A QM/MM Investigation of the Catalytic Mechanism of
Metal-Ion-Independent Core 2
beta1,6-N-Acetylglucosaminyltransferase

J 2013

A QM/MM Investigation of the Catalytic Mechanism of Metal-Ion-Independent Core 2 beta1,6-N-Acetylglucosaminyltransferase

TVAROŠKA, Igor, Stanislav KOZMON, Michaela WIMMEROVÁ and Jaroslav KOČA

Basic information

Original name

A QM/MM Investigation of the Catalytic Mechanism of Metal-Ion-Independent Core 2 beta1,6-N-Acetylglucosaminyltransferase

Authors

TVAROŠKA, Igor (703 Slovakia, belonging to the institution), Stanislav KOZMON (703 Slovakia, belonging to the institution), Michaela WIMMEROVÁ (203 Czech Republic, belonging to the institution) and Jaroslav KOČA (203 Czech Republic, guarantor, belonging to the institution)

Edition

Chemistry - A European Journal, Weinheim, WILEY-VCH Verlag, 2013, 0947-6539

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10600 1.6 Biological sciences

Country of publisher

Germany

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.696

RIV identification code

RIV/00216224:14740/13:00068539

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1002/chem.201300383

UT WoS

000320134200020

Keywords in English

computer chemistry; density functional calculations; molecular modeling; reaction mechanisms; transferases; transition state

Abstract

V originále

Beta 1,6-GlcNAc-transferase (C2GnT) is an important controlling factor of biological functions for many glycoproteins and its activity has been found to be altered in breast, colon, and lung cancer cells, in leukemia cells, in the lymhomonocytes of multiple sclerosis patients, leukocytes from diabetes patients, and in conditions causing an immune deficiency. The result of the action of C2GnT is the core 2 structure that is essential for the further elongation of the carbohydrate chains of O-glycans. The catalytic mechanism of this metal-ion-independent glycosyltransferase is of paramount importance and is investigated here by using quantum mechanical (QM) (density functional theory (DFT))/molecular modeling (MM) methods with different levels of theory. The structural model of the reaction site used in this report is based on the crystal structures of C2GnT. The entire enzyme-substrate system was subdivided into two different subsystems: the QM subsystem containing 206 atoms and the MM region containing 5914 atoms. Three predefined reaction coordinates were employed to investigate the catalytic mechanism. The calculated potential energy surfaces discovered the existence of a concerted SN2-like mechanism. In this mechanism, a nucleophilic attack by O6 facilitated by proton transfer to the catalytic base and the separation of the leaving group all occur almost simultaneously.

Links

ED1.1.00/02.0068, research and development project

Name: CEITEC - central european institute of technology

2SGA2747, interní kód MU

Name: Saccharide - protein dispersion interactions involved in the bacterial recognition processes (Acronym: SaProDI)

Investor: South-Moravian Region, Incoming grants

286154, interní kód MU

Name: SYLICA - Synergies of Life and Material Sciences to Create a New Future (Acronym: SYLICA)

Investor: European Union, Capacities

Citovat

TVAROŠKA, Igor, Stanislav KOZMON, Michaela WIMMEROVÁ and Jaroslav KOČA. A QM/MM Investigation of the Catalytic Mechanism of Metal-Ion-Independent Core 2 beta1,6-N-Acetylglucosaminyltransferase. Chemistry - A European Journal. Weinheim: WILEY-VCH Verlag, 2013, vol. 19, No 25, p. 8153-8162. ISSN 0947-6539. Available from: https://dx.doi.org/10.1002/chem.201300383.

@article{1111000,
   author = {Tvaroška, Igor and Kozmon, Stanislav and Wimmerová, Michaela and Koča, Jaroslav},
   article_location = {Weinheim},
   article_number = {25},
   doi = {http://dx.doi.org/10.1002/chem.201300383},
   keywords = {computer chemistry; density functional calculations; molecular modeling; reaction mechanisms; transferases; transition state},
   language = {eng},
   issn = {0947-6539},
   journal = {Chemistry - A European Journal},
   title = {A QM/MM Investigation of the Catalytic Mechanism of Metal-Ion-Independent Core 2 beta1,6-N-Acetylglucosaminyltransferase},
   url = {http://onlinelibrary.wiley.com/doi/10.1002/chem.201300383/abstract},
   volume = {19},
   year = {2013}
}

TY  - JOUR
ID  - 1111000
AU  - Tvaroška, Igor - Kozmon, Stanislav - Wimmerová, Michaela - Koča, Jaroslav
PY  - 2013
TI  - A QM/MM Investigation of the Catalytic Mechanism of Metal-Ion-Independent Core 2 beta1,6-N-Acetylglucosaminyltransferase
JF  - Chemistry - A European Journal
VL  - 19
IS  - 25
SP  - 8153-8162
EP  - 8153-8162
PB  - WILEY-VCH Verlag
SN  - 09476539
KW  - computer chemistry
KW  - density functional calculations
KW  - molecular modeling
KW  - reaction mechanisms
KW  - transferases
KW  - transition state
UR  - http://onlinelibrary.wiley.com/doi/10.1002/chem.201300383/abstract
L2  - http://onlinelibrary.wiley.com/doi/10.1002/chem.201300383/abstract
N2  - Beta 1,6-GlcNAc-transferase (C2GnT) is an important controlling factor of biological functions for many glycoproteins and its activity has been found to be altered in breast, colon, and lung cancer cells, in leukemia cells, in the lymhomonocytes of multiple sclerosis patients, leukocytes from diabetes patients, and in conditions causing an immune deficiency. The result of the action of C2GnT is the core 2 structure that is essential for the further elongation of the carbohydrate chains of O-glycans. The catalytic mechanism of this metal-ion-independent glycosyltransferase is of paramount importance and is investigated here by using quantum mechanical (QM) (density functional theory (DFT))/molecular modeling (MM) methods with different levels of theory. The structural model of the reaction site used in this report is based on the crystal structures of C2GnT. The entire enzyme-substrate system was subdivided into two different subsystems: the QM subsystem containing 206 atoms and the MM region containing 5914 atoms. Three predefined reaction coordinates were employed to investigate the catalytic mechanism. The calculated potential energy surfaces discovered the existence of a concerted SN2-like mechanism. In this mechanism, a nucleophilic attack by O6 facilitated by proton transfer to the catalytic base and the separation of the leaving group all occur almost simultaneously.
ER  -

TVAROŠKA, Igor, Stanislav KOZMON, Michaela WIMMEROVÁ and Jaroslav KOČA. A QM/MM Investigation of the Catalytic Mechanism of Metal-Ion-Independent Core 2 beta1,6-N-Acetylglucosaminyltransferase. \textit{Chemistry - A European Journal}. Weinheim: WILEY-VCH Verlag, 2013, vol.~19, No~25, p.~8153-8162. ISSN~0947-6539. Available from: https://dx.doi.org/10.1002/chem.201300383.

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