Angiotensin-Converting Enzyme: Difference between revisions
David Canner (talk | contribs) No edit summary |
David Canner (talk | contribs) No edit summary |
||
| Line 14: | Line 14: | ||
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. | 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. | ||
<br /> | <br /> | ||
{| class="wikitable" border="1" width="100%" style="text-align:center" align=right | {| class="wikitable" border="1" width="100%" style="text-align:center" align=right | ||
|- | |- | ||
| Line 45: | Line 37: | ||
|} | |} | ||
==Structural Analysis, Mechanism, & Activation== | |||
<StructureSection load='1dq8' size='500' side='right' scene='Angiotensin-Converting_Enzyme/Ace_opening/1' caption='Crystal Structure of Human tACE, [[1o8a]] '> | |||
==Structure of ACE1== | |||
The larger, somatic form of ACE1 has two metalloproteinase domains (N- and C-terminal domains), each containing the canonical Zn binding motif, HEXXH. Despite their similar structures and protease activity, only the C-terminal domain is critical for blood pressure regulation.<ref>PMID:11303049</ref> The smaller, testis-specific form of ACE1 (tACE) only contains the C-terminal metalloproteinase domain (identical to that of somatic ACE1), along with a hydrophobic membrane-anchoring domain and a small highly glycosylated N-terminal region. <ref name="Brew"/> The structure of tACE adopts a predominantly helical ellipsoid structure with a <scene name='Angiotensin-Converting_Enzyme/Central_groove/3'>central groove extending 30 angstroms into the molecule</scene> , dividing the protein into two subdomains, S1 (Green) and SII (Purple). The boundaries of the groove are formed by helices 13, 14, 15, and 17 as well as beta strand 4. On top of the groove a <scene name='Angiotensin-Converting_Enzyme/Lid/1'>lid is formed by helices 1, 2, and 3</scene>, preventing bulky ligands from accessing the active site and adding to ACE1’s specificity. <ref name="Natesh">PMID:12540854</ref> | |||
<br /> | <br /> | ||