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; Stanislav KOZMON; Petr KULHÁNEK; Jakub ŠTĚPÁN; Igor TVAROŠKA a Jaroslav KOČA

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

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14740/15:00085002

Organizační jednotka

Středoevropský technologický institut

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://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 = {https://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://doi.org/10.1021/jp511235f.

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