Angiotensin-converting enzyme C-terminal catalytic domain is the main site of angiotensin I cleavage in vivo.
Angiotensin-converting enzyme (ACE) plays a central role in the production of the vasoconstrictor angiotensin II. ACE is a single polypeptide, but it contains 2 homologous and independent catalytic domains, each of which binds zinc. To understand the in vivo role of these 2 domains, we used gene targeting to create mice with point mutations in the ACE C-domain zinc-binding motif. Such mice, termed ACE13/13, produce a full-length ACE protein with tissue expression identical to wild-type mice. Analysis of ACE13/13 mice showed that they produce ACE having only N-domain catalytic activity, as determined by the hydrolysis of domain specific substrates and by chloride sensitivity. ACE13/13 mice have blood pressure and blood angiotensin II levels similar to wild-type mice. However, plasma renin concentration is increased 2.6-fold and blood angiotensin I levels are increased 7.5-fold. Bradykinin peptide levels are not different from wild-type levels. ACE13/13 mice have a reduced increase of blood pressure after intravenous infusion of angiotensin I. ACE13/13 mice have a normal renal structure, but they are not able to concentrate urine after dehydration as effectively as wild-type mice. This study shows that the C-domain of ACE is the predominant site of angiotensin I cleavage in vivo. Although mice lacking C-domain activity have normal physiology under laboratory conditions, they respond less well to the stress of dehydration.
D000803:Angiotensin I / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D000804:Angiotensin II / Q000096:biosynthesis*; D000809:Angiotensins / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000097:blood; D020134:Catalytic Domain / Q000235:genetics*; D006400:Hematocrit; D007262:Infusions, Intravenous; D007668:Kidney / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D009994:Osmolar Concentration; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D012083:Renin / Q000097:blood; D013379:Substrate Specificity; D016335:Zinc Fingers / Q000235:genetics
D000809:Angiotensins; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D001920:Bradykinin