Publication details
Exploring Reaction Pathways for O-GlcNAc Transferase Catalysis. A String Method Study
| Authors | |
|---|---|
| Year of publication | 2015 |
| Type | Article in Periodical |
| Magazine / Source | Journal of Physical Chemistry B |
| MU Faculty or unit | |
| Citation | |
| web | http://pubs.acs.org/doi/pdf/10.1021/jp511235f |
| Doi | http://dx.doi.org/10.1021/jp511235f |
| Field | Physical chemistry and theoretical chemistry |
| Keywords | CATALYTIC MECHANISM; PK(A) VALUES; ENERGY PATHS; GLYCOSYLTRANSFERASES; SIMULATIONS; PROTEIN; RATIONALIZATION; METABOLISM; SUBSTRATE; CLEAVAGE |
| Description | 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. |
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