scholarly journals The binding of captopril to angiotensin I-converting enzyme triggers activation of signaling pathways

2018 ◽  
Vol 315 (3) ◽  
pp. C367-C379 ◽  
Author(s):  
Rosana I. Reis ◽  
Marie D. Nogueira ◽  
Ana Lucia Campanha-Rodrigues ◽  
Larissa Miranda Pereira ◽  
Maria Claudina C. Andrade ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ace Inhibitors ◽  
Mesangial Cells ◽  
Primary Cultures ◽  
Chinese Hamster ◽  
Physiological Role ◽  
Converting Enzyme ◽  
Angiotensin I ◽  
Pathway Activation ◽  
Captopril Treatment

Hypertension is a global health problem, and angiotensin I (ANG I)-converting enzyme (ACE) inhibitors are largely used to control this pathology. Recently, it has been shown that ACE can also act as a transducer signal molecule when its inhibitors or substrates bind to it. This new role of ACE could contribute to understanding some of the effects not explained by its catalytic activity only. In this study, we investigated signaling pathway activation in Chinese hamster ovary (CHO) cells stably expressing ACE (CHO-ACE) under different conditions. We also investigated gene modulation after 4 h and 24 h of captopril treatment. Our results demonstrated that CHO-ACE cells when stimulated with ANG I, ramipril, or captopril led to JNK and ERK1/2 phosphorylation. To verify any physiological role at the endogenous level, we made use of primary cultures of mesangial cells from spontaneously hypertensive rats (SHR) and Wistar rats. Our results showed that ERK1/2 activation occurred mainly in primary cultures of mesangial cells from SHR rats upon captopril stimulation, suggesting that this signaling pathway could be differentially regulated during hypertension. Our results also showed that captopril treatment leads to a decrease of cyclooxygenase 2, interleukin-1β, and β-arrestin2 and a significant increase of AP2 gene expression levels. Our findings strengthen the fact that, in addition to the blockage of enzymatic activity, ACE inhibitors also trigger signaling pathway activation, and this may contribute to their beneficial effects in the treatment of hypertension and other pathologies.

Transforming Non-Selective Angiotensin-Converting Enzyme Inhibitors in C- and N-domain Selective Inhibitors by Using Computational Tools

2020 ◽  
Vol 20 (14) ◽  
pp. 1436-1446 ◽  
Author(s):  
Sergio Alfaro ◽  
Carlos Navarro-Retamal ◽  
Julio Caballero
Keyword(s):  
Molecular Modeling ◽  
Ace Inhibitors ◽  
Physiological Role ◽  
Free Energy Calculations ◽  
Rational Drug Design ◽  
Critical Conditions ◽  
Converting Enzyme ◽  
Selective Inhibitors ◽  
Angiotensin I ◽  
Modeling Methods

The two-domain dipeptidylcarboxypeptidase Angiotensin-I-converting enzyme (EC 3.4.15.1; ACE) plays an important physiological role in blood pressure regulation via the reninangiotensin and kallikrein-kinin systems by converting angiotensin I to the potent vasoconstrictor angiotensin II, and by cleaving a number of other substrates including the vasodilator bradykinin and the anti-inflammatory peptide N-acetyl-SDKP. Therefore, the design of ACE inhibitors is within the priorities of modern medical sciences for treating hypertension, heart failures, myocardial infarction, and other related diseases. Despite the success of ACE inhibitors for the treatment of hypertension and congestive heart failure, they have some adverse effects, which could be attenuated by selective domain inhibition. Crystal structures of both ACE domains (nACE and cACE) reported over the last decades could facilitate the rational drug design of selective inhibitors. In this review, we refer to the history of the discovery of ACE inhibitors, which has been strongly related to the development of molecular modeling methods. We stated that the design of novel selective ACE inhibitors is a challenge for current researchers which requires a thorough understanding of the structure of both ACE domains and the help of molecular modeling methodologies. Finally, we performed a theoretical design of potential selective derivatives of trandolaprilat, a drug approved to treat critical conditions of hypertension, to illustrate how to use molecular modeling methods such as de novo design, docking, Molecular Dynamics (MD) simulations, and free energy calculations for creating novel potential drugs with specific interactions inside nACE and cACE binding sites.

