User:Sachin Sundar/Sandbox 1: Difference between revisions

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<Structure load='lovastatin' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />
<Structure load='75/758442/Lovastatin/1' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />


== Overview ==
== Overview ==
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== Structure ==
== 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 <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 (16).  Hydroxymethylglutaryl-CoA (HMG-CoA)
The structure of HMG-CoA Reductase in humans (class I)  contains two domains.The N-terminal is a sterol sensing domain, and the C-terminal is the catalytic domain which is where the substrate must bind in order to activate this enzyme. Bacteria HMG-CoA Reductase (class II)
The molecular formula of <scene name='75/758442/Lovastatin/1'>Lovastatin</scene> is C24H36O5 [1] and the molecular weight is 404.55 [1] Lovastatin contains two domains of Integrin alpha-L. Integrin alpha-L contains an alpha and beta chain, length is 182 amino acids, weighs 20.82 KDa. The image below shows the two domains of <scene name='75/758442/Integrin_alpha-l/2'>Integrin Alpha-L</scene> in lovastatin.
The image (top) shows two copies of Integrin alpha-L bound to lovastatin.<ref name= "nine"> 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. <ref name= "nine">
[[Image:pic_4.jpg]]
An image of beta-hydroxyacid form of lovastatin.


==Mechanism==
==Mechanism==


Lovastatin 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 HMG-COA Reducatase (HMG-COA reductase bound to NAD+, HMG, And COA) 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>
<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>




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<ref name= "eight">Crystal Structure Analysis of the Complex LFA-1 (CD11A) I-Domain / Lovastatin at 2.6 A Resolution. Protein Data Bank in Europe. Retrieve March 28, 2017 from http://www.ebi.ac.uk/pdbe/entry/pdb/1cqp</ref>
<ref name= "eight">Crystal Structure Analysis of the Complex LFA-1 (CD11A) I-Domain / Lovastatin at 2.6 A Resolution. Protein Data Bank in Europe. Retrieve March 28, 2017 from http://www.ebi.ac.uk/pdbe/entry/pdb/1cqp</ref>


 
<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>.


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