Publication details

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

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TVAROŠKA Igor KOZMON Stanislav WIMMEROVÁ Michaela KOČA Jaroslav

Year of publication 2013
Type Article in Periodical
Magazine / Source Chemistry - A European Journal
MU Faculty or unit

Central European Institute of Technology

Field Biochemistry
Keywords computer chemistry; density functional calculations; molecular modeling; reaction mechanisms; transferases; transition state
Description 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.
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