An Atomic-Level Perspective of HMG-CoA-Reductase: The Target Enzyme to Treat Hypercholesterolemia.

This review provides an updated atomic-level perspective regarding the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR), linking the more recent data on this enzyme with a structure/function interpretation. This enzyme catalyzes one of the most important steps in cholesterol biosynthesis and is regarded as one of the most important drug targets in the treatment of hypercholesterolemia. Taking this into consideration, we review in the present article several aspects of this enzyme, including its structure and biochemistry, its catalytic mechanism and different reported and proposed approaches for inhibiting this enzyme, including the commercially available statins or the possibility of using dimerization inhibitors.

Cholesterol Biosynthesis: A Mechanistic Overview.

Cholesterol is an essential component of cell membranes and the precursor for the synthesis of steroid hormones and bile acids. The synthesis of this molecule occurs partially in a membranous world (especially the last steps), where the enzymes, substrates, and products involved tend to be extremely hydrophobic. The importance of cholesterol has increased in the past half-century because of its association with cardiovascular diseases, which are considered one of the leading causes of death worldwide. In light of the current need for new drugs capable of controlling the levels of cholesterol in the bloodstream, it is important to understand how cholesterol is synthesized in the organism and identify the main enzymes involved in this process. Taking this into account, this review presents a detailed description of several enzymes involved in the biosynthesis of cholesterol. In this regard, the structure and catalytic mechanism of the enzymes involved in cholesterol biosynthesis, from the initial two-carbon acetyl-CoA building block, will be reviewed and their current pharmacological importance discussed. We believe that this review may contribute to a deeper level of understanding of cholesterol metabolism and that it will serve as a useful resource for future studies of the cholesterol biosynthesis pathway.

Unraveling the enigmatic mechanism of L-asparaginase II with QM/QM calculations.

In this paper, we have studied the catalytic mechanism of L-asparaginase II computationally. The reaction mechanism was investigated using the ONIOM methodology. For the geometry optimization we used the B3LYP/6-31G(d):AM1 level of theory, and for the single points we used the M06-2X/6-311++G(2d,2p):M06-2X/6-31G(d) level of theory. It was demonstrated that the full mechanism involves three sequential steps and requires the nucleophilic attack of a water molecule on the substrate prior to the release of ammonia. There are three rate-limiting states, which are the reactants, the first transition state, and the last transition state. The energetic span is 20.2 kcal/mol, which is consistent with the experimental value of 16 kcal/mol. The full reaction is almost thermoneutral. The proposed catalytic mechanism involves two catalytic triads that play different roles in the reaction. The first triad, Thr12-Lys162-Asp90, acts by deprotonating a water molecule that subsequently binds to the substrate. The second triad, Thr12-Ty25-Glu283, acts by stabilizing the tetrahedral intermediate that is formed after the nucleophilic attack of the water molecule to the substrate. We have shown that a well-known Thr12-substrate covalent intermediate is not formed in the wild-type mechanism, even though our results suggest that its formation is expected in the Thr89Val mutant. These results have provided a new understanding of the catalytic mechanism of L-asparaginases that is in agreement with the available experimental data, even though it is different from all earlier proposals. This is of particular importance since this enzyme is currently used as a chemotherapeutic drug against several types of cancer and in the food industry to control the levels of acrylamide in food.