Molecular recognition and regulation of human angiotensin-I converting enzyme (ACE) activity by natural inhibitory peptides.
Angiotensin-I converting enzyme (ACE), a two-domain dipeptidylcarboxypeptidase, is a key regulator of blood pressure as a result of its critical role in the renin-angiotensin-aldosterone and kallikrein-kinin systems. Hence it is an important drug target in the treatment of cardiovascular diseases. ACE is primarily known for its ability to cleave angiotensin I (Ang I) to the vasoactive octapeptide angiotensin II (Ang II), but is also able to cleave a number of other substrates including the vasodilator bradykinin and N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a physiological modulator of hematopoiesis. For the first time we provide a detailed biochemical and structural basis for the domain selectivity of the natural peptide inhibitors of ACE, bradykinin potentiating peptide b and Ang II. Moreover, Ang II showed selective competitive inhibition of the carboxy-terminal domain of human somatic ACE providing evidence for a regulatory role in the human renin-angiotensin system (RAS).
Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, UK.
Geoffrey
G
Masuyer
Sylva L U
SL
Schwager
Edward D
ED
Sturrock
R Elwyn
RE
Isaac
K Ravi
KR
Acharya
D000804:Angiotensin II / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D009842:Oligopeptides / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012084:Renin-Angiotensin System
D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; C006791:bradykinin potentiating factors; D000804:Angiotensin II; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A