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Roles of the two active sites of somatic angiotensin-converting enzyme in the cleavage of angiotensin I and bradykinin: insights from selective inhibitors.
Circ Res. 2003 Jul 25; 93(2):148-54.CircR

Abstract

Somatic angiotensin-converting enzyme (ACE) contains two homologous domains, each bearing a functional active site. The in vivo contribution of each active site to the release of angiotensin II (Ang II) and the inactivation of bradykinin (BK) is still unknown. To gain insights into the functional roles of these two active sites, the in vitro and in vivo effects of compounds able to selectively inhibit only one active site of ACE were determined, using radiolabeled Ang I or BK, as physiological substrates of ACE. In vitro studies indicated that a full inhibition of the Ang I and BK cleavage requires a blockade of the two ACE active sites. In contrast, in vivo experiments in mice demonstrated that the selective inhibition of either the N-domain or the C-domain of ACE by these inhibitors prevents the conversion of Ang I to Ang II, while BK protection requires the inhibition of the two ACE active sites. Thus, in vivo, the cleavage of Ang I and BK by ACE appears to obey to different mechanisms. Remarkably, in vivo the conversion of Ang I seems to involve the two active sites of ACE, free of inhibitor. Based on these findings, it might be suggested that the gene duplication of ACE in vertebrates may represent a means for regulating the cleavage of Ang I differently from that of BK.

Authors+Show Affiliations

Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Zografou, Athens, Greece.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12805239

Citation

Georgiadis, Dimitris, et al. "Roles of the Two Active Sites of Somatic Angiotensin-converting Enzyme in the Cleavage of Angiotensin I and Bradykinin: Insights From Selective Inhibitors." Circulation Research, vol. 93, no. 2, 2003, pp. 148-54.
Georgiadis D, Beau F, Czarny B, et al. Roles of the two active sites of somatic angiotensin-converting enzyme in the cleavage of angiotensin I and bradykinin: insights from selective inhibitors. Circ Res. 2003;93(2):148-54.
Georgiadis, D., Beau, F., Czarny, B., Cotton, J., Yiotakis, A., & Dive, V. (2003). Roles of the two active sites of somatic angiotensin-converting enzyme in the cleavage of angiotensin I and bradykinin: insights from selective inhibitors. Circulation Research, 93(2), 148-54.
Georgiadis D, et al. Roles of the Two Active Sites of Somatic Angiotensin-converting Enzyme in the Cleavage of Angiotensin I and Bradykinin: Insights From Selective Inhibitors. Circ Res. 2003 Jul 25;93(2):148-54. PubMed PMID: 12805239.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Roles of the two active sites of somatic angiotensin-converting enzyme in the cleavage of angiotensin I and bradykinin: insights from selective inhibitors. AU - Georgiadis,Dimitris, AU - Beau,Fabrice, AU - Czarny,Bertrand, AU - Cotton,Joël, AU - Yiotakis,Athanasios, AU - Dive,Vincent, Y1 - 2003/06/12/ PY - 2003/6/14/pubmed PY - 2003/8/23/medline PY - 2003/6/14/entrez SP - 148 EP - 54 JF - Circulation research JO - Circ Res VL - 93 IS - 2 N2 - Somatic angiotensin-converting enzyme (ACE) contains two homologous domains, each bearing a functional active site. The in vivo contribution of each active site to the release of angiotensin II (Ang II) and the inactivation of bradykinin (BK) is still unknown. To gain insights into the functional roles of these two active sites, the in vitro and in vivo effects of compounds able to selectively inhibit only one active site of ACE were determined, using radiolabeled Ang I or BK, as physiological substrates of ACE. In vitro studies indicated that a full inhibition of the Ang I and BK cleavage requires a blockade of the two ACE active sites. In contrast, in vivo experiments in mice demonstrated that the selective inhibition of either the N-domain or the C-domain of ACE by these inhibitors prevents the conversion of Ang I to Ang II, while BK protection requires the inhibition of the two ACE active sites. Thus, in vivo, the cleavage of Ang I and BK by ACE appears to obey to different mechanisms. Remarkably, in vivo the conversion of Ang I seems to involve the two active sites of ACE, free of inhibitor. Based on these findings, it might be suggested that the gene duplication of ACE in vertebrates may represent a means for regulating the cleavage of Ang I differently from that of BK. SN - 1524-4571 UR - https://www.unboundmedicine.com/medline/citation/12805239/Roles_of_the_two_active_sites_of_somatic_angiotensin_converting_enzyme_in_the_cleavage_of_angiotensin_I_and_bradykinin:_insights_from_selective_inhibitors_ L2 - https://www.ahajournals.org/doi/10.1161/01.RES.0000081593.33848.FC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -