Angiotensin-Converting Enzyme: Difference between revisions
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ACE is a Zn and Chloride dependent type-1 membrane protein (N-terminal regions are outside the cell). Two types of Angiotensin-converting enzyme exist, ACE1 and ACE2, although the most focus has been on ACE1 which has been attributed with receptor-mediated effects like vasoconstriction, inflammation and cell growth/proliferation. <ref name="Ferrario">PMID:17083068</ref> The Renin-Angiotensin System (RAS) is a major regulator of blood pressure in the human body. [[Renin]] is an enzyme produced by the liver which cleaves Angiotensinogen into Angiotensin I Angiotensin Ihas the sequence, DRVTIHPFHL, and does not appear to have any biological activity. Angiotensin 1 (See:[[1n9u]]) is converted into Angiotensin II (See:[[1n9v]]) via the removal of the two C-terminal residues by ACE, yielding the active peptide: DRVTIHPF. <ref>PMID:12752436</ref> | ACE is a Zn and Chloride dependent type-1 membrane protein (N-terminal regions are outside the cell). Two types of Angiotensin-converting enzyme exist, ACE1 and ACE2, although the most focus has been on ACE1 which has been attributed with receptor-mediated effects like vasoconstriction, inflammation and cell growth/proliferation. <ref name="Ferrario">PMID:17083068</ref> The Renin-Angiotensin System (RAS) is a major regulator of blood pressure in the human body. [[Renin]] is an enzyme produced by the liver which cleaves Angiotensinogen into Angiotensin I Angiotensin Ihas the sequence, DRVTIHPFHL, and does not appear to have any biological activity. Angiotensin 1 (See:[[1n9u]]) is converted into Angiotensin II (See:[[1n9v]]) via the removal of the two C-terminal residues by ACE, yielding the active peptide: DRVTIHPF. <ref>PMID:12752436</ref> | ||
Angiotensin II interacts with two receptor subtypes, AT1 and AT2, which are widely distributed throughout the body. <ref name="Brew">PMID:12915047</ref> Binding of Angiotensin II to ATI leads to vasoconstriction by vascular smooth muscle cells, resulting in increased blood pressure, as well as the release of fluid and electrolyte homeostasis regulator, aldosterone, by the adrenal glands. Further, Angiotensin II binds to kidney AT1 receptors resulting in sodium ion reabsorption, leading to increased water retention in the blood and subsequent increased blood pressure. <ref name="Sturrock">PMID:15549168</ref> Additionally, Bradykinin, which is inactivated by ACE1, has vasodilatory | Angiotensin II interacts with two receptor subtypes, AT1 and AT2, which are widely distributed throughout the body. <ref name="Brew">PMID:12915047</ref> Binding of Angiotensin II to ATI leads to vasoconstriction by vascular smooth muscle cells, resulting in increased blood pressure, as well as the release of fluid and electrolyte homeostasis regulator, aldosterone, by the adrenal glands. Further, Angiotensin II binds to kidney AT1 receptors resulting in sodium ion reabsorption, leading to increased water retention in the blood and subsequent increased blood pressure. <ref name="Sturrock">PMID:15549168</ref> Additionally, Bradykinin, which is inactivated by ACE1, has vasodilatory and cardioprotective properties by promoting the formation of nitric oxide by the [http://en.wikipedia.org/wiki/Endothelium endothelium]. <ref>PMID:12767053</ref> The essential role ACE1 plays in blood pressure homeostasis is further supported by knockout mice created by Cole et. al. ACE1 knockout mice exhibited an approximate 35% reduction in blood pressure, resulting in hypotension and subsequent organ damage. Thus despite the many systems contributing to blood pressure in mammals, i.e. nitric oxide, endothelin and andregenic stimulation etc. these redundant systems are not enough to overcome a disruption of the RAAS. <ref>PMID:11967804</ref> It should be noted that AT2 binding of Angiotensin II results in many processes that counterbalance the binding of AT1. See the schematic image of the Renin-Angiotensin-Aldosterone System at the left for a visual description and the table below for selected Angiotensin receptor-mediated effects of binding Angiotensin II. | ||
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===Medical Implications and Inhibitor Binding=== | ===Medical Implications and Inhibitor Binding=== | ||
[[Image: Lisinopril.png|320px|left|thumb| The ACE Inhibitor, Lisinopril]] | [[Image: Lisinopril.png|320px|left|thumb| The ACE Inhibitor, Lisinopril]] | ||
Several | 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] (Capoten), [http://en.wikipedia.org/wiki/Ramipril Ramipril] (Altace, Sanofi Aventis), [http://en.wikipedia.org/wiki/Lisinopril Lisinopril], (Prinivil, Merck), and [http://en.wikipedia.org/wiki/Benazepril Benazepril] (Lotensin, Novartis) 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"/> <scene name='Angiotensin-Converting_Enzyme/Lisinopril/1'> Lisinopril makes a 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, <scene name='Angiotensin-Converting_Enzyme/Captopril/1'>Captopril, 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. <scene name='Angiotensin-Converting_Enzyme/Enalalprilat/2'>Enalaprilat, a third competitive inhibitor</scene>, binds via electrostatic interactions 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> | 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"/> <scene name='Angiotensin-Converting_Enzyme/Lisinopril/1'> Lisinopril makes a 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, <scene name='Angiotensin-Converting_Enzyme/Captopril/1'>Captopril, 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. <scene name='Angiotensin-Converting_Enzyme/Enalalprilat/2'>Enalaprilat, a third competitive inhibitor</scene>, binds via electrostatic interactions 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> | ||