Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50502 (Hip)
 7,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antiontensin-converting enzyme (peptidyldipeptide hydrolase, EC 3.4.15.1) has been solubilized from canine pulmonary particles and purified to apparent homogeneity. A value of approx. 140000 was estimated for the molecular weight of the native and the reduced, denatured forms of the enzyme. No free NH2-terminal residue was detected by the dansylation procedure. Carbohydrate accounted for 17% of the weight of the enzyme, and the major residues were galactose, mannose and N-acetylglucosamine with smaller amounts of sialic acid and fucose. Removal of sialic acid residues with neuraminidase did not alter enzymatic activity. The enzyme contained one molar equivalent of zinc. Addition of this metal reversed stimulation and inhibition of activity observed in the presence of Co2+ and Mn2+, respectively. Immunologic homology of pure dog and rabbit enzymes was demonstrable with goat antisera. Fab fragments and intact IgG antibodies displayed similar inhibition dose vs. response curves with homologous enzyme, whereas the fragments were poor inhibitors of heterologous activity compared to the holoantibodies. The canine glycoprotein was much less active than the rabbit preparation in catalyzing hydrolysis of Hip-His-Leu. In contrast, the two enzymes exhibited comparable kinetic parameters with angiotensin I as substrate.
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PMID:Canine pulmonary angiotensin-converting enzyme. Physicochemical, catalytic and immunological properties. 20 22

Angiotensin I(AI)-converting enzyme (ACE) (EC 3.4.15.1) was solubilized from the membrane fraction of chicken lung using trypsin and nonidet P40 extraction, and then purified to homogeneity by captopril affinity chromatography. Comparison of trypsin-extracted and detergent-solubilized membrane-bound converting enzyme by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and isoelectric focusing indicated that the membrane-binding sequence contributed to a large extent to the size and charge of the enzyme. Both forms of the enzyme were glycoproteins but they differed in the glucidic content; 4.5% by weight of the enzyme in the trypsin-extracted ACE and 15% by weight of the enzyme in the detergent-solubilized ACE. In both cases hexoses were the most abundant residues. Both forms of the enzyme were found to contain 1 g-atom zinc/mol enzyme. The purified enzymes did not only split Hip-His-Leu but also AI and bradykinin. The Michaelis constant (Km) and maximum velocity (Vmax) values of the trypsin-extracted ACE for Hip-His-Leu were 52 x 10(-5) mol/l and 15.36 nmol/min respectively, and for AI they were 7.8 x 10(-5) mol/l and 0.45 nmol/min respectively. The Km and Vmax values of the detergent-solubilized ACE for Hip-His-Leu were 32 x 10(-5) mol/l and 11.75 nmol/min respectively, and for AI they were 6.5 x 10(-5) mol/l and 0.97 nmol/min.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of chicken lung angiotensin I-converting enzyme. 131 47

The new ACE inhibitor trandolapril was administered to normal volunteers at daily doses of 0.5, 2, and 8 mg for 10 days. Twenty-one volunteers, aged 21-30 years, were included in the study. To randomly selected groups of seven subjects, each dose was administered in a single-blind fashion. None of the doses induced a consistent fall in blood pressure. Angiotensin-converting enzyme activity (ACE) was measured in vitro using three different synthetic substrates (i.e., Hip-Gly-Gly, Z-Phe-His-Leu, or angiotensin I). Although the degree of ACE inhibition assessed with the three methods varied widely, all methods clearly indicated dose-dependent ACE inhibition. These in vitro results were confirmed by measuring ACE inhibition in vivo using the ratio of plasma angiotensin II (ANG II) to blood angiotensin I (ANG I). The dose-dependent ACE inhibition was paralleled by a dose-dependent rise in active renin and blood angiotensin I levels, most evident on day 10. In contrast, plasma ANG II levels on day 10 were not different whether the volunteers received 0.5 or 8 mg trandolapril. Thus, whereas increasing doses of this new ACE inhibitor progressively enhanced the blockade of ACE activity, this was not reflected by additional reductions of plasma ANG II levels. The progressive enhancement of ACE inhibition seemed to be offset by the accentuation of the compensatory rise in renin and ANG I, which was still partially converted to ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reactive hyperreninemia is a major determinant of plasma angiotensin II during ACE inhibition. 168 24

