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Abstract
Statins are important drugs in the regulation of cholesterol levels in the human body that have as a primary target the enzyme β-hydroxy-β-methylglutaryl-CoA reductase (HMGR). This enzyme plays a crucial role in the mevalonate pathway, catalyzing the four-electron reduction of HMG-CoA to mevalonate. A second reduction step of this reaction mechanism has been the subject of much speculation in the literature, with different conflicting theories persisting to the present day. In this study, the different mechanistic hypotheses were evaluated with atomic-level detail through a combination of molecular dynamics simulations (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations. The obtained Gibbs free activation and Gibbs free reaction energy (15 kcal mol−1 and −40 kcal mol−1) show that this hydride step takes place with the involvement of a cationic His405 and Lys639, and a neutral Glu98, while Asp715 remains in an anionic state. The results provide an atomic-level portrait of this step, clearly demonstrating the nature and protonation state of the amino acid residues involved, the energetics associated, and the structure and charge of the key participating atoms in the several intermediate states, finally elucidating this missing step.
Highlights
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Organisms that can survive on mevalonate as a source of carbon are known as Pseudomonas mevalonii (Pm), and it has been discovered that large quantities of PmHMGR are involved in mevalonate catabolism, which is a reversed mevalonate pathway [15]
The PmHMGR structure confirmed that Asp283, Lys267, and Asn271 were conserved in the active site and that the Lys267/Lys639 is located close to Glu83/Glu98 and Asp283/Asp715; Tabernero et al offered a new mechanism where Lys267/Lys639 protonated the carbonyl of the substrate [18]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The reaction mechanism of this enzyme has been studied both by computational models and experimentally. Earlier studies have shown that the reaction mechanism involves two hydride transfers, a cofactor exchange and a hemithioacetal decomposition step; the hypothesis of a hemithioacetal intermediate was developed but never proven due to its non-reactivity toward NADP(H) [6,7,8,9,10,12]. The PmHMGR structure confirmed that Asp283, Lys267, and Asn271 (analogous to Asp715, Lys639, and Asn643) were conserved in the active site and that the Lys267/Lys639 is located close to Glu83/Glu and Asp283/Asp715; Tabernero et al offered a new mechanism where Lys267/Lys639 protonated the carbonyl of the substrate [18]
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