Angiotensin I-converting enzyme activity in tubular fluid along the rat nephron

1997 ◽  
Vol 272 (3) ◽  
pp. F405-F409 ◽  
Author(s):  
D. E. Casarini ◽  
M. A. Boim ◽  
R. C. Stella ◽  
M. H. Krieger-Azzolini ◽  
J. E. Krieger ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Proximal Tubule ◽  
Mesangial Cells ◽  
Collecting Duct ◽  
Physiological Role ◽  
Converting Enzyme ◽  
Angiotensin I ◽  
Angiotensin I Converting Enzyme ◽  
Ace Activity

The activity of angiotensin I-converting enzyme (ACE) was determined in tubular fluid collected from several portions of the rat nephron and urine and in total and efferent arteriolar blood using hippuryl-L-His-Leu as substrate. ACE activity decreased 30% from the pre- to the postglomerular arterioles (P < 0.001), suggesting a role of the glomerulus in ACE clearance. The enzyme activity was found to be present throughout the rat nephron. However, the highest activities were found in the proximal tubule and urine (0.692 +/- 0.007 and 1.05 +/- 0.015 pmol x microl(-1) x min(-1), respectively). Compared with other segments, ACE activity decreased from the initial portion of the proximal tubule to the distal nephron and increased again in the urine. Along the proximal tubule, ACE was secreted and degraded and/or reabsorbed and then secreted again into the collecting duct; no ACE activity was found in the late distal tubule, but a high level was detected in the urine, indicating a potential physiological role in the inactivation of the kinins formed by kallikrein beyond the connecting tubules. Moreover, the possible role of mesangial cells (MC) in the decrease of intraglomerular ACE was also evaluated. The analysis of ACE gene showed that MC in culture are able to express ACE mRNA. Moreover, ACE is produced as an ectoenzyme and as a secreted form of the enzyme, indicating a potential effect of local angiotensin II production on MC function.

Characterization of signaling pathways of Angiotensin I‐Converting Enzyme in mesangial cells of spontaneously hypertensive rats (SHR)

2011 ◽  
Vol 25 (S1) ◽  
Author(s):  
Rosana Inácio Reis ◽  
Lucas Tabajara Parreiras‐e‐Silva ◽  
Christiane Becari ◽  
Maria Claudina Andrade ◽  
Maria Cristina Oliveira Salgado ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Spontaneously Hypertensive Rats ◽  
Mesangial Cells ◽  
Converting Enzyme ◽  
Hypertensive Rats ◽  
Angiotensin I ◽  
Spontaneously Hypertensive ◽  
Angiotensin I Converting Enzyme

Catalytic properties of recombinant dipeptidyl carboxypeptidase from Escherichia coli: a comparative study with angiotensin I-converting enzyme

2009 ◽  
Vol 390 (9) ◽  
Author(s):  
Carlos Eduardo L. Cunha ◽  
Helena de Fátima Magliarelli ◽  
Thaysa Paschoalin ◽  
Aloysius T. Nchinda ◽  
Jackson C. Lima ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Ace Inhibitors ◽  
Catalytic Properties ◽  
Resonance Energy ◽  
Human Testis ◽  
Converting Enzyme ◽  
Angiotensin I ◽  
Acceptor Pair ◽  
Angiotensin I Converting Enzyme ◽  
Dipeptidyl Carboxypeptidase

Abstract Dipeptidyl carboxypeptidase from Escherichia coli (EcDcp) is a zinc metallopeptidase with catalytic properties closely resembling those of angiotensin I-converting enzyme (ACE). However, EcDcp and ACE are classified in different enzyme families (M3 and M2, respectively) due to differences in their primary sequences. We cloned and expressed EcDcp and studied in detail the enzyme's S3 to S1′ substrate specificity using positional-scanning synthetic combinatorial (PS-SC) libraries of fluorescence resonance energy transfer (FRET) peptides. These peptides contain ortho-aminobenzoic acid (Abz) and 2,4-dinitrophenyl (Dnp) as donor/acceptor pair. In addition, using FRET substrates developed for ACE [Abz-FRK(Dnp)P-OH, Abz-SDK(Dnp)P-OH and Abz-LFK(Dnp)-OH] as well as natural ACE substrates (angiotensin I, bradykinin, and Ac-SDKP-OH), we show that EcDcp has catalytic properties very similar to human testis ACE. EcDcp inhibition studies were performed with the ACE inhibitors captopril (K i=3 nm) and lisinopril (K i=4.4 μm) and with two C-domain-selective ACE inhibitors, 5-S-5-benzamido-4-oxo-6-phenylhexanoyl-L-tryptophan (kAW; K i=22.0 μm) and lisinopril-Trp (K i=0.8 nm). Molecular modeling was used to provide the basis for the differences found in the inhibitors potency. The phylogenetic relationship of EcDcp and related enzymes belonging to the M3 and M2 families was also investigated and the results corroborate the distinct origins of EcDcp and ACE.

scholarly journals Drosophila melanogaster angiotensin I-converting enzyme expressed in Pichia pastoris resembles the C domain of the mammalian homologue and does not require glycosylation for secretion and enzymic activity

