Lovastatin-Mevacor

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HMG-CoA Reductase Class II bound to Lovastatin (PDB code 1t02)

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Contents

Overview

, 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. [1] 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 [2]

History/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 [2]

Function

As Lovastatin is ingested after being taken orally, water inside an individual's body will hydrolyze this lactone into its β-hydroxyacid form. [3] This metabolite is crucial as it is the active form of the inhibitor. The β-hydroxyacid moiety is structurally similar to the HMG moiety of the substrate HMG-CoA, and both moieties form strong hydrogen bonds to the active site on the HMG-CoA reductase [4] As food is digested, it is normally taken to the liver where it is further broken down in order to produce cholesterol, or fuel for an individual’s body. To begin the biosynthesis pathway of cholesterol, Acetyl-CoA is first produced in the process of breaking down the ingested food. Acetyl-CoA will become cholesterol through several biochemical steps, and the most important point in this process is the rate-limiting step known as HMG-CoA (3-hydroxy-methylglutarylcoenzyme A) reductase. This enzyme is considered to be the rate limiting step because it can stop the process of forming Mevalonate, which is the main reason for the biosynthesis pathway to continue. Due to this important information, statins target the HMG-CoA reductase enzyme in order to inhibit the biosynthesis pathway.  As Lovastatin binds to the reductase, this lowers the production of cholesterol in the liver. When cholesterol levels become low, this initiates an active protease to cleave sterol regulatory element-binding proteins (SREBP) in the endoplasmic reticulum. The nucleus detects the cleavage, and increases the expression of the LDL receptor gene causing an increase of LDL receptors to the cell surface. This will then increase the receptor-mediated endocytosis of LDL, causing LDL levels from the blood to lower. This process also increases HDL and decreases triglycerides in the plasmid. [3]


Structure

Lovastatin mimics the binding of HMG-CoA substrate, therefore it is confirmed that these two structures are similar. The molecular formula of Lovastatin is C24H36O5 and the molecular weight is 405 Da. [5] Lovastatin is in a lactone ring conformation when in the inactivated form. Lactones are cyclic esters, or a ring consisting of two or more carbon atoms and one oxygen atom with a ketone group located on one of the carbons adjacent to the other oxygen [6](Image of Lovastatin 2D Structure)[7] Hydroxymethylglutaryl-CoA (HMG-CoA) is an intermediate in the mevalonate pathway with a molecular formula of C27H44N7O20P3S and a molecular weight of 911.659 g/mol. [8](Image of HMG-CoA 2D Structure)[9] The structure of HMG-CoA reductase in humans consists of a tetramer, which is the catalytic portion of this enzyme. The tetramer consists of monomers wrapped around each other in the form of two dimers. Within each dimer are two active sites formed by the residues in both monomers. Each monomer consists of three binding sites; two of which are the S and L domains and are connected via a cis-loop, and is essential for NADP binding [10]

Image of 2D comparison of Lovastatin and HMG-CoA[10]


Mechanism

is meant to interrupt the rate limiting step in the biosynthesis of cholesterol via the mevalonic acid pathway. Lovastatin is similar to hydroxymethyglutarate (HMG), which is a substituent of HMG-Coenzyme A (HMG-CoA). HMG-CoA is a substrate of the cholestrol biosynthesis via the mevalonic acid pathway. Lovastatin has a binding affinity which is 20,000 times greater than that of HMG-CoA. Lovastatin is activated by in vivo hydrolysis of the lactone ring.[7]To begin the mechanism, a water molecule performs a nucleophilic attack on the carbonyl carbon on Lovastatin, resulting in the opening of the ring which produces the ß-hydroxyacid form of the drug. This hydrolyzed molecule results in a terminal carboxylic acid group. This group is similar to the thioester group found on HMG-COA (3-hydroxyl-3-methylgutarylcoenzyme A) which is then reduced to an alcohol by , through a NADPH-dependent reduction to form mevalonate.  It is thought that HMG-CoA reductase reduces the ß-hydroxyacid on Lovastatin at its carboxylic acid end in a similar manner. There are two binding domains on HMG-CoA reductase as it works synchronously with NADH. NADH binds to the smaller domain within the dimer as the substrate, HMG-CoA, binds to the larger domain of the dimer. Through competitive inhibition, Lovastatin binds to the larger domain in this manner with the carboxylic acid end facing the NADH. This reduces the probability of HMG-CoA reductase binding to HMG-CoA which then prevents the production of mevalonate which is essential to producing cholesterol. [11]


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(Image of His-381 Flap Structure)[12], 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. [13]

Image of LOV sites relative to Lovastatin[13]

Health & Disease in Humans

Cells require cholesterol because it aids in the structure of cell membranes by restricting the membrane from being too fluid [14]. 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. [15] . A total cholesterol level less than 200 mg/dL is recommended by healthcare providers [16]. Elevated levels of cholesterol in the arteries can directly influence the risk of heart attacks, strokes, atherosclerosis and other heart diseases [15]. 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[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 [7]. Mevacor (Lovastatin) can treat high levels of LDL cholesterol and triglyceride. This in turn leads to the reduction of  heart attacks, angina, coronary revascularization procedures in individuals without symptomatic cardiovascular disease. Also used for individuals suffering from coronary heart disease [15]. Severe side effects when taking Lovastatin include constipation, memory loss or forgetfulness, confusion. Other side effects that occur when taking this drug include headache, nausea, vomiting, diarrhea, abdominal pain, and muscle pain [18] . 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 [18].


