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spinqualitylabelsall models HMG-CoA Reductase Class II bound to Lovastatin Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

OverviewOverview

, generic for Mevacor, is a potent anticholesteremic agent, a common drug used to lower LDL (low-density lipoprotein) and triglyceride levels of patients susceptible to heart attacks, strokes, and chest pain due to clogged arteries. This statin works to suppress cholesterol synthesis by controlling the changes in activity of HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, leading to changes in the rate of cholesterol synthesis

History/OriginHistory/Origin

Increasing evidence about the correlation between high cholesterol levels and disease in the 1905’s and 1960’s lead scientists to discover new forms of constraining this link. Many companies researched more about the biosynthetic pathway of cholesterol in order to determine which step is important to slow down the production of cholesterol. Towards the end of the 1970’s, various pharmaceutical companies searched for different alternatives after the discovery of compactin, a potential inhibitor discovered earlier in the decade but was not effective due to its dangerous side effects (caused cancer in dogs). Then in 1979, a statin called mevinolin, isolated from Aspergillus terreus, and another statin called monacolin K, isolated from Monascus ruber, were discovered to be the same compound and were structurally similar to compactin. Later on, this compound was labeled as Lovastatin. Merck Research Laboratories initiated clinical studies using Lovastatin in 1980, until rumors began about Lovastatin being similar to compactin, therefore has the ability to cause cancer and caused research to be shut down. However, it was later  proved by Michael Brown and Joseph Goldstein that the drug can increase cell surface LDL receptors in the liver and decrease LDL levels from a dog’s plasma. With this conclusion, Lovastatin was used in clinical trials using human subjects and produced the same results as shown in the dogs. In 1982, Lovastatin showed success due to its ability to lower LDL levels with individuals suffering from severe hypercholesterolemia. This drug was also beneficial because it did not cause any tumors, nor did it have any serious negative side effects. Lovastatin received FDA approval in 1986, and has lowered the possibility of developing heart diseases or atherosclerosis in millions of individuals suffering from elevated cholesterol levels

A study done by Tabernero et al. using lovastatin and P. manovalli HMG-COA reductase helps us understand the mechanism by which lovastatin inhibits the binding of HMG-COA, which is an intermediary substrate in the biosynthetic process of producing cholesterol. There are two classes of HMG-CoA reductase that is mentioned in  this study. The first being Class I, which is the human HMG-CoA reductase, and Class II which is the P. mevalonii HMG-CoA reductase.  The Lovastatin seems to interact with four different sites within the HMG-COA reductase in P. manovalli. In the first site, LOV- 1, the c5-OH group and it does so through interactions with residues (Asn-755 in Class I), (Lys-691 in Class I) and (Glu-559 in Class I). The second site, LOV-2, binds to the C3-OH group through water mediated hydrogen bonds. One bond is formed with (Arg-590 in Class I) and two hydrogen bonds with through the water mediated hydrogen bonds. The third site, LOV-3 interacts with the carboxylate group and creates a hydrogen bond with Arg-261. In the Class I enzyme Lys-735 and Lys-692 form hydrogen bonds and bind in a similar manner to in LOV-3. Two additional hydrogen bonds are formed to the carboxylate group through a water mediated process with Ser-684 in LOV-3 as well in the Class I enzyme. The fourth and final site, LOV-4, interacts with the decalin ring and forms hydrophobic interactions with and found on the hydrophobic region of the alpha helix of the large domain. (Leu-562 and Val-683 are thought to have similar hydrophobic interactions with decalin ring in the Class I enzyme) The remaining three residues that interact within LOV-4 are Ser-85, Ile-86, and Ala-89 which is located in the alpha helix region downstream from the catalytic residue Glu-83. This binding of lovastatin to the active site inhibits binding of substrate, HMG-COA, as well as preventing the closure of the flap domain, that contains the catalytic His-381, which enables the process of reduction from taking place. The misalignment and failure to close the active site inhibits the function of the protein and prevents catalysis.

Image of LOV sites relative to Lovastatin

Health & Disease in HumansHealth & Disease in Humans

Cells require cholesterol because it aids in the structure of cell membranes by restricting the membrane from being too fluid Low-density lipoproteins (LDL) and high-density lipoproteins (HDL) carry cholesterol to and from cells. Also, cholesterol is also not able to dissolve in blood and require these lipoproteins for transportation. These lipoproteins and an individual's triglyceride level is what makes up their total cholesterol count. LDL is termed as “bad” cholesterol because of its relationship with plaque, a thick and hard build of cholesterol that can block arteries. HDL aids in the removal of LDL from the arteries and carries it back to the liver where it can be broken down and expelled from the body . A total cholesterol level less than 200 mg/dL is recommended by healthcare providers . Elevated levels of cholesterol in the arteries can directly influence the risk of heart attacks, strokes, atherosclerosis and other heart diseases . Typically, diet and exercise can limit the buildup of cholesterol in the body. Dieting includes consuming lower amounts of saturated fat and cholesterol, and exercise includes regular physical activity every other day for 30 minutes is ideal. However, there are cases where dieting and exercise do not help reduce elevated LDL levels. In these situations, health care providers will recommend the use of medications. Statins are drugs typically used for lowering elevated cholesterol levels in the blood (17). Statins interrupt the production of cholesterol in your liver by increasing the amount of LDL receptors on cell surfaces, which increases LDL uptake by cells and lowers the amount of LDL left in the blood

Cells require cholesterol because it aids in the structure of cell membranes by restricting the membrane from being too fluid . Low-density lipoproteins (LDL) and high-density lipoproteins (HDL) carry cholesterol to and from cells. Also, cholesterol is also not able to dissolve in blood and require these lipoproteins for transportation. These lipoproteins and triglyceride levels are what account for an individual’s total cholesterol count. LDL is termed as “bad” cholesterol because of its relationship with plaque, a thick and hard build of cholesterol that can block arteries. HDL aids in the removal of LDL from the arteries and carries it back to the liver where it can be broken down and expelled from the body . A total cholesterol level less than 200 mg/dL is recommended by healthcare providers . Elevated levels of cholesterol in the arteries can directly influence the risk of heart attacks, strokes, atherosclerosis and other heart diseases . Typically, diet and exercise can limit the buildup of cholesterol in the body. Dieting includes consuming lower amounts of saturated fat and cholesterol, and exercise includes regular physical activity every other day for 30 minutes is ideal. However, there are cases where dieting and exercise do not help reduce elevated LDL levels. In these situations, health care providers will recommend the use of medications. Statins are drugs used for lowering elevated cholesterol levels in the blood . In rare cases, this drug can result in Rhabdomyolysis, a condition that results in the breakdown of skeletal muscle tissue and can lead to tissue failure .