Angiotensin-converting enzyme C-terminal catalytic domain is the main site of angiotensin I cleavage in vivo

Hypertension. 2008 Feb;51(2):267-74. doi: 10.1161/HYPERTENSIONAHA.107.097865. Epub 2007 Dec 24.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / administration & dosage
  • Angiotensin I / metabolism*
  • Angiotensin I / pharmacology
  • Angiotensin II / biosynthesis*
  • Angiotensins / blood
  • Animals
  • Blood Pressure / drug effects
  • Bradykinin / blood
  • Catalytic Domain / genetics*
  • Hematocrit
  • Infusions, Intravenous
  • Kidney / physiology
  • Mice
  • Mice, Mutant Strains
  • Osmolar Concentration
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism*
  • Point Mutation
  • Renin / blood
  • Substrate Specificity
  • Zinc Fingers / genetics


  • Angiotensins
  • Angiotensin II
  • Angiotensin I
  • Peptidyl-Dipeptidase A
  • Renin
  • Bradykinin