4i6w Citations

A novel role for CoA during hydride transfer in 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Abstract

In this study we take advantage of the ability of HMG-CoA reductase (HMGR) from Pseudomonas mevalonii to remain active while in crystallized form to study the changing interactions between the ligands and protein as the first reaction intermediate is created. HMG-CoA reductase catalyzes one of the few double oxidation/reduction reactions in intermediary metabolism that take place in a single active site. Our laboratory has undertaken an exploration of this reaction space using structures of HMG-CoA reductase complexed with various substrate, nucleotide, product, and inhibitor combinations. Focusing in this publication on the first hydride transfer, our structures follow this reduction reaction as the enzyme converts the HMG-CoA thioester from a flat sp2 like geometry to a pyramidal thiohemiacetal configuration consistent with a transition to an sp3 orbital. This change in the geometry propagates through the CoA ligand whose first amide bond is rotated 180 degrees where it anchors a web of hydrogen bonds that weave together the nucleotide, the reaction intermediate, the enzyme and the catalytic residues. This creates a stable intermediate structure prepared for nucleotide exchange and the second reduction reaction within the HMG-CoA reductase active site. Identification of this reaction intermediate provides a template for the development of an inhibitor that would act as an antibiotic effective against the HMG-CoA reductase of methicillin-resistant Staphylococcus aureus.

Articles citing this publication (1)

  1. Altered liver expression of genes involved in lipid and glucose metabolism in mice with partial IGF-1 deficiency: an experimental approach to metabolic syndrome. De Ita JR, Castilla-Cortázar I, Aguirre GA, Sánchez-Yago C, Santos-Ruiz MO, Guerra-Menéndez L, Martín-Estal I, García-Magariño M, Lara-Díaz VJ, Puche JE, Muñoz U. J Transl Med 13 326 (2015)