![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Institut National de la Santé et de la Recherche
Médicale Unité 36, Collège de France, 75005 Paris,
France
Angiotensin I-converting enzyme (ACE) is composed of two highly similar
domains (referred to here as the N and C domains) that play a central
role in blood pressure regulation; ACE inhibitors are widely used in
the treatment of hypertension. However, the negative regulator of
hematopoiesis, N-acetyl-seryl-aspartyl-lysyl-prolyl (AcSDKP), is a specific substrate of the N domain-active site; thus, in
addition to the cardiovascular function of ACE, the enzyme may be
involved in hematopoietic stem cell regulation, raising the interest of
designing N domain-specific ACE inhibitors. We analyzed the inhibition
of angiotensin I and AcSDKP hydrolysis as well as that of three
synthetic ACE substrates by wild-type ACE and the N and C domains by
using a range of specific ACE inhibitors. We demonstrate that
captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP
hydrolysis by wild-type ACE, with Ki values in the subnanomolar
range. However, of the inhibitors tested, captopril is the only
compound able to differentiate to some degree between AcSDKP and
angiotensin I inhibition of hydrolysis by wild-type ACE: the
Ki value with AcSDKP as substrate
was 16-fold lower than that with angiotensin I as substrate. This
raises the possibility of using captopril to enhance plasma AcSDKP
levels with the aim of normal hematopoeitic stem cell protection during
chemotherapy and a limited effect on the cardiovascular function of
ACE.
This article has been cited by other articles:
|
|
 |
|
  S. Fuchs, H. D. Xiao, C. Hubert, A. Michaud, D. J. Campbell, J. W. Adams, M. R. Capecchi, P. Corvol, and K. E. Bernstein Angiotensin-Converting Enzyme C-Terminal Catalytic Domain Is the Main Site of Angiotensin I Cleavage In Vivo Hypertension, February 1, 2008; 51(2): 267 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Hemming and D. J. Selkoe Amyloid {beta}-Protein Is Degraded by Cellular Angiotensin-converting Enzyme (ACE) and Elevated by an ACE Inhibitor J. Biol. Chem., November 11, 2005; 280(45): 37644 - 37650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H.M. van Esch, B. Tom, V. Dive, W. W. Batenburg, D. Georgiadis, A. Yiotakis, J. M.G. van Gool, R. J.A. de Bruijn, R. de Vries, and A.H. J. Danser Selective Angiotensin-Converting Enzyme C-Domain Inhibition Is Sufficient to Prevent Angiotensin I-Induced Vasoconstriction Hypertension, January 1, 2005; 45(1): 120 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. Tzakos, A. S. Galanis, G. A. Spyroulias, P. Cordopatis, E. Manessi-Zoupa, and I. P. Gerothanassis Structure-function discrimination of the N- and C- catalytic domains of human angiotensin-converting enzyme: implications for Cl- activation and peptide hydrolysis mechanisms Protein Eng. Des. Sel., December 1, 2003; 16(12): 993 - 1003. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Georgiadis, F. Beau, B. Czarny, J. Cotton, A. Yiotakis, and V. Dive 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., July 25, 2003; 93(2): 148 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Tom, R. de Vries, P. R. Saxena, and A.H. J. Danser Bradykinin Potentiation by Angiotensin-(1-7) and ACE Inhibitors Correlates With ACE C- and N-Domain Blockade Hypertension, July 1, 2001; 38(1): 95 - 99. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Junot, M.-F. Gonzales, E. Ezan, J. Cotton, G. Vazeux, A. Michaud, M. Azizi, S. Vassiliou, A. Yiotakis, P. Corvol, et al. RXP 407, a Selective Inhibitor of the N-Domain of Angiotensin I-Converting Enzyme, Blocks in Vivo the Degradation of Hemoregulatory Peptide Acetyl-Ser-Asp-Lys-Pro with No Effect on Angiotensin I Hydrolysis J. Pharmacol. Exp. Ther., April 12, 2001; 297(2): 606 - 611. [Abstract] [Full Text]
|
|
|
|
|
|
M. Azizi, C. Massien, A. Michaud, and P. Corvol In Vitro and In Vivo Inhibition of the 2 Active Sites of ACE by Omapatrilat, a Vasopeptidase Inhibitor Hypertension, June 1, 2000; 35(6): 1226 - 1231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Junot, L. Nicolet, E. Ezan, M.-F. Gonzales, J. Menard, and M. Azizi Effect of Angiotensin-Converting Enzyme Inhibition on Plasma, Urine, and Tissue Concentrations of Hemoregulatory Peptide Acetyl-Ser-Asp-Lys-Pro in Rats J. Pharmacol. Exp. Ther., December 1, 1999; 291(3): 982 - 987. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. E. Chisi, J. Wdzieczak-Bakala, J. Thierry, C. V. Briscoe, and A. C. Riches Captopril Inhibits the Proliferation of Hematopoietic Stem and Progenitor Cells in Murine Long-Term Bone Marrow Cultures Stem Cells, November 1, 1999; 17(6): 339 - 344. [Abstract] [Full Text]
|
|
|
|
|
|
C. Junot, J. Menard, M.-F. Gonzales, A. Michaud, P. Corvol, and E. Ezan In Vivo Assessment of Captopril Selectivity of Angiotensin I-Converting Enzyme Inhibition: Differential Inhibition of Acetyl-Ser-Asp-Lys-Pro and Angiotensin I Hydrolysis J. Pharmacol. Exp. Ther., June 1, 1999; 289(3): 1257 - 1261. [Abstract] [Full Text]
|
|
|
|
 |
|
 V. Dive, J. Cotton, A. Yiotakis, A. Michaud, S. Vassiliou, J. Jiracek, G. Vazeux, M.-T. Chauvet, P. Cuniasse, and P. Corvol RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites PNAS, April 13, 1999; 96(8): 4330 - 4335. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
