Angiotensin-Converting Enzyme: Difference between revisions
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Several studies have validated a pathological role for Angiotensin II in cardiac, renal and vascular diseases like hypertension and diabetic renal failure. <ref name="Ferrario"/> The increased blood pressure and oxidative stress associated with elevated levels of Angiotensin II can result in endothelial dysfunction and microvascular damage, ultimately leading to heart failure, stroke and kidney disease among other clinical manifestations. <ref name="Weir">PMID:18035185</ref> Bradykinin, a small peptide that counterbalance the effects of Angiotensin II by acting as a strong vasodilator upon binding AT2, is degraded by the same ACE1 enzymes which create Angiotensin II from Angiotensin I. Since ACE1 is the primary producer of Angiotensin II and primary degrader of Bradykinins, the development of ACE1 inhibitors has been a major focus for drug developers looking to fight these cardiovascular and renal conditions. <ref name="Weir"/> ACE1 inhibitors like [http://en.wikipedia.org/wiki/Captopril Captopril] ([[1uzf]], [[Capoten]]), Ramipril ([[Altace]]), Lisinopril, ([[1o86]], [[Perindopril]], [[Prinivil]]), and Benazepril ([[Lotensin]]) have proven to be effective at reducing Angiotensin II based pathologies. Sale of ACE1 inhibitors topped $5 billion in 2009 with over 150 million prescriptions filled.<ref name="Inhibit">http://www.yourlawyer.com/topics/overview/ace_inhibitors</ref> | Several studies have validated a pathological role for Angiotensin II in cardiac, renal and vascular diseases like hypertension and diabetic renal failure. <ref name="Ferrario"/> The increased blood pressure and oxidative stress associated with elevated levels of Angiotensin II can result in endothelial dysfunction and microvascular damage, ultimately leading to heart failure, stroke and kidney disease among other clinical manifestations. <ref name="Weir">PMID:18035185</ref> Bradykinin, a small peptide that counterbalance the effects of Angiotensin II by acting as a strong vasodilator upon binding AT2, is degraded by the same ACE1 enzymes which create Angiotensin II from Angiotensin I. Since ACE1 is the primary producer of Angiotensin II and primary degrader of Bradykinins, the development of ACE1 inhibitors has been a major focus for drug developers looking to fight these cardiovascular and renal conditions. <ref name="Weir"/> ACE1 inhibitors like [http://en.wikipedia.org/wiki/Captopril Captopril] ([[1uzf]], [[Capoten]]), Ramipril ([[Altace]]), Lisinopril, ([[1o86]], [[Perindopril]], [[Prinivil]]), and Benazepril ([[Lotensin]]) have proven to be effective at reducing Angiotensin II based pathologies. Sale of ACE1 inhibitors topped $5 billion in 2009 with over 150 million prescriptions filled.<ref name="Inhibit">http://www.yourlawyer.com/topics/overview/ace_inhibitors</ref> | ||
Crystal structures of ACE1 with bound competitive inhibitors reveal the mechanism of inhibition. Lisinopril binds to the ACE1 binding site in an extended conformation, with its phenyl group oriented toward the active site lid while the lysine chain parallels the zinc binding motif helix. <ref name="Natesh"/> [[Lisinopril]] makes a <scene name='Angiotensin-Converting_Enzyme/Lisinopril/1'> number of electrostatic interactions with ACE1 binding site residues and the Zinc Ion</scene>, utilizing His 353, Ala 354 (backbone oxygen), Glue 384, Lys 511, His 513, Tyr 520, Tyr 523 and Glu 162 as well as van der Waals interactions between the phenylpropyl group and Val 518. <ref name="Natesh"/>. Another inhibitor, [[Captopril]], <scene name='Angiotensin-Converting_Enzyme/Captopril/1'>binds in a similar fashion</scene>, forming electrostatic interactions with His 353, Glu 384, Lys 511, His 513 and Tyr 520, along with zinc cation. [[Enalaprilat]], a third competitive inhibitor<scene name='Angiotensin-Converting_Enzyme/Enalalprilat/2'> binds via electrostatic interactions</scene> ([[1uze]]), with His 353, Ala 354 (Backbone oxygen), Glue 384, Lys 511, His 513, Tyr 520 and Tyr 523 along with the zinc cation. All three inhibitors are very effective and are FDA approved for treatment of Angiotensin II related hypertension and other cardiovascular and renal disorders. <ref>PMID:15236580</ref> Other ACE Inhibitors approved by the FDA include [[Ramipril]], [[Benazepril]], [[Perindopril]] and [[Trandolapril]] | Crystal structures of ACE1 with bound competitive inhibitors reveal the mechanism of inhibition. Lisinopril binds to the ACE1 binding site in an extended conformation, with its phenyl group oriented toward the active site lid while the lysine chain parallels the zinc binding motif helix. <ref name="Natesh"/> [[Lisinopril]] makes a <scene name='Angiotensin-Converting_Enzyme/Lisinopril/1'> number of electrostatic interactions with ACE1 binding site residues and the Zinc Ion</scene>, utilizing His 353, Ala 354 (backbone oxygen), Glue 384, Lys 511, His 513, Tyr 520, Tyr 523 and Glu 162 as well as van der Waals interactions between the phenylpropyl group and Val 518. <ref name="Natesh"/>. Another inhibitor, [[Captopril]], <scene name='Angiotensin-Converting_Enzyme/Captopril/1'>binds in a similar fashion</scene>, forming electrostatic interactions with His 353, Glu 384, Lys 511, His 513 and Tyr 520, along with zinc cation. [[Enalaprilat]], a third competitive inhibitor<scene name='Angiotensin-Converting_Enzyme/Enalalprilat/2'> binds via electrostatic interactions</scene> ([[1uze]]), with His 353, Ala 354 (Backbone oxygen), Glue 384, Lys 511, His 513, Tyr 520 and Tyr 523 along with the zinc cation. All three inhibitors are very effective and are FDA approved for treatment of Angiotensin II related hypertension and other cardiovascular and renal disorders. <ref>PMID:15236580</ref> Other ACE Inhibitors approved by the FDA include [[Ramipril]], [[Benazepril]], [[Perindopril]], [[Trandolapril]] and [[Trandolapril]] | ||
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