User:Sachin Sundar/Sandbox 1: Difference between revisions

<scene name='75/758442/Lovastatin/1'>Lovastatin</scene>, 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. <ref name= "six">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</ref> 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 <ref name= "fourteen">ENDO, A. A historical perspective on the discovery of statins https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108295/ (accessed Apr 20, 2017).</ref>

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 <ref name= "fifteen">Tabernero‡§, L.; and, V. W. R. Lydia Tabernero http://www.jbc.org/content/278/22/19933.long#F4 (accessed Apr 20, 2017)</ref> 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. <ref name="two"/>

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. <ref name="nine">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</ref> 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 <ref name= "sixteen">Chemistry Products No delete http://www.sigmaaldrich.com/chemistry/chemistry-products.html?TablePage=16270948 (accessed Apr 20, 2017)</ref>[[Media:lov2d.jpg|(Image of Lovastatin 2D Structure)]]<ref name= "eighteen">HMG-CoA Reductase http://proteopedia.org/wiki/index.php/HMG-CoA_Reductase#cite_note-Meigs-2 (accessed Apr 20, 2017).</ref>  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. <ref name= "nineteen"> hydroxymethylglutaryl-CoA https://pubchem.ncbi.nlm.nih.gov/compound/445127 (accessed Apr 20, 2017)</ref>[[Media:hmgcoa2d.jpg|(Image of HMG-CoA 2D Structure)]]<ref name= "hmg">HMG-CoA https://pubchem.ncbi.nlm.nih.gov/compound/439218#section=Top (accessed Apr 20, 2017)</ref> 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 <ref name="eighteen">HMG-CoA Reductase http://proteopedia.org/wiki/index.php/HMG-CoA_Reductase#cite_note-Meigs-2 (accessed Apr 20, 2017)</ref>  

[[Media:lovhmg.jpg|Image of 2D comparison of Lovastatin and HMG-CoA]]<ref name= "eighteen"/>

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 <scene name='75/758442/Asn271/3'>Asn-271</scene> (Asn-755 in Class I), <scene name='75/758442/Lys267/2'>Lys-267</scene> (Lys-691 in Class I) and <scene name='75/758442/Glu83/1'>Glu-83</scene> (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 <scene name='75/758442/Asn365/1'>Asn-365</scene>(Arg-590 in Class I) and two hydrogen bonds with <scene name='75/758442/Asn216/1'>Asn-216</scene> 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 <scene name='75/758442/Arg261/1'>Arg-261</scene> 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 <scene name='75/758442/Ala368/1'>Ala-368</scene> and <scene name='75/758442/Leu372/1'>Leu-372</scene> 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. <ref name= "thirteen">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).</ref>

[[Media:lov.jpg|Image of LOV sites relative to Lovastatin]]<ref name= "thirteen"/>

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. <ref name= "twelve">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</ref>. 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 <ref name= "twelve"/>. 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 <ref name= "seventeen">Statins: MedlinePlus https://medlineplus.gov/statins.html (accessed Apr 20, 2017).</ref> 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  <ref name= "one">Lovastatin. National Center for Biotechnology Information. PubChem Compound Database;  CID=53232. Retrieved March 28, 2017 from https://pubchem.ncbi.nlm.nih.gov/compound/53232</ref>