Article

Different in vivo functions of the two catalytic domains of angiotensin-converting enzyme (ACE).

Department of Biomedical Sciences, Cedars-Sinai Medical Center, 110 N. George Burns Rd, Los Angeles, CA 90048, USA.
Current Opinion in Pharmacology (impact factor: 6.86). 12/2010; 11(2):105-11. DOI:10.1016/j.coph.2010.11.001 pp.105-11
Source: PubMed

ABSTRACT Angiotensin-converting enzyme (ACE) can cleave angiotensin I, bradykinin, neurotensin and many other peptide substrates in vitro. In part, this is due to the structure of ACE, a protein composed of two independent catalytic domains. Until very recently, little was known regarding the specific in vivo role of each ACE domain, and they were commonly regarded as equivalent. This is not true, as shown by mouse models with a genetic inactivation of either the ACE N- or C-domain. In vivo, most angiotensin II is produced by the ACE C-domain. Some peptides, such as the anti-fibrotic peptide AcSDKP, are substrates only of the ACE N-domain. Knowing the in vivo role of each ACE domain has great significance for developing ACE domain-specific inhibitors and for understanding the full effects of the anti-ACE pharmaceuticals in widespread clinical use.

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  • Article: 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, Kenneth E Bernstein
    [show abstract] [hide abstract]
    ABSTRACT: 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.
    Journal of Biological Chemistry 05/2004; 279(16):15946-53. · 4.77 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

ACE C-domain
 
ACE domain
 
ACE domain-specific inhibitors
 
ACE N-
 
ACE N-domain
 
angiotensin II
 
Angiotensin-converting enzyme
 
anti-ACE pharmaceuticals
 
anti-fibrotic peptide AcSDKP
 
C-domain
 
full effects
 
independent catalytic domains
 
mouse models
 
peptide substrates
 
peptides
 
substrates
 
vivo role
 
widespread clinical use