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

Logo poskytovatele
Logo poskytovatele

Varování

Publikace nespadá pod Fakultu sportovních studií, ale pod Středoevropský technologický institut. Oficiální stránka publikace je na webu muni.cz.
Autoři

KUMARI Manju KOZMON Stanislav KULHÁNEK Petr ŠTĚPÁN Jakub TVAROŠKA Igor KOČA Jaroslav

Rok publikování 2015
Druh Článek v odborném periodiku
Časopis / Zdroj Journal of Physical Chemistry B
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
www http://pubs.acs.org/doi/pdf/10.1021/jp511235f
Doi http://dx.doi.org/10.1021/jp511235f
Obor Fyzikální chemie a teoretická chemie
Klíčová slova CATALYTIC MECHANISM; PK(A) VALUES; ENERGY PATHS; GLYCOSYLTRANSFERASES; SIMULATIONS; PROTEIN; RATIONALIZATION; METABOLISM; SUBSTRATE; CLEAVAGE
Popis 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.
Související projekty:

Používáte starou verzi internetového prohlížeče. Doporučujeme aktualizovat Váš prohlížeč na nejnovější verzi.

Další info