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
Impakt faktor
Impact factor: 3.187
Kód RIV
RIV/00216224:14740/15:00085002
Organizační jednotka
Středoevropský technologický institut
UT WoS
000351971100004
Klíčová slova anglicky
CATALYTIC MECHANISM; PK(A) VALUES; ENERGY PATHS; GLYCOSYLTRANSFERASES; SIMULATIONS; PROTEIN; RATIONALIZATION; METABOLISM; SUBSTRATE; CLEAVAGE
Štítky
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 |
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LH13055, projekt VaV |
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286154, interní kód MU |
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