HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 16, 15946-15953, April 16, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/16/15946    most recent M400149200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fuchs, S. Articles by Bernstein, K. E. Search for Related Content PubMed PubMed Citation Articles by Fuchs, S. Articles by Bernstein, K. E. Social Bookmarking                      What's this?

Role of the N-terminal Catalytic Domain of Angiotensin-converting Enzyme Investigated by Targeted Inactivation in Mice^*

Sebastien Fuchs, Hong D. Xiao¶, Justin M. Cole, Jonathan W. Adams, Kristen Frenzel, Annie Michaud||, Hui Zhao, George Keshelava, Mario R. Capecchi**, Pierre Corvol||, and Kenneth E. Bernstein

From the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, the ^**Howard Hughes Medical Institute, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah 84112, and the ^||Institut National de la Santé et de la Recherche Medicale Unit 36, College de France, Paris 75005, France

Angiotensin-converting enzyme (ACE) produces the vasoconstrictor angiotensin II. The ACE protein is composed of two homologous domains, each binding zinc and each independently catalytic. To assess the physiologic significance of the two ACE catalytic domains, we used gene targeting in mice to introduce two point mutations (H395K and H399K) that selectively inactivated the ACE N-terminal catalytic site. This modification does not affect C-terminal enzymatic activity or ACE protein expression. In addition, the testis ACE isozyme is not affected by the mutations. Analysis of homozygous mutant mice (termed ACE 7/7) showed normal plasma levels of angiotensin II but an elevation of plasma and urine N-acetyl-Ser-Asp-Lys-Pro, a peptide suggested to inhibit bone marrow maturation. Despite this, ACE 7/7 mice had blood pressure, renal function, and hematocrit that were indistinguishable from wild-type mice. We also studied compound heterozygous mice in which one ACE allele was null (no ACE expression) and the second allele encoded the mutations selectively inactivating the N-terminal catalytic domain. These mice produced approximately half the normal levels of ACE, with the ACE protein lacking N-terminal catalytic activity. Despite this, the mice have a phenotype indistinguishable from wild-type animals. This study shows that, in vivo, the presence of the C-terminal ACE catalytic domain is sufficient to maintain a functional renin-angiotensin system. It also strongly suggests that the anemia present in ACE null mice is not due to the accumulation of the peptide N-acetyl-Ser-Asp-Lys-Pro.

Received for publication, January 7, 2004

^* This work was supported by grants from the National Institutes of Health (DK39777, DK44280, DK51445, and DK55503) and from Bristol Meyer Squibb. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a postdoctoral fellowship from INSERM.

^¶ Supported by a research fellowship from the Georgia affiliate of the National Kidney Foundation.

To whom correspondence should be addressed: Rm. 7107A WMB, Dept. of Pathology, Emory University, Atlanta, GA 30322. Tel.: 404-727-3134; Fax: 404-727-8540; E-mail: kbernst{at}emory.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				X. Liu, C. O. C. Bellamy, M. A. Bailey, L. J. Mullins, D. R. Dunbar, C. J. Kenyon, G. Brooker, S. Kantachuvesiri, K. Maratou, A. Ashek, et al. Angiotensin-converting Enzyme Is a Modifier of Hypertensive End Organ Damage J. Biol. Chem., June 5, 2009; 284(23): 15564 - 15572. [Abstract] [Full Text] [PDF]

				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]

				K. E. Bernstein Views of the Renin-Angiotensin System: Brilling, Mimsy, and Slithy Tove Hypertension, March 1, 2006; 47(3): 509 - 514. [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]

				V. Thimon, S. Metayer, M. Belghazi, F. Dacheux, J.-L. Dacheux, and J.-L. Gatti Shedding of the Germinal Angiotensin I-Converting Enzyme (gACE) Involves a Serine Protease and Is Activated by Epididymal Fluid Biol Reprod, November 1, 2005; 73(5): 881 - 890. [Abstract] [Full Text] [PDF]

				K. E. Bernstein, H. D. Xiao, K. Frenzel, P. Li, X. Z. Shen, J. W. Adams, and S. Fuchs Six Truisms Concerning ACE and the Renin-Angiotensin System Educed From the Genetic Analysis of Mice Circ. Res., June 10, 2005; 96(11): 1135 - 1144. [Full Text] [PDF]

				K. E. Bernstein, H. D. Xiao, J. W. Adams, K. Frenzel, P. Li, X. Z. Shen, J. M. Cole, and S. Fuchs Establishing the Role of Angiotensin-Converting Enzyme in Renal Function and Blood Pressure Control through the Analysis of Genetically Modified Mice J. Am. Soc. Nephrol., March 1, 2005; 16(3): 583 - 591. [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]