User:Sachin Sundar/Sandbox 1: Difference between revisions

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">http://www.sigmaaldrich.com/chemistry/chemistry-products.html?TablePage=16270948

Chemistry Products No delete http://www.sigmaaldrich.com/chemistry/chemistry-products.html?TablePage=16270948 (accessed Apr 20, 2017)<ref/>

hydroxymethylglutaryl-CoA https://pubchem.ncbi.nlm.nih.gov/compound/445127 (accessed Apr 20, 2017)<ref/>

HMG-CoA Reductase http://proteopedia.org/wiki/index.php/HMG-CoA_Reductase#cite_note-Meigs-2 (accessed Apr 20, 2017)<ref/>  

<scene name='75/758442/Lovastatin/1'>Lovastatin</scene> 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.<ref name= "one"/> 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 <scene name='75/758442/Hmg-coa_reducatase/3'>HMG-COA reductase (HMG-COA Reductase bound to Lovastatin)</scene>, 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. <ref name= "seven">Lovastatin. (n.d.). Retrieved March 28, 2017, from http://community.middlebury.edu/~sontum/chemistry/students/ho/lovastatin.html</ref>

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"/>. 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 (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  <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>  

Cells require cholesterol because it aids in the structure of cell membranes by restricting the membrane from being too fluid <ref name= "ten">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</ref>. 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 <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 <ref name= "eleven">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>. 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 used for lowering elevated cholesterol levels in the blood <ref name= "seventeen"> https://medlineplus.gov/statins.html

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"/>.