Angiotensin-Converting Enzyme C-Terminal Catalytic Domain Is the Main Site of Angiotensin I Cleavage In Vivo

Fuchs, Sébastien; Xiao, Hong; Hübert, Christine; Michaud, Annie; Campbell, Duncan J.; Adams, Jonathan; Capecchi, Mario R.; Corvol, Pierre; Bernstein, Kenneth E.

doi:10.1161/hypertensionaha.107.097865

Cited by 118 publications

(89 citation statements)

References 31 publications

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“…1, C and F), suggesting that each catalytic domain of ACE regulates the activity of the other, and both domains are required for normal substrate recognition and degradation. Mice with a selective inactivation of either the N-or C-domain of ACE were generated, and the C-domain was demonstrated to be the main site of angiotensin I cleavage (18,22), which is consistent with our in vitro finding. However, the role of the N-domain of ACE toward A␤42 to A␤40 conversion in vivo needs to be addressed.…”

Section: Discussionsupporting

confidence: 87%

“…1C). F-ACE was found to have the highest Hip-His-Leu-degrading activity and C-ACE had 63% ACE activity compared with F-ACE, whereas N-ACE had a significantly reduced ACE activity, confirming the finding of the ACE C-domain as the main site of angiotensin I cleavage in vivo (18) (Fig. 1C).…”

Section: Ace N-domain But Not C-domain Converts A␤42 To A␤40-supporting

confidence: 73%

“…For example, AcSDKP, a peptide suggested to inhibit bone marrow maturation, is found to be preferentially cleaved by the N-domain of ACE in vitro (17). In contrast, the ACE C-domain is demonstrated to be the main site of angiotensin I cleavage in vivo (18). The N-linked glycosylation of testicular ACE, a homologue of the somatic ACE N-domain, is essential for its enzymatic activity and for preventing degradation (19).…”

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confidence: 99%

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Aβ42-to-Aβ40- and Angiotensin-converting Activities in Different Domains of Angiotensin-converting Enzyme

Zou

Maeda

Watanabe

et al. 2009

Journal of Biological Chemistry

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Amyloid ␤-protein 1-42 (A␤42) is believed to play a causative role in the development of Alzheimer disease (AD), although it is a minor part of A␤. In contrast, A␤40 is the predominant secreted form of A␤ and recent studies have suggested that A␤40 has neuroprotective effects and inhibits amyloid deposition. We have reported that angiotensin-converting enzyme (ACE) converts A␤42 to A␤40, and its inhibition enhances brain A␤42 deposition (Zou, K., Yamaguchi, H., Akatsu, H., Sakamoto, T., Ko, M., Mizoguchi, K., Gong, J. S., Yu, W., Yamamoto, T., Kosaka, K., Yanagisawa, K., and Michikawa, M. (2007) J. Neurosci. 27, 8628 -8635). ACE has two homologous domains, each having a functional active site. In the present study, we identified the domain of ACE, which is responsible for converting A␤42 to A␤40. Interestingly, A␤42-to-A␤40-converting activity is solely found in the N-domain of ACE and the angiotensinconverting activity is found predominantly in the C-domain of ACE. We also found that the N-linked glycosylation is essential for both A␤42-to-A␤40-and angiotensin-converting activities and that unglycosylated ACE rapidly degraded. The domainspecific converting activity of ACE suggests that ACE inhibitors could be designed to specifically target the angiotensin-converting C-domain, without inhibiting the A␤42-to-A␤40-converting activity of ACE or increasing neurotoxic A␤42. Angiotensin-converting enzyme (ACE)4 plays a key role in the renin-angiotensin system (RAS), which is involved in the long-term regulation of blood pressure and blood volume in the human body. Recent genetic, pathologic, and biochemical studies have associated ACE with onset of Alzheimer disease (AD) (1, 2). The I allele of the ACE gene, which results in a reduced serum ACE level, has been demonstrated to be associated with AD (3-5). Hypertension is a risk factor for AD and ACE inhibitors for treatment of hypertension were shown to be the only drug class among the antihypertensives to potentially be associated with a slight increased incidence of AD (adjusted hazard ratio 1.13) (6, 7). A mechanistic link between ACE and AD was suggested when ACE was shown to degrade A␤40 and A␤42 (8, 9). Overexpression of A␤40 in transgenic mice does not cause brain amyloid deposition, the major pathological hallmark of AD, whereas expression of A␤42 is shown to be essential for amyloid deposition (10, 11). In addition, A␤40 has an inhibitory effect on amyloid deposition in vitro and in vivo and has neuroprotective effects (12)(13)(14). These lines of evidence suggest that converting A␤42 to A␤40 may be a potential strategy for development of an AD therapy. In our previous study, we identified ACE as an A␤42-to-A␤40-converting (A␤-converting) enzyme and showed that ACE inhibitor enhances brain A␤42 deposition in transgenic mice (15). Clarifying the molecular base of ACE domain-specific enzymatic activity on A␤42 to A␤40 conversion, A␤ degradation, and angiotensin conversion emerges to be important for development of a strategy for hypertension and AD treatment.AC...

