HMG-CoA Reductase: Difference between revisions
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<StructureSection load='1dq8' size=' | <StructureSection load='1dq8' size='350' side='right' scene='HMG-CoA_Reductase/1dq8_starting_scene/1' caption='Crystal Structure of HMG-CoA, (PDB code [[1dq8]])'>[[HMG-CoA Reductase]] (or '''3-hydroxy-3-methyl-glutaryl-CoA reductase''' or '''HMGR''') is the rate-controlling enzyme of the mevalonate pathway, responsible for cholesterol and other isoprenoid biosynthesis. HMGR is a transmembrane protein, containing 8 domains, that is anchored in the membrane of the endoplasmic reticulum.<ref name="Roitelman">PMID:1374417</ref> It is the major target of the Statins, a cholesterol lowering drug class and the best selling pharmaceutical drugs in the world. See also [[Ephrin Type-A Receptor]] and [[Neurodevelopmental Disorders]]. | ||
[[Image: HMG-CoA_reductase_pathway.png|350px|left|thumb| Mevalonate Pathway. Note the early stage at which the statins interfere in the pathway]] | [[Image: HMG-CoA_reductase_pathway.png|350px|left|thumb| Mevalonate Pathway. Note the early stage at which the statins interfere in the pathway]] | ||
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The statins are HMG-CoA reductase inhibitors. Discovered by Akira Endo in 1971, statins are similar in structure to HMG-CoA and act by competitively inhibiting HMGR. Since HMGR is the first committed enzyme in the cascade that eventually produces cholesterol, use of statins can dramatically reduce blood cholesterol levels.<ref>PMID:16386050</ref> As a drug class, statins generated over $20 billion in sales in 2009 with Pfizer’s [[Lipitor]] being the best selling drug in the world at the time of writing.<ref>http://www.drugs.com/top200.html</ref><ref> http://www.medicalnewstoday.com/articles/25046.php</ref> Statin development stands as a triumph for rational drug design validating rational drug design as a proven approach toward creating selective, therapeutic compounds.<ref>PMID:17206841</ref> | The statins are HMG-CoA reductase inhibitors. Discovered by Akira Endo in 1971, statins are similar in structure to HMG-CoA and act by competitively inhibiting HMGR. Since HMGR is the first committed enzyme in the cascade that eventually produces cholesterol, use of statins can dramatically reduce blood cholesterol levels.<ref>PMID:16386050</ref> As a drug class, statins generated over $20 billion in sales in 2009 with Pfizer’s [[Lipitor]] being the best selling drug in the world at the time of writing.<ref>http://www.drugs.com/top200.html</ref><ref> http://www.medicalnewstoday.com/articles/25046.php</ref> Statin development stands as a triumph for rational drug design validating rational drug design as a proven approach toward creating selective, therapeutic compounds.<ref>PMID:17206841</ref> | ||
A number of crystal structures of HMGR with bound statins have been solved which elucidate how the statin molecule is bound by HMGR. Statins in general occupy the active site of HMGR, preventing HMG-CoA from binding. The structure of HMGR with bound statins (<scene name='HMG-CoA_Reductase/Statin_ator/7'>here atorvastatin,</scene> ([[1hwk]]) marketed as [[Lipitor]]) shows that the cis loop forms a number of polar interactions with the statin inhibitor, particularly residues Ser 684, Asp 690, Lys 691, Lys 692, and hydrogen bond interactions between Glu 559 and Asp 767 with the O5-hydroxyl of the statins. Van der Waals interactions between Leu 562, Val 683, Leu 853, Ala 856, and Leu 857 of HMGR and hydrophobic ring structures of the statins contribute to binding as well.<ref>PMID:11349148</ref> These interactions result in the statins binding to HMGR with a K<sub>i</sub> of between .1-2.3nM while the Michaelis constant K<sub>M</sub> for HMG-CoA is 4uM, allowing the statins to outcompete HMG-CoA in binding to HMGR.<ref>PMID:7784310</ref> Additional structures of HMGR with the statins <scene name='HMG-CoA_Reductase/Statin_meva/5'>mevastatin (compactin)</scene> ([[1hw8]]), <scene name='HMG-CoA_Reductase/Statin_simva/5'>simvastatin</scene> ([[1hw9]], [[Zocor]]), <scene name='HMG-CoA_Reductase/Statin_fluva/6'>fluvastatin </scene>([[1hwi]], [[Lescol]]), <scene name='HMG-CoA_Reductase/Statin_ceriv/3'>cerivastatin</scene> ([[1hwj]], [[Baycol]]), and <scene name='HMG-CoA_Reductase/Statin_rosu/5'>rosuvastatin</scene> ([[1hwl]], [[Crestor]]) highlight the important residues involved in inhibitor binding. Other statins approved by the FDA include [[Lovastatin]]. | A number of crystal structures of HMGR with bound statins have been solved which elucidate how the statin molecule is bound by HMGR. Statins in general occupy the active site of HMGR, preventing HMG-CoA from binding. The structure of HMGR with bound statins (<scene name='HMG-CoA_Reductase/Statin_ator/7'>here atorvastatin,</scene> ([[1hwk]]) marketed as [[Lipitor]]) shows that the cis loop forms a number of polar interactions with the statin inhibitor, particularly residues Ser 684, Asp 690, Lys 691, Lys 692, and hydrogen bond interactions between Glu 559 and Asp 767 with the O5-hydroxyl of the statins. Van der Waals interactions between Leu 562, Val 683, Leu 853, Ala 856, and Leu 857 of HMGR and hydrophobic ring structures of the statins contribute to binding as well.<ref>PMID:11349148</ref> These interactions result in the statins binding to HMGR with a K<sub>i</sub> of between .1-2.3nM while the Michaelis constant K<sub>M</sub> for HMG-CoA is 4uM, allowing the statins to outcompete HMG-CoA in binding to HMGR.<ref>PMID:7784310</ref> Additional structures of HMGR with the statins <scene name='HMG-CoA_Reductase/Statin_meva/5'>mevastatin (compactin)</scene> ([[1hw8]]), <scene name='HMG-CoA_Reductase/Statin_simva/5'>simvastatin</scene> ([[1hw9]], [[Zocor]]), <scene name='HMG-CoA_Reductase/Statin_fluva/6'>fluvastatin </scene>([[1hwi]], [[Lescol]]), <scene name='HMG-CoA_Reductase/Statin_ceriv/3'>cerivastatin</scene> ([[1hwj]], [[Baycol]]), and <scene name='HMG-CoA_Reductase/Statin_rosu/5'>rosuvastatin</scene> ([[1hwl]], [[Crestor]]) highlight the important residues involved in inhibitor binding. Other statins approved by the FDA include [[Lovastatin]] and [[Fluvastatin]]. | ||
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</StructureSection> | </StructureSection> | ||
