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. 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.

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

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 10600 1.6 Biological sciences
• Country of publisher: Germany
• Confidentiality degree: is not subject to a state or trade secret
• WWW: 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
• Tags: ok, rivok
• Tags: International impact, Reviewed

Abstract

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