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Section: Discussionsupporting

confidence: 87%

Section: Ace N-domain But Not C-domain Converts A␤42 To A␤40-supporting

confidence: 73%

mentioning

confidence: 99%

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Aβ42-to-Aβ40- and Angiotensin-converting Activities in Different Domains of Angiotensin-converting Enzyme

Zou

Maeda

Watanabe

et al. 2009

Journal of Biological Chemistry

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“…The MEROPS database classification is clan MA, subclan MA(E), family M2, and peptidase XM02-001 (Rawlings et al, 2008). Expression of each ACE domain in Chinese hamster ovary cells and the creation of mice with ACE genetic mutations has shown that each domain binds zinc and is independently catalytic (Wei et al, 1991a;Fuchs et al, 2004Fuchs et al, , 2008.…”

Section: E Structure Of Angiotensin-converting Enzymementioning

confidence: 99%

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

et al. 2012

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“…[9][10][11] ACE contains two homologous domains (C-and N-domain), each bearing a catalytic site, that have been demonstrated to have differential enzymatic activities. In brief, work with both N-domain and C-domain knockout mice 12,13 has indicated that Ang 1-10 hydrolysis to Ang 1-8 is predominately catalysed by the C-domain whilst the antifibrotic tetrapeptide N-acetyl-seryl-aspartyl-lysylproline (Ac-SDKP) is a highly specific substrate for the N-domain catalytic site. 14 As presently prescribed ACEi target both domains similarly, design of C-domain selective inhibitors is a logical step toward improving the side effect profile of ACE inhibition.…”

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confidence: 99%

Pharmacodynamic effects of C-domain-specific ACE inhibitors on the renin-angiotensin system in myocardial infarcted rats

Sharp

Poglitsch

Zilla

et al. 2015

J Renin Angiotensin Aldosterone Syst

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Introduction: The renin-angiotensin system (RAS) is a dynamic network that plays a critical role in blood pressure regulation and fluid and electrolyte homeostasis. Modulators of the RAS, such as angiotensin-converting enzyme (ACE) inhibitors, are widely used to treat hypertension, heart failure and myocardial infarction. Methods: The effect of ACE inhibitors (lisinopril and C-domain-selective LisW-S) on the constituent peptides of the RAS following myocardial infarction was examined in rats. Ten angiotensin peptides were analysed using a sensitive LC-MS/MS-based assay to examine both the circulating and equilibrium levels of these peptides. Results: Administration of lisinopril or LisW-S caused a significant decrease in Ang 1–8/Ang 1–10 ratios as determined by circulating and equilibrium peptide level analysis. Furthermore, Ang 1–7 levels were elevated by both ACE inhibitors, but only lisinopril decreased the Ang 1–5/Ang 1–7 ratio. This indicates LisW-S C-domain specificity as Ang 1–5 is generated by hydrolysis of Ang 1–7 by the N-domain. Further corroboration of LisW-S C-domain specificity is that only lisinopril increased the circulating levels of the N-domain ACE substrate Ac-SDKP. Conclusion: LisW-S is able to effectively block ACE in vivo by C-domain-selective inhibition. The LC-MS/MS-based assay allows the evaluation of the pharmacologic impact of RAS inhibitors in different pathophysiological conditions.

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Angiotensin-Converting Enzyme C-Terminal Catalytic Domain Is the Main Site of Angiotensin I Cleavage In Vivo

Cited by 118 publications

References 31 publications

Aβ42-to-Aβ40- and Angiotensin-converting Activities in Different Domains of Angiotensin-converting Enzyme

Aβ42-to-Aβ40- and Angiotensin-converting Activities in Different Domains of Angiotensin-converting Enzyme

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

Pharmacodynamic effects of C-domain-specific ACE inhibitors on the renin-angiotensin system in myocardial infarcted rats

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