QM/MM study of the mechanism of reduction of 3-hydroxy-3-methylglutaryl coenzyme A catalyzed by human HMG-CoA reductase

• Type: Article in International Scientific Journal
• Date: 2016

Authors

Oliveira, EF (Author) Other; Nuno M F S A Cerqueira (Author) FCUP; Ramos, MJ (Author) FCUP; Pedro A Fernandes (Author) FCUP

Journal

Title: Catalysis Science and Technology

Vol. 6

Pages: 7172-7185

ISSN: 2044-4753

Publisher: Royal Society of Chemistry

Indexing

ISI Web of Knowledge - 18 Citations

Scopus - 18 Citations

Other information

Authenticus ID: P-00M-3VB

DOI: 10.1039/c6cy00356g

Abstract (EN): Detailing with atomistic resolution the reaction mechanism of human HMG-CoA reductase (HMG-CoA-R) might provide valuable insights for the development of new cholesterol-lowering drugs. In the pursuit 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 catalytically 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 the increase of the stabilizing effect of Lys691 over the transition state.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14