User:Sachin Sundar/Sandbox 1: Difference between revisions

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[[Image:pic_1.jpg]]

~~[[Image:pic_3.jpg]]~~

The image (top) shows two copies of Integrin alpha-L bound to lovastatin. (9)(9) Since lovastatin inhibits HMG-~~CoA~~ reductase, it is reasonable to hypothesize that the two molecules, HMG-CoA and lovastatin, share some common structural features. Images were captured using X-ray diffraction. (9)

The image (top) shows two copies of Integrin alpha-L bound to lovastatin. (9)(9) Since lovastatin inhibits <scene name='75/758442/Hmg-coa_reducatase/3'>HMG-COA reductase (HMG-COA Reductase bound to Lovastatin)</scene>, it is reasonable to hypothesize that the two molecules, HMG-CoA and lovastatin, share some common structural features. Images were captured using X-ray diffraction. (9)

[[Image:pic4]]

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[[Image:pic5]]

Lovastatin is structurally similar to hydroxymethylglutarate (HMG), a substituent of HMG-Coenzyme A (HMG-CoA), a substrate of the cholesterol biosynthesis pathway via the mevalonic acid pathway. Lovastatin is a competitive inhibitor of HMG-~~CoA~~ reductase with a binding affinity 20, 000 times greater than HMG-CoA. Lovastatin is activated by in vivo hydrolysis of the lactone ring. (1) 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/2'>HMG-COA Reducatase</scene> through a NADPH-dependent reduction to form mevalonate in the isopentenyl pyrophosphate formation process. It is thought that HMG-CoA 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. (7)

Lovastatin is structurally similar to hydroxymethylglutarate (HMG), a substituent of HMG-Coenzyme A (HMG-CoA), a substrate of the cholesterol biosynthesis pathway via the mevalonic acid pathway. Lovastatin is a competitive inhibitor of HMG-COA reductase with a binding affinity 20, 000 times greater than HMG-CoA. Lovastatin is activated by in vivo hydrolysis of the lactone ring. (1) 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/2'>HMG-COA Reducatase (HMG-COA reductase bound to NAD+, HMG, And COA)</scene> through a NADPH-dependent reduction to form mevalonate in the isopentenyl pyrophosphate formation process. It is thought that HMG-CoA 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. (7)

== Health & Disease in Humans ==

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 [[Image:pic_1.jpg]]
-[[Image:pic_3.jpg]]
-The image (top) shows two copies of Integrin alpha-L bound to lovastatin. (9)(9) Since lovastatin inhibits HMG-CoA reductase, it is reasonable to hypothesize that the two molecules, HMG-CoA and lovastatin, share some common structural features. Images were captured using X-ray diffraction. (9)
+The image (top) shows two copies of Integrin alpha-L bound to lovastatin. (9)(9) Since lovastatin inhibits <scene name='75/758442/Hmg-coa_reducatase/3'>HMG-COA reductase (HMG-COA Reductase bound to Lovastatin)</scene>, it is reasonable to hypothesize that the two molecules, HMG-CoA and lovastatin, share some common structural features. Images were captured using X-ray diffraction. (9)
 [[Image:pic4]]
@@ Line 33: / Line 32: @@
 [[Image:pic5]]
-Lovastatin is structurally similar to hydroxymethylglutarate (HMG), a substituent of HMG-Coenzyme A (HMG-CoA), a substrate of the cholesterol biosynthesis pathway via the mevalonic acid pathway. Lovastatin is a competitive inhibitor of HMG-CoA reductase with a binding affinity 20, 000 times greater than HMG-CoA. Lovastatin is activated by in vivo hydrolysis of the lactone ring.  (1) 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/2'>HMG-COA Reducatase</scene> through a NADPH-dependent reduction to form mevalonate in the isopentenyl pyrophosphate formation process. It is thought that HMG-CoA 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. (7)
+Lovastatin is structurally similar to hydroxymethylglutarate (HMG), a substituent of HMG-Coenzyme A (HMG-CoA), a substrate of the cholesterol biosynthesis pathway via the mevalonic acid pathway. Lovastatin is a competitive inhibitor of HMG-COA reductase with a binding affinity 20, 000 times greater than HMG-CoA. Lovastatin is activated by in vivo hydrolysis of the lactone ring.  (1) 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/2'>HMG-COA Reducatase (HMG-COA reductase bound to NAD+, HMG, And COA)</scene> through a NADPH-dependent reduction to form mevalonate in the isopentenyl pyrophosphate formation process. It is thought that HMG-CoA 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. (7)
 == Health & Disease in Humans ==