Sandbox 55: Difference between revisions
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=Atorvastatin= | =Atorvastatin= | ||
Atorvastatin, commercially known as Lipitor is a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA Reductase) inhibitor that works primarily in the liver<ref>LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref>. It is part of a class of medications known as statins that are cholesterol-lowering medications<ref>Phizer Inc. "Lipitor." Lipitor: Atorvastatin Calcium Tablets. Phizer Inc., 2011. Web. 09 Mar. 2011. <http://www.lipitor.com/aboutLipitor.aspx>.</ref>. HMG-CoA reductase catalyzes the committed step in cholesterol synthesis, so by inhibiting this step, low density lipoprotein (LDL) cholesterol can be effectively lowered as well as increasing high density lipoprotein (HDL) levels. By lowering LDL, the likelihood of stroke and heart attack can be decreased<ref>NIH. "Atorvastatin." PubMed Health. National Institutes of Health, 01 July 2010. Web. 09 Mar. 2011. <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000009/>.</ref>. | Atorvastatin, commercially known as Lipitor is a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA Reductase) inhibitor that works primarily in the liver<ref>LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref>. It is part of a class of medications known as statins that are cholesterol-lowering medications<ref>Phizer Inc. "Lipitor." Lipitor: Atorvastatin Calcium Tablets. Phizer Inc., 2011. Web. 09 Mar. 2011. <http://www.lipitor.com/aboutLipitor.aspx>.</ref>. HMG-CoA reductase catalyzes the committed step in cholesterol synthesis, so by inhibiting this step, low density lipoprotein (LDL) cholesterol can be effectively lowered as well as increasing high density lipoprotein (HDL) levels. By lowering LDL, the likelihood of stroke and heart attack can be decreased particularly in patients with hypercholesterolemia, mixed dyslipidemia, and homozygous familial hypercholesterolemia<ref>NIH. "Atorvastatin." PubMed Health. National Institutes of Health, 01 July 2010. Web. 09 Mar. 2011. <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000009/>.</ref>. | ||
Bruce Roth, a Phizer employee, first synthesized atorvastatin in 1985. In 2008 Lipitor was the top-selling pharmaceutical in the world with $12.4 billion in sales. However, Lipitor's US patent protection is scheduled to expire in June 2011<ref>^"Pfizer wins patent extension on cholesterol drug". Associated Press. 6 January 2009. http://www.nj.com/business/index.ssf/2009/01/pfizer_wins_patent_extension_o.html.</ref>. | Bruce Roth, a Phizer employee, first synthesized atorvastatin in 1985. In 2008 Lipitor was the top-selling pharmaceutical in the world with $12.4 billion in sales. However, Lipitor's US patent protection is scheduled to expire in June 2011<ref>^"Pfizer wins patent extension on cholesterol drug". Associated Press. 6 January 2009. http://www.nj.com/business/index.ssf/2009/01/pfizer_wins_patent_extension_o.html.</ref>. | ||
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The <scene name='Sandbox_55/Four_active_sites_and_residues/1'>four active sites</scene> of HMG-CoA reductase are located at the interface of the two monomers of a | The <scene name='Sandbox_55/Four_active_sites_and_residues/1'>four active sites</scene> of HMG-CoA reductase are located at the interface of the two monomers of a | ||
<scene name='Sandbox_55/Dimer/1'>dimer</scene> (represented by the ball and stick residues). Each active site has a loop that folds over part of the binding pocket; the loop contains an unusual cis-peptide bond that is highly conserved. The loop folds over the active site when both substrates (HMG-CoA and NADPH) are bound to exclude solvent from the active site. | <scene name='Sandbox_55/Dimer/1'>dimer</scene> (represented by the ball and stick residues). Each active site has a loop that folds over part of the binding pocket; the loop contains an unusual cis-peptide bond that is highly conserved. The loop folds over the active site when both substrates (HMG-CoA and NADPH) are bound to exclude solvent from the active site. In this view of the <scene name='Sandbox_55/Hydrophobic_residues/1'>hydrophobic and hydrophilic regions</scene> of the enzyme (hydrophobic:gray), the active sites contain many hydrophobic residues, which would not have favorable energetics with solvent. | ||
The HMG binding pocket is the site of catalysis for HMG-CoA reductase. Three residues are essential for catalysis, E559, D767, and K691. K691 is positioned only 2.7 angstroms from the HMG O2 carbonyl oxygen, and stabilizes the negative charge of the first intermediate. H866 also stabilizes the thiol group. It is also believed that the closeness of E559 and D767 increases the pKa of E559, which allows it to be a proton donor for the final reduction of mevaldehyde to mevalonate. The HMG-CoA is bound by a domain consisting of combination of <scene name='Sandbox_55/Secondary_structure/1'>secondary structures</scene>, a central alpha helix surrounded by a triangular set of walls of beta sheets and alpha helices. | The HMG binding pocket is the site of catalysis for HMG-CoA reductase. Three residues are essential for catalysis, E559, D767, and K691. K691 is positioned only 2.7 angstroms from the HMG O2 carbonyl oxygen, and stabilizes the negative charge of the first intermediate. H866 also stabilizes the thiol group. It is also believed that the closeness of E559 and D767 increases the pKa of E559, which allows it to be a proton donor for the final reduction of mevaldehyde to mevalonate. The HMG-CoA is bound by a domain consisting of combination of <scene name='Sandbox_55/Secondary_structure/1'>secondary structures</scene>, a central alpha helix surrounded by a triangular set of walls of beta sheets and alpha helices. | ||
