Substrate Assisted Catalytic Mechanism of O GlcNAc Transferase
Discovered by Quantum Mechanics/Molecular Mechanics
Investigation

J 2012

Substrate Assisted Catalytic Mechanism of O GlcNAc Transferase Discovered by Quantum Mechanics/Molecular Mechanics Investigation

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

Základní údaje

Originální název

Substrate Assisted Catalytic Mechanism of O GlcNAc Transferase Discovered by Quantum Mechanics/Molecular Mechanics Investigation

Autoři

TVAROŠKA, Igor (703 Slovensko, garant, domácí), Stanislav KOZMON (703 Slovensko, domácí), Michaela WIMMEROVÁ (203 Česká republika, domácí) a Jaroslav KOČA (203 Česká republika, domácí)

Vydání

J. Am. Chem. Soc. Washington, American Chemical Society, 2012, 0002-7863

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10403 Physical chemistry

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 10.677

Kód RIV

RIV/00216224:14740/12:00064660

Organizační jednotka

Středoevropský technologický institut

DOI

http://dx.doi.org/10.1021/ja307040m

UT WoS

000308830600067

Klíčová slova anglicky

Glycosyltransferases reaction mechanism qm/mm

Štítky

ok, rivok

Změněno: 28. 1. 2017 19:06, prof. RNDr. Jaroslav Koča, DrSc.

Anotace

V originále

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.

Návaznosti

ED1.1.00/02.0068, projekt VaV

Název: CEITEC - central european institute of technology

ME08008, projekt VaV

Název: Návrh antibakteriálních a antivirových léků na bázi cukrů a glykomimetik

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Návrh antibakteriálních a antivirových léků na bázi cukrů a glykomimetik, Program výzkumu a vývoje KONTAKT (ME)

2SGA2747, interní kód MU

Název: Saccharide - protein dispersion interactions involved in the bacterial recognition processes (Akronym: SaProDI)

Investor: Jihomoravský kraj, Saccharide - protein dispersion interactions involved in the bacterial recognition processes, Granty pro zahraniční vědce

286154, interní kód MU

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

Investor: Evropská unie, SYLICA - Synergies of Life and Material Sciences to Create a New Future, Kapacity

Citovat

TVAROŠKA, Igor, Stanislav KOZMON, Michaela WIMMEROVÁ a 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, roč. 134, č. 37, s. 15563-15571. ISSN 0002-7863. Dostupné z: https://dx.doi.org/10.1021/ja307040m.

@article{1094624,
   author = {Tvaroška, Igor and Kozmon, Stanislav and Wimmerová, Michaela and Koča, Jaroslav},
   article_location = {Washington},
   article_number = {37},
   doi = {http://dx.doi.org/10.1021/ja307040m},
   keywords = {Glycosyltransferases reaction mechanism qm/mm},
   language = {eng},
   issn = {0002-7863},
   journal = {J. Am. Chem. Soc.},
   title = {Substrate Assisted Catalytic Mechanism of O GlcNAc Transferase Discovered by Quantum Mechanics/Molecular Mechanics Investigation},
   url = {http://pubs.acs.org/doi/abs/10.1021/ja307040m},
   volume = {134},
   year = {2012}
}

TY  - JOUR
ID  - 1094624
AU  - Tvaroška, Igor - Kozmon, Stanislav - Wimmerová, Michaela - Koča, Jaroslav
PY  - 2012
TI  - Substrate Assisted Catalytic Mechanism of O GlcNAc Transferase Discovered by Quantum Mechanics/Molecular Mechanics Investigation
JF  - J. Am. Chem. Soc.
VL  - 134
IS  - 37
SP  - 15563-15571
EP  - 15563-15571
PB  - American Chemical Society
SN  - 00027863
KW  - Glycosyltransferases reaction mechanism qm/mm
UR  - http://pubs.acs.org/doi/abs/10.1021/ja307040m
L2  - http://pubs.acs.org/doi/abs/10.1021/ja307040m
N2  - 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.
ER  -

TVAROŠKA, Igor, Stanislav KOZMON, Michaela WIMMEROVÁ a Jaroslav KOČA. Substrate Assisted Catalytic Mechanism of O GlcNAc Transferase Discovered by Quantum Mechanics/Molecular Mechanics Investigation. \textit{J. Am. Chem. Soc.}. Washington: American Chemical Society, 2012, roč.~134, č.~37, s.~15563-15571. ISSN~0002-7863. Dostupné z: https://dx.doi.org/10.1021/ja307040m.

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