Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selectivity of captopril, enalapril (MK-421), enalaprilat (MK-422), ketoace, and SA-300 for inhibiting kininase II when angiotensin (ANG) I versus bradykinin (BK) is the substrate has been studied in vitro. Potency for inhibiting purified rabbit lung ANG I-converting enzyme (ACE) using a tripeptide substrate with an ANG I-like (hippurylhistidylleucine, HHL) or a BK-like (hippurylphenylalanylarginine, HPA) cleavable dipeptide was determined. Inhibition of ANG I-induced and potentiation of BK-induced contractions of isolated guinea pig ileum strips was measured. For the enzyme assay, the inhibitor concentration which reduced the rate of HHL and HPA hydrolysis 50% (IC50) from the control value was estimated. All tested compounds more potently inhibited hydrolysis of the ANG I-related tripeptide by the purified enzyme. Ketoace, with a selectivity ratio (HPA IC50:HHL IC50) of 23, was the most substrate-dependent inhibitor. For the isolated ileum assay, the inhibitor concentration which augmented the contractile response to BK by 50% (AC50) or inhibited the contractile response to ANG I by 50% (IC50) was calculated. Only enalaprilat retained a selectivity ratio (BK AC50:ANG I IC50) in the guinea pig ileum system greater than one. Ketoace, with a ratio of 0.038, was the least ANG I-selective by this criterion. In vivo selectivity data on captopril seem more in accord with the ileum, rather than the enzyme, results. It was concluded that converting enzyme inhibitors differ in their relative selectivity for inhibiting kininase II reactions using different substrates.
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PMID:Selectivity of converting-enzyme inhibitors for angiotensin I versus bradykinin hydrolysis reactions. 216 22

Plasma angiotensin I-converting enzyme "activity" (CEA) was estimated as its enzymatic effect on the synthetic substrate HHL in normal subjects and patients with untreated sarcoidosis, alcoholic decompensated liver cirrhosis and scleroderma. CEA was above the upper limit of normal in 60% of sarcoidosis cases and 30% of cirrhotics; it was within normal in scleroderma. The assessment of the influence of chloride concentration on CEA showed that maximum was obtained for a concentration of 300 mM. In addition the inhibitory effect of angiotensin I and the converting enzyme inhibitors SQ 14225 and MK 422 was demonstrated together with the action of high concentrations of penicillamine. The inhibitory influence of these substances was similar when added to the plasma of normal or sarcoidosis subjects.
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PMID:[Clinical value of the estimation of plasma converting enzyme activity]. 608 53

The angiotensin converting enzyme (ACE) activity in the plasma collected from normotensive and hypertensive patients was measured chromatographically by two different methods using hippuryl-histidyl-leucine (HHL-ACE) and synthetic angiotensin I (AI-ACE) as substrates. A single peak was observed in the elution profiles of HHL-ACE on both Sephadex G 150 column and DEAE Sephadex A 50 cellulose column chromatographies. A single peak of AI-ACE appeared on the gel-filtration. However, several peaks of AI-ACE were seen on DEAE Sephadex A 50 cellulose column chromatography, suggesting that there are various types of ACE which hydrolyze angiotensin I but not HHL.
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PMID:Chromatographic elution profiles of angiotensin converting enzyme measured by the methods using different substrates in the plasma from normotensive and hypertensive subjects. 609 90

We compared angiotensin I-converting enzyme (ACE) and carboxypeptidase A (CPA), two zinc metallopeptidases, for the hydrolysis of the usual ACE synthetic substrate benzoylglycyl-histidyl-leucine (HHL) investigating the possible interference by CPA in the determination of ACE activity in biological fluids. Both purified enzymes hydrolyse HHL in a radiochemical assay with the same optimal pH, a characteristic divalent metal requirement, a close similar behavior against inhibitors of other metallopeptidases, such as enkephalinase and kininase I, and the involvement of arginine and lysine residues in their active site. Conversely, CPA does not show the other catalytic properties of ACe, i.e. chloride dependence, low Km for HHL, inhibition by specific synthetic ACE inhibitors and antibody, also hydrolysis of the other ACE substrate furylacryloylphenylalanyl-glycyl-glycine (FAPGG). We advise the use of ACE inhibitors to validate ACE measurement with HHL or, alternatively, FAPGG, which is a more specific substrate for ACE, must be preferred, although the poor sensitivity of the spectrophotometric assay with this substrate limits its use to blood samples.
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PMID:Carboxypeptidase A hydrolyses benzoylglycyl-histidyl-leucine but not furylacryloyl-phenylalanyl-glycyl-glycine, two usual substrates for angiotensin I-converting enzyme. 758 46

