Angiotensin-Converting Enzyme: Difference between revisions
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[[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. See [[Hypertension & Congestive Heart Failure]]. ACE catalyzes the conversion of the decapeptide | [[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. See [[Hypertension & Congestive Heart Failure]]. ACE catalyzes the conversion of the decapeptide Angiotensin I to the octapeptide Angiotensin 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> | ||
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[[Hypertension & Congestive Heart Failure]]<br /> | [[Hypertension & Congestive Heart Failure]]<br /> | ||
[[Lisinopril-Angiotensin Converting Enzyme]]<br /> | [[Lisinopril-Angiotensin Converting Enzyme]]<br /> | ||
[[ACE2 (Hebrew)]]<br /> | |||
[[Treatments:Hypertension]]. | [[Treatments:Hypertension]]. | ||
== | ==ACE2 and coronavirus (SARS-CoV and COVID-19) entry into the cell== | ||
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='41/413151/Cv/1'>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"/> | 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='41/413151/Cv/1'>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"/> | ||
In 2020 Zhou et al. (Nature. 2020; 579: 270-273) and Hoffmann et al. (Cell. 2020; 181: 271-280) showed that SARS-CoV-2, the COVID-19 coronavirus causing the global 2019-2020 pandemia, uses ACE2 as a receptor protein to enter and infect cells, just as SARS-CoV does. Cell entry requires the binding of the S1 region of the virus spike (S) protein to ACE2 followed by the fusion of the viral and cellular membranes produced by the S2 subunit of the S protein. Beforehand, this process requires priming of the S protein by host cell proteases, which is performed by TMPRSS2 and the endosomal cysteine proteases cathepsin B and L (CatB/L). These results suggest therapeutic targets for COVID-19. One is targeting the binding interface between SARS-2-S protein and ACE2, and the other is to inhibit the serine protease activity of the proteases responsible for SARS-2-S protein priming. | |||
==3D Structures of Angiotensin-Converting Enzyme== | ==3D Structures of Angiotensin-Converting Enzyme== | ||