1. Angiotensin converting enzyme inhibitor has been isolated from the venom of Vipera aspis aspis by gel filtration and reverse phase HPLC. 2. The purified inhibitor is a decapeptide, whose amino-terminal is blocked, with mol. wt 1044 determined by fast atom bombardment mass spectrometry. 3. The peptide inhibited the conversion of angiotensin I to angiotensin II, and Ki values were determined to be 7.54 x 10(-4) and 1.36 x 10(-4) M, respectively, using Hip-His-Leu and Hip-Gly-Gly as substrates 4. The peptide also inhibited the degradation of bradykinin, induced hypotension in spontaneously hypertensive rats and caused an increase in capillary permeability in rabbits, however, it possessed no lethality.
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PMID:Characterization of a new inhibitor for angiotensin converting enzyme from the venom of Vipera aspis aspis. 216 39

The reaction of the renin-angiotensin system to acute angiotensin converting enzyme inhibition was investigated in a single-blind, crossover study in nine normal volunteers receiving two out of three regimens in random order: the new converting enzyme inhibitor benazepril (20 mg once or 5 mg four times at 6-hour intervals) or enalapril (20 mg). Plasma converting enzyme activity, drug levels, angiotensin I and angiotensin II, active renin, and aldosterone were measured before and 1-4 hours and 14-30 hours after drug intake. Baseline in vitro plasma converting enzyme activity was 97 +/- 15 nmol/ml/min (mean +/- SD) when Hip-Gly-Gly was used as substrate, but with carbobenzoxy-Phe-His-Leu (Z-Phe-His-Leu) or angiotensin I as substrate it was only 20 +/- 4 and 1.7 +/- 0.3 nmol/ml/min, respectively. Discriminating power at peak converting enzyme inhibition was enhanced with the two latter substrates. In vivo converting enzyme activity was estimated by the plasma angiotensin II/angiotensin I ratio, which correlated well with in vitro converting enzyme activity using Z-Phe-His-Leu as substrate (r = 0.76, n = 252). Angiotensin II levels returned to baseline less than 24 hours after drug administration, whereas in vitro and in vivo converting enzyme activity remained considerably inhibited and active renin together with angiotensin I levels were still elevated. A close linear relation was found between plasma angiotensin II and the angiotensin I/drug level ratio (r = 0.91 for benazeprilat and r = 0.88 for enalaprilat, p less than 0.001). Thus, plasma angiotensin II truly reflects the resetting of the renin-angiotensin system at any degree of converting enzyme inhibition. The ratio of plasma angiotensin II to angiotensin I represents converting enzyme inhibition more accurately than in vitro assays, which vary considerably depending on substrates and assay conditions used.
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PMID:Determinants of angiotensin II generation during converting enzyme inhibition. 217 61

Incubation of various authentic peptides with rat CSF in vitro and analysis of their products by HPLC demonstrated the presence in CSF of a peptidyl dipeptidase [peptidyl dipeptide hydrolase; angiotensin I converting enzyme (ACE); kininase II; EC 3.4.15.1] which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II. This CSF enzyme was gel-chromatographed by means of HPLC, and the molecular weight was estimated. The susceptibility to various peptidase inhibitors of the rat CSF enzyme, as well as the effect of NaCl on the degradation of BK and Hip-His-Leu catalyzed by it, was also determined. These properties were compared with those of ACE or kininase II from brain or other tissues, as described in the literature. NaCl was shown to exert specific and concentration-dependent effects on each step of the sequential degradation of BK, via BK(1-7) to BK(1-5), catalyzed by the enzyme. In addition, the enzyme system for metabolism of BK appears to differ between rat CSF and blood, the former containing exclusively kininase II, whereas the latter contains both kininase I (carboxypeptidase N; EC 3.4.12.7) and kininase II.
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PMID:Some characteristics of a peptidyl dipeptidase (kininase II) from rat CSF: differential effects of NaCl on the sequential degradation steps of bradykinin. 217 62

Cilazapril is the monoethyl ester prodrug form of a potent, specific. long-acting antihypertensive inhibitor of angiotensin-converting enzyme (ACE). The biochemical and pharmacological properties of this compound have been compared with those of captopril and enalapril. In all test systems, cilazapril was the most potent and the longest acting. The active diacid of cilazapril was more potent than the corresponding diacid of enalapril in inhibiting the cleavage of angiotensin I and of Hip-His-Leu by ACE in vitro, in antagonising the angiotensin I-induced contractions of the isolated ileum of the guinea pig, in potentiating the vasodepressor responses to bradykinin, and in reducing the angiotensin I-induced rise in blood pressure of the rat. Parent drug absorption and diacid bioavailability in the rat were higher than for enalapril, and the inhibition of plasma ACE of longer duration. Single doses of cilazapril were more potent than enalapril in lowering the blood pressure of spontaneously hypertensive rats (SHR) and two-kidney renal hypertensive rats. On repeated daily oral dosing to SHR, both compounds had a cumulative antihypertensive effect. The acute antihypertensive effect was enhanced by simultaneous treatment with hydrochlorothiazide.
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PMID:Biological properties of the angiotensin-converting enzyme inhibitor cilazapril. 241 Jun 92

