User:Sachin Sundar/Sandbox 1: Difference between revisions

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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>

[[Media:lov2d.jpg|(Image of Lovastatin 2D Structure)]]. 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"> https://pubchem.ncbi.nlm.nih.gov/compound/445127

[[Media:lov2d.jpg|(Image of Lovastatin 2D Structure)]] 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"> https://pubchem.ncbi.nlm.nih.gov/compound/445127

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

hydroxymethylglutaryl-CoA https://pubchem.ncbi.nlm.nih.gov/compound/445127 (accessed Apr 20, 2017)</ref>[[Media:hmgcoa2d.jpg|(Image of HMG-CoA 2D Structure)]] 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">http://proteopedia.org/wiki/index.php/HMG-CoA_Reductase#cite_note-Meigs-2

[[Media:hmgcoa2d.jpg|(Image of HMG-CoA 2D Structure)]] 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">http://proteopedia.org/wiki/index.php/HMG-CoA_Reductase#cite_note-Meigs-2

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

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==Mechanism==

<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">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>

<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">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>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>

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>

@@ Line 20: / Line 20: @@
 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>
-  [[Media:lov2d.jpg|(Image of Lovastatin 2D Structure)]].  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"> https://pubchem.ncbi.nlm.nih.gov/compound/445127
+  [[Media:lov2d.jpg|(Image of Lovastatin 2D Structure)]]  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"> https://pubchem.ncbi.nlm.nih.gov/compound/445127
-hydroxymethylglutaryl-CoA https://pubchem.ncbi.nlm.nih.gov/compound/445127 (accessed Apr 20, 2017)</ref>,
+hydroxymethylglutaryl-CoA https://pubchem.ncbi.nlm.nih.gov/compound/445127 (accessed Apr 20, 2017)</ref>[[Media:hmgcoa2d.jpg|(Image of HMG-CoA 2D Structure)]] 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">http://proteopedia.org/wiki/index.php/HMG-CoA_Reductase#cite_note-Meigs-2
-[[Media:hmgcoa2d.jpg|(Image of HMG-CoA 2D Structure)]] 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">http://proteopedia.org/wiki/index.php/HMG-CoA_Reductase#cite_note-Meigs-2
 HMG-CoA Reductase http://proteopedia.org/wiki/index.php/HMG-CoA_Reductase#cite_note-Meigs-2 (accessed Apr 20, 2017)</ref>
@@ Line 30: / Line 29: @@
 ==Mechanism==
-<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">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>
+<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">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>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>
- 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>