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@article{1319407,
author = {Kumari, Manju and Kozmon, Stanislav and Kulhánek, Petr and Štěpán, Jakub and Tvaroška, Igor and Koča, Jaroslav},
article_location = {WASHINGTON},
article_number = {12},
doi = {http://dx.doi.org/10.1021/jp511235f},
keywords = {CATALYTIC MECHANISM; PK(A) VALUES; ENERGY PATHS; GLYCOSYLTRANSFERASES; SIMULATIONS; PROTEIN; RATIONALIZATION; METABOLISM; SUBSTRATE; CLEAVAGE},
language = {eng},
issn = {1520-6106},
journal = {Journal of Physical Chemistry B},
title = {Exploring Reaction Pathways for O-GlcNAc Transferase Catalysis. A String Method Study},
url = {http://pubs.acs.org/doi/pdf/10.1021/jp511235f},
volume = {119},
year = {2015}
}
TY - JOUR
ID - 1319407
AU - Kumari, Manju - Kozmon, Stanislav - Kulhánek, Petr - Štěpán, Jakub - Tvaroška, Igor - Koča, Jaroslav
PY - 2015
TI - Exploring Reaction Pathways for O-GlcNAc Transferase Catalysis. A String Method Study
JF - Journal of Physical Chemistry B
VL - 119
IS - 12
SP - 4371-4381
EP - 4371-4381
PB - AMER CHEMICAL SOC
SN - 15206106
KW - CATALYTIC MECHANISM
KW - PK(A) VALUES
KW - ENERGY PATHS
KW - GLYCOSYLTRANSFERASES
KW - SIMULATIONS
KW - PROTEIN
KW - RATIONALIZATION
KW - METABOLISM
KW - SUBSTRATE
KW - CLEAVAGE
UR - http://pubs.acs.org/doi/pdf/10.1021/jp511235f
L2 - http://pubs.acs.org/doi/pdf/10.1021/jp511235f
N2 - The inverting O-GlcNAc glycosyltransferase (OGT) is an important post-translation enzyme, which catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine (UDP-GlcNAc) to the hydroxyl group of the Ser/Thr of cytoplasmic, nuclear, and mitochondrial proteins. In the past, three different catalytic bases were proposed for the reaction: His498, alpha-phosphate, and Asp554. In this study, we used hybrid quantum mechanics/molecular mechanics (QM/MM) Car-Parrinello molecular dynamics to investigate reaction paths using alpha-phosphate and Asp554 as the catalytic bases. The string method was used to calculate the free-energy reaction profiles of the tested mechanisms. During the investigations, an additional mechanism was observed. In this mechanism, a proton is transferred to alpha-phosphate via a water molecule. Our calculations show that the mechanism with alpha-phosphate acting as the base is favorable. This reaction has a rate-limiting free-energy barrier of 23.5 kcal/mol, whereas reactions utilizing Asp554 and water-assisted alpha-phosphate have barriers of 41.7 and 40.9 kcal/mol, respectively. Our simulations provide a new insight into the catalysis of OGT and may thus guide rational drug design of transition-state analogue inhibitors with potential therapeutic use.
ER -
KUMARI, Manju, Stanislav KOZMON, Petr KULHÁNEK, Jakub ŠTĚPÁN, Igor TVAROŠKA a Jaroslav KOČA. Exploring Reaction Pathways for O-GlcNAc Transferase Catalysis. A String Method Study. \textit{Journal of Physical Chemistry B}. WASHINGTON: AMER CHEMICAL SOC, roč.~119, č.~12, s.~4371-4381. ISSN~1520-6106. doi:10.1021/jp511235f. 2015.
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