The most sensitive nonradiometric routine assay for angiotensin-converting enzyme (ACE) activity uses fluorometry to detect His-Leu released from Hip-His-Leu. Our results indicate that, in contrast to human serum, rat serum and plasma contain large and variable amounts of dipeptidase activity that lead to a subestimation of the ACE activity measured in 0.1 M potassium phosphate buffer, pH 8.3, containing 0.3 M NaCl, the most commonly used assay for human serum and tissue ACE. We describe and validate an assay for 1 to 10 microL rat and human serum or plasma using 5 mM Hip-His-Leu in 500 microL of 0.4 M sodium borate buffer, pH 8.3, containing 0.9 M NaC1 at 37 degrees C that reduced the subestimation error to less than or equal to 3% (rat serum) and less than or equal to 0.1% (human serum) and increased the ACE activity twofold to threefold. The Km and Vmax are reported for rat serum ACE (Hip-His-Leu) and dipeptidase (His-Leu) in borate buffer and phosphate buffer. Rat serum ACE hydrolysis of Hip-His-Leu measured by fluorometry correlated (r = 0.99, p less than 0.05) with the hydrolysis of angiotensin I measured by high-performance liquid chromatography. A direct method based on amino acid analysis is described for evaluating the dipeptidase error of complex mixtures such as tissue extracts and other physiological fluids. We have found that the assay can be used to measure ACE activity in 25 samples (in duplicate) in 2 hours with small intraassay (2.2%) and interassay (3.9%) coefficients of variation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An improved fluorometric assay of rat serum and plasma converting enzyme. 298 18

A highly sensitive assay for angiotensin I converting enzyme has been developed by using angiotensin I as a substrate. Angiotensin II generated in the reaction mixture was measured by a newly developed specific radioimmunoassay. To protect against angiotensin II destruction, bestatin, an inhibitor of renin, was also used to inhibit plasma renin activity. The reaction was stopped by adding EDTA and MK-521, inhibitors of angiotensin I converting enzyme. The specificity of the antiserum used for the angiotensin II radioimmunoassay was very high. The cross reactivity with angiotensin I was less than 0.5% and none of the proteolytic enzyme inhibitors crossreacted in the assay. The inhibitory effect of pepstatin on plasma renin activity was very high (more than 80%) under the standard assay conditions employed. Serum angiotensinase activity was completely inhibited by the addition of bestatin. An excellent correlation was obtained between this new method and the spectrophotometric method using a synthetic substrate, Hip-His-Leu. The generation of as little as 12 pM of Angiotensin II can be detected. Such low concentration have not been measurable with the usual spectrophotometric method. This new method will facilitate clinical and experimental studies on this unique enzyme, since very low levels of activity can be determined by this highly sensitive radioimmunoassay for angiotensin II.
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PMID:An improved method for measuring angiotensin I converting enzyme activity using a highly sensitive angiotensin II radioimmunoassay. 300 65

An angiotensin-converting enzyme was isolated from human heart using N[-1(S)-carboxy-5-aminopentyl]glycyl-glycine as an affinity adsorbent. The isolation procedure resulted in an enzyme purified 1650-fold. The enzyme specific activity was 38.0 u./mg protein, Mr = 150 kD. The pH optimum for the angiotensin-converting enzyme towards Hip-His-Leu lies at 7.8, Km = 1.2 mM. The enzyme was inhibited by the substrate (Ks' = 14 mM). The enzyme effectively catalyzed the hydrolysis of angiotensin I (Km = 10 microM; kcat = 250 s-1). NaCl, CaCl2 as well as Na2SO4 in the absence of Cl- activated the enzyme, whereas CH3COONa and NaNO3 did not influence the enzyme activity. It was found that the bradykinin-potentiating factor inhibited the cardiac angiotensin-converting enzyme with IC50 = 4.0 X 10(-8) M.
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PMID:[Isolation and molecular kinetic properties of the angiotensin-converting enzyme from the human heart]. 302 99


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