These calculations also identified, for the first time for glycosyltransferases, the substrate-assisted mechanism in which the N-acetamino group of the donor participates in the catalytic mechanism.
ER -
TVAROŠKA, Igor, Stanislav KOZMON, Michaela WIMMEROVÁ a Jaroslav KOČA. Substrate Assisted Catalytic Mechanism of O GlcNAc Transferase Discovered by Quantum Mechanics/Molecular Mechanics Investigation. \textit{J. Am. Chem. Soc.}. Washington: American Chemical Society, roč.~134, č.~37, s.~15563-15571. ISSN~0002-7863. doi:10.1021/ja307040m. 2012.
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