Exploring Reaction Pathways for O-GlcNAc Transferase Catalysis.
A String Method Study

J 2015

Exploring Reaction Pathways for O-GlcNAc Transferase Catalysis. A String Method Study

KUMARI, Manju, Stanislav KOZMON, Petr KULHÁNEK, Jakub ŠTĚPÁN, Igor TVAROŠKA et. al.

Základní údaje

Originální název

Exploring Reaction Pathways for O-GlcNAc Transferase Catalysis. A String Method Study

Autoři

KUMARI, Manju (356 Indie, domácí), Stanislav KOZMON (703 Slovensko, domácí), Petr KULHÁNEK (203 Česká republika, domácí), Jakub ŠTĚPÁN (203 Česká republika, domácí), Igor TVAROŠKA (703 Slovensko, domácí) a Jaroslav KOČA (203 Česká republika, garant, domácí)

Vydání

Journal of Physical Chemistry B, WASHINGTON, AMER CHEMICAL SOC, 2015, 1520-6106

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: 3.187

Kód RIV

RIV/00216224:14740/15:00085002

Organizační jednotka

Středoevropský technologický institut

DOI

http://dx.doi.org/10.1021/jp511235f

UT WoS

000351971100004

Klíčová slova anglicky

CATALYTIC MECHANISM; PK(A) VALUES; ENERGY PATHS; GLYCOSYLTRANSFERASES; SIMULATIONS; PROTEIN; RATIONALIZATION; METABOLISM; SUBSTRATE; CLEAVAGE

Štítky

rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 30. 11. 2015 09:39, Martina Prášilová

Anotace

V originále

The inverting O-GlcNAc glycosyltransferase (OGT) is an important post-translation enzyme, which catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine (UDP-GlcNAc) to the hydroxyl group of the Ser/Thr of cytoplasmic, nuclear, and mitochondrial proteins. In the past, three different catalytic bases were proposed for the reaction: His498, alpha-phosphate, and Asp554. In this study, we used hybrid quantum mechanics/molecular mechanics (QM/MM) Car-Parrinello molecular dynamics to investigate reaction paths using alpha-phosphate and Asp554 as the catalytic bases. The string method was used to calculate the free-energy reaction profiles of the tested mechanisms. During the investigations, an additional mechanism was observed. In this mechanism, a proton is transferred to alpha-phosphate via a water molecule. Our calculations show that the mechanism with alpha-phosphate acting as the base is favorable. This reaction has a rate-limiting free-energy barrier of 23.5 kcal/mol, whereas reactions utilizing Asp554 and water-assisted alpha-phosphate have barriers of 41.7 and 40.9 kcal/mol, respectively. Our simulations provide a new insight into the catalysis of OGT and may thus guide rational drug design of transition-state analogue inhibitors with potential therapeutic use.

Návaznosti

ED1.1.00/02.0068, projekt VaV

Název: CEITEC - central european institute of technology

LH13055, projekt VaV

Název: Multidisciplinární přístup k návrhu léčiv - Inhibice proteinů s návazností na cukry (Akronym: MADICA)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Multidisciplinární přístup k návrhu léčiv - Inhibice proteinů s návazností na sacharidy

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

KUMARI, Manju, Stanislav KOZMON, Petr KULHÁNEK, Jakub ŠTĚPÁN, Igor TVAROŠKA a Jaroslav KOČA. Exploring Reaction Pathways for O-GlcNAc Transferase Catalysis. A String Method Study. Journal of Physical Chemistry B. WASHINGTON: AMER CHEMICAL SOC, 2015, roč. 119, č. 12, s. 4371-4381. ISSN 1520-6106. Dostupné z: https://dx.doi.org/10.1021/jp511235f.

@article{1319407,
   author = {Kumari, Manju and Kozmon, Stanislav and Kulhánek, Petr and Štěpán, Jakub and Tvaroška, Igor and Koča, Jaroslav},
   article_location = {WASHINGTON},
   article_number = {12},
   doi = {http://dx.doi.org/10.1021/jp511235f},
   keywords = {CATALYTIC MECHANISM; PK(A) VALUES; ENERGY PATHS; GLYCOSYLTRANSFERASES; SIMULATIONS; PROTEIN; RATIONALIZATION; METABOLISM; SUBSTRATE; CLEAVAGE},
   language = {eng},
   issn = {1520-6106},
   journal = {Journal of Physical Chemistry B},
   title = {Exploring Reaction Pathways for O-GlcNAc Transferase Catalysis. A String Method Study},
   url = {http://pubs.acs.org/doi/pdf/10.1021/jp511235f},
   volume = {119},
   year = {2015}
}

TY  - JOUR
ID  - 1319407
AU  - Kumari, Manju - Kozmon, Stanislav - Kulhánek, Petr - Štěpán, Jakub - Tvaroška, Igor - Koča, Jaroslav
PY  - 2015
TI  - Exploring Reaction Pathways for O-GlcNAc Transferase Catalysis. A String Method Study
JF  - Journal of Physical Chemistry B
VL  - 119
IS  - 12
SP  - 4371-4381
EP  - 4371-4381
PB  - AMER CHEMICAL SOC
SN  - 15206106
KW  - CATALYTIC MECHANISM
KW  - PK(A) VALUES
KW  - ENERGY PATHS
KW  - GLYCOSYLTRANSFERASES
KW  - SIMULATIONS
KW  - PROTEIN
KW  - RATIONALIZATION
KW  - METABOLISM
KW  - SUBSTRATE
KW  - CLEAVAGE
UR  - http://pubs.acs.org/doi/pdf/10.1021/jp511235f
L2  - http://pubs.acs.org/doi/pdf/10.1021/jp511235f
N2  - The inverting O-GlcNAc glycosyltransferase (OGT) is an important post-translation enzyme, which catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine (UDP-GlcNAc) to the hydroxyl group of the Ser/Thr of cytoplasmic, nuclear, and mitochondrial proteins. In the past, three different catalytic bases were proposed for the reaction: His498, alpha-phosphate, and Asp554. In this study, we used hybrid quantum mechanics/molecular mechanics (QM/MM) Car-Parrinello molecular dynamics to investigate reaction paths using alpha-phosphate and Asp554 as the catalytic bases. The string method was used to calculate the free-energy reaction profiles of the tested mechanisms. During the investigations, an additional mechanism was observed. In this mechanism, a proton is transferred to alpha-phosphate via a water molecule. Our calculations show that the mechanism with alpha-phosphate acting as the base is favorable. This reaction has a rate-limiting free-energy barrier of 23.5 kcal/mol, whereas reactions utilizing Asp554 and water-assisted alpha-phosphate have barriers of 41.7 and 40.9 kcal/mol, respectively. Our simulations provide a new insight into the catalysis of OGT and may thus guide rational drug design of transition-state analogue inhibitors with potential therapeutic use.
ER  -

KUMARI, Manju, Stanislav KOZMON, Petr KULHÁNEK, Jakub ŠTĚPÁN, Igor TVAROŠKA a Jaroslav KOČA. Exploring Reaction Pathways for O-GlcNAc Transferase Catalysis. A String Method Study. \textit{Journal of Physical Chemistry B}. WASHINGTON: AMER CHEMICAL SOC, 2015, roč.~119, č.~12, s.~4371-4381. ISSN~1520-6106. Dostupné z: https://dx.doi.org/10.1021/jp511235f.

Podrobný výpis o publikaci