Angiotensin-Converting Enzyme: Difference between revisions

<StructureSection load='1o8a' size='450' side='right' scene='Angiotensin-Converting_Enzyme/Ace_opening/1' caption='Human ACE complex with Zn+2 (grey) and Cl- (yellow) ions (PDB code [[1o8a]])'>

[[Angiotensin-Converting Enzyme]] (ACE) is both an exopeptidase and endopeptindase first discovered by Skeggs et al. in 1956. <ref>Skeggs, L. T., Dorer, F. E., Kahn, J. R., Lentz, K. E., Levin, M. (1981) Experimental renal hypertension: the discovery of the Renin-Angiotensin system. Soffer, R. eds. Biochemical Regulation of Blood Pressure ,3-38 John Wiley & Sons, Inc. Hoboken.</ref> ACE is a zinc- and chloride-dependent metallopeptidase that is responsible for the metabolism of key biologically active peptides, namely Angiotensin I and Bradykinin. These two peptides play a critical role in maintaining appropriate blood pressure in the human body along with a host of other homeostatic circulatory functions. ACE catalyzes the conversion of the decapeptide Angiostensin I to the octapeptide Angiostensin II. Due to its critical role in the Renin-Angiotensin-Aldosterone System (RAAS), ACE has been targeted by a number of pharmaceutical compounds to treat hypertension, diabetic nephropathy, and renal failure. <ref>PMID:10780101</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]], [[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]]

During the SARS scare of 2002-2003, extensive research was focused on the interactions between the SARS virus and its host cells. It was determined that the severe acute respiratory syndrome conavirus (SARS-CoV) enters cells through the activities of a spike shaped protein on its outer envelope. <ref name="SARS">PMID:18448527</ref> The Receptor Binding Domain (RBD) of SARS-CoV binds to ACE2, on the surface of the cell. It was determined that by changing a few selected residues on either the SARS-CoV RBD or the ACE2 binding site, the virus becomes significantly more infectious. <scene name='Angiotensin-Converting_Enzyme/Sars/2'>It is believed that these mutations</scene> ([[3d0g]]), namely at residues 31, 35, 38, & 353 in ACE2 or residues 479 and 487 in the SARS-CoV RBD, are what allowed for SARS transmission from [http://en.wikipedia.org/wiki/Civet Civets] to Humans. In fact, in those SARS strains which were determined to be most infectious, the unfavorable electrostatic interactions at the binding interface were removed via mutations at the critical residues 479 and 487. <ref name="SARS"/>

</StructureSection>

==3D Structures of Angiotensin-Converting Enzyme==

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**[[1o8a]] – hANCE - human<br />

**[[2x8y]] – DmANCE – ''Drosophila melanogaster''<br />