Loading...
Please wait, while we are loading the content...
Similar Documents
QM/MM Study of The Mechanism of Reduction of 3-hydroxy-3-methylglutaryl co- enzyme A Catalyzed by Human HMG-CoA Reductase
| Content Provider | Semantic Scholar |
|---|---|
| Author | Oliveira, Eduardo F. T. Cerqueira, Nuno M. F. S. A. Ramos, María Jesús Fernandes, Pedro Alexandrino |
| Copyright Year | 2016 |
| Abstract | Detailing with atomistic resolution the reaction mechanism of human HMG-CoA reductase (HMG-CoA-R) might provide valuable insight for the development of new cholesterol-lowering drugs. On the pursue of that goal we developed three molecular models of human HMG-CoA-R with different active site protonation states and employed molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM)/MM) calculations to detail the first reduction step, the rate-limiting step, of HMG-CoA-R. Our results predict an active site with a neutral glutamate (Glu559) as the most catalytic competent structure. The favored reaction pathway suggests the formation of a mevaldyl-CoA intermediate protonated by a conserved active site lysine (Lys691), corroborating previous site-directed mutagenesis studies. The conserved active site glutamate and aspartate residues (Glu559 and Asp767), along with the ribose moiety of NADPH, form a hydrogen bond network crucial to increase the stabilizing effect of Lys691 over the transition state. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://pubs.rsc.org/en/content/getauthorversionpdf/C6CY00356G |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