A set of in vitro assay conditions were selected for the determination of ACE-inhibitory activity, and the need was demonstrated to standardize this assay so that the results obtained by different authors may be comparable. The conditions selected were as follows: 10 mM HHL concentration in 0.2 M potassium phosphate buffer and 0.3 M NaCl and 26 mU of ACE/mL as reaction medium; incubation time, 80 min at 37 degrees C. The method was applied to the study of ACE-inhibitory activity of dairy product and wine samples. Of the samples assayed, it was infant formulae whey that produces the greatest ACE inhibition. Red wine also presents a high inhibition percentage. This latter sample has an important matrix effect that must be corrected in the calculation. ACE-inhibition type was also studied, using a yogurt whey and a Captropil solution as substrates. The whey produced noncompetitive inhibition and the Captropil competitive inhibition.
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PMID:Assessment of the spectrophotometric method for determination of angiotensin-converting-enzyme activity: influence of the inhibition type. 1284 80

Bioactive ACE inhibiting peptides are gaining interest in hypertension treatment. We have designed and screened six synthetic heptapeptides (PACEI48 to PACEI53) based on two hexapeptide leads (PACEI32 and PACEI34) to improve ACE inhibitory properties and assess their antihypertensive effects. ACE activity was assayed in vitro and ex vivo. Selected peptides were administered to spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. In vitro cytotoxicity was assessed with the MTT reduction test. The six heptapeptides at low micromolar concentration produced different degrees of in vitro inhibition of ACE activity using the synthetic substrate HHL or the natural substrate angiotensin I; and ex vivo inhibition of ACE-dependent, angiotensin I-induced vasoconstriction, but not angiotensin II-induced vasoconstriction. Oral administration of the hexapeptide PACEI32L, and the heptapeptides PACEI50L and PACEI52L, induced reductions in systolic blood pressure lasting up to 3h in SHRs but not in WKY rats. Intravenous injection of PACEI32L and PACEI50L, but not PACEI52L, induced acute transient reductions in mean blood pressure of SHRs. d-Amino acid peptides showed five-fold less ACE inhibitory potency, no inhibitory effect on angiotensin I-induced vasoconstriction, and antihypertensive effect in SHRs after i.v. injection, but not after oral administration. The toxicity of peptides to reduce the viability of cultured cells was in the millimolar range. In conclusion, we have obtained novel rationally designed heptapeptides with improved ACE inhibitory properties when compared to lead hexapeptides. One selected hexapeptide and two heptapeptides show oral antihypertensive effects in SHRs and appear safe in cytotoxicity assays.
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PMID:Novel antihypertensive hexa- and heptapeptides with ACE-inhibiting properties: from the in vitro ACE assay to the spontaneously hypertensive rat. 2160 9

Epithelial cells of prostate express significant level of ACE and, as a result, seminal fluid has 50-fold more ACE than plasma. The substitution of highly specialized prostate epithelial cells by tumor cells results in dramatic decrease in ACE production in prostate tissues. We performed detailed characterization of ACE status in prostate tissues from patients with benign prostate hyperplasia (BPH) and prostate cancer (PC) using new approach- ACE phenotyping, that includes evaluation of: 1) ACE activity with two substrates (HHL and ZPHL); 2) the ratio of the rates of their hydrolysis (ZPHL/HHL ratio); 3) the ratio of immunoreactive ACE protein to ACE activity; 4) the pattern of mAbs binding to different epitopes on ACE - ACE conformational fingerprint - to reveal conformational changes in prostate ACE due to prostate pathology. ACE activity dramatically decreased and the ratio of immunoreactive ACE protein to ACE activity increased in PC tissues. The catalytic parameter, ZPHL/HHL ratio, increased in prostate tissues from all patients with PC, but was did not change for most |BPH patients. Nevertheless, prostate tissues of several patients diagnosed with BPH based on histology, also demonstrated decreased ACE activity and increased immunoreactive ACE protein/ACE activity and ZPHL/HHL ratios, that could be considered as more early indicators of prostate cancer development than routine histology. Thus, ACE phenotyping of prostate biopsies has a potential to be an effective approach for early diagnostics of prostate cancer or at least for differential diagnostics of BPH and PC.
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PMID:Tissue ACE phenotyping in prostate cancer. 3169 43