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@article{1300938,
author = {Trnka, Tomáš and Kozmon, Stanislav and Tvaroška, Igor and Koča, Jaroslav},
article_location = {SAN FRANCISCO},
article_number = {4},
doi = {http://dx.doi.org/10.1371/journal.pcbi.1004061},
keywords = {POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE; ENZYMATIC GLYCOSYL TRANSFER; ACETYL-D-GALACTOSAMINE; UDP-GALNAC; GALACTOSYLTRANSFERASE LGTC; DENSITY FUNCTIONALS; INTEGRATION SCHEME; CORRELATION-ENERGY; TRANSITION-STATE; LECTIN DOMAIN},
language = {eng},
issn = {1553-734X},
journal = {PLoS Computational Biology},
title = {Stepwise Catalytic Mechanism via Short-Lived Intermediate Inferred from Combined QM/MM MERP and PES Calculations on Retaining Glycosyltransferase ppGalNAcT2},
url = {http://www.ploscompbiol.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pcbi.1004061&representation=PDF},
volume = {11},
year = {2015}
}
TY - JOUR
ID - 1300938
AU - Trnka, Tomáš - Kozmon, Stanislav - Tvaroška, Igor - Koča, Jaroslav
PY - 2015
TI - Stepwise Catalytic Mechanism via Short-Lived Intermediate Inferred from Combined QM/MM MERP and PES Calculations on Retaining Glycosyltransferase ppGalNAcT2
JF - PLoS Computational Biology
VL - 11
IS - 4
SP - "nestránkováno"
EP - "nestránkováno"
PB - PUBLIC LIBRARY SCIENCE
SN - 1553734X
KW - POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE
KW - ENZYMATIC GLYCOSYL TRANSFER
KW - ACETYL-D-GALACTOSAMINE
KW - UDP-GALNAC
KW - GALACTOSYLTRANSFERASE LGTC
KW - DENSITY FUNCTIONALS
KW - INTEGRATION SCHEME
KW - CORRELATION-ENERGY
KW - TRANSITION-STATE
KW - LECTIN DOMAIN
UR - http://www.ploscompbiol.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pcbi.1004061&representation=PDF
L2 - http://www.ploscompbiol.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pcbi.1004061&representation=PDF
N2 - The glycosylation of cell surface proteins plays a crucial role in a multitude of biological processes, such as cell adhesion and recognition. To understand the process of protein glycosylation, the reaction mechanisms of the participating enzymes need to be known. However, the reaction mechanism of retaining glycosyltransferases has not yet been sufficiently explained. Here we investigated the catalytic mechanism of human isoform 2 of the retaining glycosyltransferase polypeptide UDP-GalNAc transferase by coupling two different QM/MM-based approaches, namely a potential energy surface scan in two distance difference dimensions and a minimum energy reaction path optimisation using the Nudged Elastic Band method. Potential energy scan studies often suffer from inadequate sampling of reactive processes due to a predefined scan coordinate system. At the same time, path optimisation methods enable the sampling of a virtually unlimited number of dimensions, but their results cannot be unambiguously interpreted without knowledge of the potential energy surface. By combining these methods, we have been able to eliminate the most significant sources of potential errors inherent to each of these approaches. The structural model is based on the crystal structure of human isoform 2. In the QM/MM method, the QM region consists of 275 atoms, the remaining 5776 atoms were in the MM region. We found that ppGalNAcT2 catalyzes a same-face nucleophilic substitution with internal return (SNi). The optimized transition state for the reaction is 13.8 kcal/mol higher in energy than the reactant while the energy of the product complex is 6.7 kcal/mol lower. During the process of nucleophilic attack, a proton is synchronously transferred to the leaving phosphate. The presence of a short-lived metastable oxocarbenium intermediate is likely, as indicated by the reaction energy profiles obtained using high-level density functionals.
ER -
TRNKA, Tomáš, Stanislav KOZMON, Igor TVAROŠKA a Jaroslav KOČA. Stepwise Catalytic Mechanism via Short-Lived Intermediate Inferred from Combined QM/MM MERP and PES Calculations on Retaining Glycosyltransferase ppGalNAcT2. \textit{PLoS Computational Biology}. SAN FRANCISCO: PUBLIC LIBRARY SCIENCE, 2015, roč.~11, č.~4, s.~''nestránkováno'', 21 s. ISSN~1553-734X. Dostupné z: https://dx.doi.org/10.1371/journal.pcbi.1004061.
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