TVAROŠKA, Igor, Stanislav KOZMON, Michaela WIMMEROVÁ and Jaroslav KOČA. Substrate Assisted Catalytic Mechanism of O GlcNAc Transferase Discovered by Quantum Mechanics/Molecular Mechanics Investigation. J. Am. Chem. Soc. Washington: American Chemical Society, 2012, vol. 134, No 37, p. 15563-15571. ISSN 0002-7863. Available from: https://dx.doi.org/10.1021/ja307040m.
Other formats:   BibTeX LaTeX RIS
Basic information
Original name Substrate Assisted Catalytic Mechanism of O GlcNAc Transferase Discovered by Quantum Mechanics/Molecular Mechanics Investigation
Authors TVAROŠKA, Igor (703 Slovakia, guarantor, 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, belonging to the institution).
Edition J. Am. Chem. Soc. Washington, American Chemical Society, 2012, 0002-7863.
Other information
Original language English
Type of outcome Article in a journal
Field of Study 10403 Physical chemistry
Country of publisher United States of America
Confidentiality degree is not subject to a state or trade secret
WWW URL
Impact factor Impact factor: 10.677
RIV identification code RIV/00216224:14740/12:00064660
Organization unit Central European Institute of Technology
Doi http://dx.doi.org/10.1021/ja307040m
UT WoS 000308830600067
Keywords in English Glycosyltransferases reaction mechanism qm/mm
Tags ok, rivok
Changed by Changed by: prof. RNDr. Jaroslav Koča, DrSc., učo 610. Changed: 28/1/2017 19:06.
Abstract
In higher eukaryotes, a variety of proteins are post-translationally modified by adding O-linked N-acetylglucosamine (GlcNAc) residue to serine or threonine residues. Misregulation of O-GlcNAcylation is linked to a wide variety of diseases, such as diabetes, cancer, and neurodegenerative diseases, including Alzheimer's disease. GlcNAc transfer is catalyzed by an inverting glycosyltransferase O-GlcNAc transferase (uridine diphospho-N-acetylglucosamine:polypeptide beta-N-acetylaminyltransferase, OGT) that belongs to the GT-B superfamily. The catalytic mechanism of this metal-independent glycosyltransferase is of primary importance and is investigated here using QM(DFT)/MM methods. The structural model of the reaction site used in this paper is based on the crystal structures of OGT. The entire enzyme substrate system was partitioned into two different subsystems: the QM subsystem containing 198 atoms, and the MM region containing 11 326 atoms. The catalytic mechanism was monitored by means of three two-dimensional potential energy maps calculated as a function of three predefined reaction coordinates at different levels of theory. These potential energy surfaces revealed the existence of a concerted S(N)2-like mechanism, in which a nucleophilic attack by O-ser, facilitated by proton transfer to the catalytic base, and the dissociation of the leaving group occur almost simultaneously. The transition state for the proposed reaction mechanism at the MPW1K level was located at C1-O-Ser = 1.92 angstrom and C1-O1 = 3.11 angstrom. The activation energy for this passage was estimated to be similar to 20 kcal mol(-1). These calculations also identified, for the first time for glycosyltransferases, the substrate-assisted mechanism in which the N-acetamino group of the donor participates in the catalytic mechanism.
Links
ED1.1.00/02.0068, research and development projectName: CEITEC - central european institute of technology
ME08008, research and development projectName: Návrh antibakteriálních a antivirových léků na bázi cukrů a glykomimetik
Investor: Ministry of Education, Youth and Sports of the CR, Design of Carbohydrates and Glycomimetics as Antibacterial and Antiviral Drugs, Research and Development Programme KONTAKT (ME)
2SGA2747, interní kód MUName: Saccharide - protein dispersion interactions involved in the bacterial recognition processes (Acronym: SaProDI)
Investor: South-Moravian Region, Incoming grants
286154, interní kód MUName: SYLICA - Synergies of Life and Material Sciences to Create a New Future (Acronym: SYLICA)
Investor: European Union, Capacities
PrintDisplayed: 20/7/2024 07:30