Sandbox 55: Difference between revisions
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==HMG-CoA Reductase== | ==HMG-CoA Reductase== | ||
<applet load=' | <applet load='1hwk' size='350' frame='true' align='left' caption='HMG-CoA Reductase in complex with Lipitor' /> | ||
HMG-CoA is an endoplasmic reticulum transmembrane glycoprotein. It is a tetramer and an NADPH-dependent enzyme. HMG-CoA reductase contains an N-terminal membrane domain and a C-terminal catalytic domain. The catalytic portion can be further subdivided into an N-domain (N-terminal), a large L-domain, and a small S-domain. The L-domain binds the substrate, and the S-domain binds NADP<ref>"Pfam: Family: HMG-CoA_red (PF00368)." Pfam: Home Page. Web. 10 Mar. 2011. <http://pfam.sanger.ac.uk/family?acc=PF00368>.</ref>. | HMG-CoA is an endoplasmic reticulum transmembrane glycoprotein. It is a tetramer and an NADPH-dependent enzyme. HMG-CoA reductase contains an N-terminal membrane domain and a C-terminal catalytic domain. The catalytic portion can be further subdivided into an N-domain (N-terminal), a large L-domain, and a small S-domain. The L-domain binds the substrate, and the S-domain binds NADP<ref>"Pfam: Family: HMG-CoA_red (PF00368)." Pfam: Home Page. Web. 10 Mar. 2011. <http://pfam.sanger.ac.uk/family?acc=PF00368>.</ref>. | ||
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HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate in the cholesterol biosynthesis pathway. Atorvastatin selectively and competitively inhibits HMG-CoA reductase. The inhibition subsequently increases the expression of LDL receptors on hepatocytes, which increases LDL uptake by hepatocytes, therefore decreasing the LDL-cholesterol concentration in the blood. Atorvastatin also increases levels of HDL-cholesterol.<ref>LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref> | HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate in the cholesterol biosynthesis pathway. Atorvastatin selectively and competitively inhibits HMG-CoA reductase. The inhibition subsequently increases the expression of LDL receptors on hepatocytes, which increases LDL uptake by hepatocytes, therefore decreasing the LDL-cholesterol concentration in the blood. Atorvastatin also increases levels of HDL-cholesterol.<ref>LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref> | ||
<applet load=' | <applet load='1dq9' size='350' frame='true' align='right' caption='Catalytic portion of HMG-CoA Reductase in complex with its substrate, HMG-CoA' /> | ||
===Active Site=== | ===Active Site=== | ||
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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 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. | ||
When atorvastatin binds, the cis loop forms polar interactions, Ser 684, Asp 690, Lys 691, Lys 692, as well as hydrogen bond interactions between Glu 559 and Asp 767 with the O5-hydroxyl of the statin. Van der Waals interactions between Leu 562, Val 683, Leu 853, Ala 856, and Leu 857 of HMG-CoA reductase and thehydrophobic ring structures of atorvastatin also contribute to binding. These interactions result in a Km for HMG-CoA of 4uM. This allows atorvastatin to outcompete HMG-CoA in binding to HMG-CoA reductase.<ref>Roitelman J, Olender EH, Bar-Nun S, Dunn WA Jr, Simoni RD. Immunological evidence for eight spans in the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for enzyme degradation in the endoplasmic reticulum. J Cell Biol. 1992 Jun;117(5):959-73.</ref> | When (<scene name='HMG-CoA_Reductase/Statin_ator/7'>atorvastatin,</scene> ([[1hwk]])binds, the cis loop forms polar interactions, Ser 684, Asp 690, Lys 691, Lys 692, as well as hydrogen bond interactions between Glu 559 and Asp 767 with the O5-hydroxyl of the statin. Van der Waals interactions between Leu 562, Val 683, Leu 853, Ala 856, and Leu 857 of HMG-CoA reductase and thehydrophobic ring structures of atorvastatin also contribute to binding. These interactions result in a Km for HMG-CoA of 4uM. This allows atorvastatin to outcompete HMG-CoA in binding to HMG-CoA reductase.<ref>Roitelman J, Olender EH, Bar-Nun S, Dunn WA Jr, Simoni RD. Immunological evidence for eight spans in the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for enzyme degradation in the endoplasmic reticulum. J Cell Biol. 1992 Jun;117(5):959-73.</ref> | ||
==Dipeptidyl peptidase 4 and Aryl hydrocarbon receptor== | ==Dipeptidyl peptidase 4 and Aryl hydrocarbon receptor== | ||
Atorvastatin is also an inhibitor of dipeptidyl peptidase 4, although it has no pharmacological effects. Dipeptidyl peptidase 4 removes N-terminal didpeptides from polypeptides and plays a role in T-cell activation, amino acid transport and metabolism<ref>.LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref>. | Atorvastatin is also an inhibitor of dipeptidyl peptidase 4, although it has no pharmacological effects. Dipeptidyl peptidase 4 removes N-terminal didpeptides from polypeptides and plays a role in T-cell activation, amino acid transport and metabolism<ref>.LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref>. | ||
<applet load='2bgr' size='350' frame='true' align='right' caption='Dipeptidyl peptidase 4' /> | <applet load='2bgr' size='350' frame='true' align='right' caption='Dipeptidyl peptidase 4' /> | ||
Atorvastatin also is an agonist of aryl hydrocarbon receptor. Aryl hydrocarbon receptor is a ligand-activated transcriptional activator that binds to the promoter region of genes it activates. It specifically activates the expression of multiple phase I and II xenobiotic metabolizing enzyme genes (E.g. CYP3A4. Aryl hydrocarbon receptor also mediates the biochemical and toxic effects of halogenated aromatic hydrocarbons, cell-cycle regulation, and plays an important role in the development and maturation of tissues.<ref>LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref> | Atorvastatin also is an agonist of aryl hydrocarbon receptor. Aryl hydrocarbon receptor is a ligand-activated transcriptional activator that binds to the promoter region of genes it activates. It specifically activates the expression of multiple phase I and II xenobiotic metabolizing enzyme genes (E.g. CYP3A4. Aryl hydrocarbon receptor also mediates the biochemical and toxic effects of halogenated aromatic hydrocarbons, cell-cycle regulation, and plays an important role in the development and maturation of tissues.<ref>LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref> | ||
