The enzyme 3-hydroxy-3-methyl-glutaryl-co-enzyme A (HMG-CoA) reductase catalyzes the conversion of HMG-CoA to mevalonate. By competitively blocking this enzyme, the HMG-CoA reductase inhibitors interfere with cholesterol formation. As a result, they decrease total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (a membrane transport complex for LDL-C), very low-density lipoprotein (VLDL), and plasma triglycerides. They also increase serum concentrations of high-density lipoprotein cholesterol (HDL).
An overview of HMG-CoA reductase
3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (also known as HMGCR), the rate-limiting enzyme in the cholesterol biosynthetic pathway, is able to significantly influences the concentrations of plasma cholesterol that may lead to coronary heart disease.
Cholesterol is a sterol and lipid that exists in the cell membrane of animal tissues and is transmitted by plasma. A small amount of cholesterol can also be found in the plant cell membrane. In the 1950s and 1960s, several laboratories figured out the details of cholesterol manufacture in different institutions and found that more than thirty enzymes were involved in the cholesterol biosynthesis process, which was complex. The entire process can be divided into three phases through intermediate products. The first step is the synthesis of HMG-CoA., and then the mevalonic acid(MVA) is produced. Finally, MVA reacts in multiple generate cholesterol.
Figure 1 The cholesterol biosynthesis pathway
Inhibition of HMG-CoA Reductase
The intricate cholesterol biosynthesis provided a natural target for drugs to reduce the concentration of plasm cholesterol, hoping that the treatments would reduce the risk of coronary heart disease. The early drugs, and lovastatin act as lead compounds in the development of inhibitors of HMG-CoA reductase.
HMG-CoA Reductase and diseases
HMG-CoA reductase is related to low-density lipoprotein and may lead to coronary heart disease. In the 1990s, fluvastatin, atorvastatin and cerivastatin were introduced into clinical use. After then, an increasing number statins came into the market and have better therapeutic effect. Statins occupy an extremely important position in the global pharmaceutical industry. Among them, atorvastatin has been ranked in the world's top ten best-selling drugs for many years. According to some experts, the contribution of statins to humans will be no less than that of penicillin. The popularization of statins is called a "statin revolution. " In the future, further research of HMG-CoA reductase and its inhibitors will contribute to the development of new drugs and the treatment of diseases.
1. Tobert, J. A. Lovastatin and beyond: The history of the HMG-CoA reductase inhibitors. Nature Reviews Drug Discovery 2, 517-526, doi:10.1038/nrd1112 (2003).
2. Demierre, M. F., Higgins, P. D. R., Gruber, S. B., Hawk, E. & Lippman, S. M. Statins and cancer prevention. Nature Reviews Cancer 5, 930-942, doi:10.1038/nrc1751 (2005).
3.Henninger, C. & Fritz, G. Statins in anthracycline-induced cardiotoxicity: Rac and Rho, and the heartbreakers. Cell Death & Disease 8, doi:10.1038/cddis.2016.418 (2017).
Products for HMG-CoA Reductase (HMGCR)