1996 ◽  
Vol 318 (1) ◽  
pp. 125-131 ◽  
Author(s):  
Tracy A. WILLIAMS ◽  
Annie MICHAUD ◽  
Xavier HOUARD ◽  
Marie-Thérèse CHAUVET ◽  
Florent SOUBRIER ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Pichia Pastoris ◽  
Ace Inhibitors ◽  
Active Sites ◽  
Chloride Concentration ◽  
Enzymic Activity ◽  
Expression Level ◽  
Converting Enzyme ◽  
Angiotensin I ◽  
Angiotensin I Converting Enzyme

Drosophila melanogaster angiotensin I-converting enzyme (AnCE) is a secreted single-domain homologue of mammalian angiotensin I-converting enzyme (ACE) which comprises two domains (N and C domains). In order to characterize in detail the enzymic properties of AnCE and to study the influence of glycosylation on the secretion and enzymic activity of this enzyme, we overexpressed AnCE (expression level, 160 mg/l) and an unglycosylated mutant (expression level, 43 mg/l) in the yeast Pichia pastoris. The recombinant enzyme was apparently homogeneous on SDS/PAGE without purification and partial deglycosylation demonstrated that all three potential sites for N-linked glycosylation were occupied by oligosaccharide chains. Each N-glycosylation sequence (Asn-Xaa-Ser/Thr) was disrupted by substituting a glutamine for the asparagine residue at amino acid positions 53, 196 and 311 by site-directed mutagenesis to produce a single mutant. Expression of the unglycosylated mutant in Pichia produced a secreted catalytically active enzyme (AnCEΔCHO). This mutant displayed unaltered kinetics for the hydrolyses of hippuryl-His-Leu, angiotensin I and N-acetyl-Ser-Asp-Lys-Pro (AcSDKP) and was equally sensitive to ACE inhibitors compared with wild-type AnCE. However, AnCEΔCHO was less stable, displaying a half-life of 4.94 h at 37 °C, compared with AnCE which retained full activity under the same conditions. Two catalytic criteria demonstrate the functional resemblance of AnCE with the human ACE C domain: first, the kcat/Km of AcSDKP hydrolysis and secondly, the kcat/Km and optimal chloride concentration for hippuryl-His-Leu hydrolysis. A range of ACE inhibitors were far less potent towards AnCE compared with the human ACE domains, except for captopril which suggests an alternative structure in AnCE corresponding to the region of the S1 subsite in the human ACE active sites.

scholarly journals Association of angiotensin I-converting enzyme gene polymorphism with susceptibility to antiproteinuric effect of angiotensin I-converting enzyme inhibitors in patients with proteinuria.

1995 ◽  
Vol 6 (6) ◽  
pp. 1676-1678
Author(s):  
T Moriyama ◽  
H Kitamura ◽  
S Ochi ◽  
M Izumi ◽  
K Yokoyama ◽  
...  
Keyword(s):  
Ace Inhibitors ◽  
Urinary Protein ◽  
Converting Enzyme ◽  
Angiotensin I ◽  
Ace Gene ◽  
Protein Excretion ◽  
Angiotensin I Converting Enzyme ◽  
Antiproteinuric Effect ◽  
The Difference ◽  
Effective Group

The antiproteinuric effect of angiotensin I-converting enzyme (ACE) inhibitors in patients with renal diseases of various origins has been well recognized. However, individual responses regarding the degree of decrease in urinary protein excretion appear to vary considerably. The mechanism underlying this variable response to ACE inhibitors has not been clarified yet. A possible role of ACE gene insertion/deletion (I/D) polymorphism in the responsiveness to antiproteinuric effect of ACE inhibitors is examined. Thirty-six patients with proteinuria (23 men and 13 woman; mean age, 47 +/- 13 yr) were studied. These patients were classified into two groups on the basis of the percent decrease in their urinary protein excretion: the effective group, those with a decrease in proteinuria (18 patients, -64 +/- 19%) and the noneffective group (18 patients, +13 +/- 40%). A 287-base pair (bp) I/D polymorphism in the ACE gene was examined by polymerase chain reaction. The allelic frequencies of the ACE gene were I/D = 0.53/0.47 in the effective group and I/D = 0.81/0.19 in the noneffective group. The difference in the allelic frequencies between the two groups was significant (chi 2 = 6.25, P = 0.0114 < 0.05). Furthermore, the difference in the responsiveness of proteinuria to ACE inhibition between genotype II versus genotype ID + DD was statistically significant (chi 2 = 4.05, P = 0.0442 < 0.05). There was no significant difference between the two groups with regard to initial urinary protein level, blood pressure, renal function, and daily sodium intake. The genetic susceptibility to the antihypertensive effect of ACE inhibitors was also studied, but no significant relation was observed. This study suggests the association of ACE gene I/D polymorphism with the antiproteinuric efficacy of ACE inhibitors in patients with proteinuria.

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