References

  1. ↑ Altoprev, Mevacor (lovastatin) Drug Side Effects, Interactions, and Medication Information on eMedicineHealth. (n.d.). Retrieved March 28, 2017, from http://www.emedicinehealth.com/drug-lovastatin/article_em.htm
  2. ↑ 2.0 2.1 ENDO, A. A historical perspective on the discovery of statins https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108295/ (accessed Apr 20, 2017).
  3. ↑ 3.0 3.1 Mevacor (Lovastatin). (2014, February). Retrieved March 28, 2017, from https://www.merck.com/product/usa/pi_circulars/m/mevacor/mevacor_pi.pdf
  4. ↑ Tabernero‡§, L.; and, V. W. R. Lydia Tabernero http://www.jbc.org/content/278/22/19933.long#F4 (accessed Apr 20, 2017)
  5. ↑ Masterjohn, C. (2005, July). Cholesterol's Importance to the Cell Membrane. Retrieved March 28, 2017, from http://www.cholesterol-and-health.com/Cholesterol-Cell-Membrane.html
  6. ↑ Chemistry Products No delete http://www.sigmaaldrich.com/chemistry/chemistry-products.html?TablePage=16270948 (accessed Apr 20, 2017)
  7. ↑ 7.0 7.1 7.2 Lovastatin. National Center for Biotechnology Information. PubChem Compound Database; CID=53232. Retrieved March 28, 2017 from https://pubchem.ncbi.nlm.nih.gov/compound/53232
  8. ↑ hydroxymethylglutaryl-CoA https://pubchem.ncbi.nlm.nih.gov/compound/445127 (accessed Apr 20, 2017)
  9. ↑ HMG-CoA https://pubchem.ncbi.nlm.nih.gov/compound/439218#section=Top (accessed Apr 20, 2017)
  10. ↑ 10.0 10.1 HMG-CoA Reductase http://proteopedia.org/wiki/index.php/HMG-CoA_Reductase#cite_note-Meigs-2 (accessed Apr 20, 2017)
  11. ↑ Lovastatin. (n.d.). Retrieved March 28, 2017, from http://community.middlebury.edu/~sontum/chemistry/students/ho/lovastatin.html
  12. ↑ Tabernero, L., Bochar, D. A., Rodwell, V. W., & Stauffacher, C. V. (1999). Substrate-induced closure of the flap domain in the ternary complex structures provides insights into the mechanism of catalysis by 3-hydroxy-3-methylglutaryl–CoA reductase. Proceedings of the National Academy of Sciences of the United States of America, 96(13), 7167–7171.
  13. ↑ 13.0 13.1 Tabernero, L.; Rodwell, V. W.; Stauffacher, C. V. Crystal structure of a statin bound to a class II hydroxymethylglutaryl-CoA reductase. https://www.ncbi.nlm.nih.gov/pubmed/?term=12621048 (accessed Apr 20, 2017).
  14. ↑ High Blood Cholesterol: What You Need To Know. (2005, June). Retrieved March 28, 2017, from https://www.nhlbi.nih.gov/health/resources/heart/heart-cholesterol-hbc-what-html
  15. ↑ 15.0 15.1 15.2 Good vs. Bad Cholesterol. (2014, April). Retrieved March 28, 2017, from http://www.heart.org/HEARTORG/Conditions/Cholesterol/AboutCholesterol/Good-vs-Bad-Cholesterol_UCM_305561_Article.jsp#.WNrV_RiZPGI
  16. ↑ Good vs. Bad Cholesterol. (2014, April). Retrieved March 28, 2017, from http://www.heart.org/HEARTORG/Conditions/Cholesterol/AboutCholesterol/Good-vs-Bad-Cholesterol_UCM_305561_Article.jsp#.WNrV_RiZPGI
  17. ↑ Statins: MedlinePlus https://medlineplus.gov/statins.html (accessed Apr 20, 2017).
  18. ↑ 18.0 18.1 Ogbru, O., PharmD. (2015, September 30). Lovastatin, Mevacor, Altoprev: Drug Facts, Side Effects and Dosing (J. W. Marks MD, Ed.). Retrieved March 28, 2017, from http://www.medicinenet.com/lovastatin/article.htm

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