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

Pulmonary endothelial aminopeptidase P (AmP) may be an important contributor to the inactivation of circulating bradykinin in certain species. To examine this possibility, we measured AMP activity in vivo and in vitro using Arg-Pro-Pro-[3H]benzylamide (3H-APPB) as substrate under conditions of first order enzyme kinetics. Utilizing multiple indicator dilution techniques, metabolism of 3H-APPB to Arg and Pro-Pro-[3H]benzylamide by AmP was not detectable during a single transpulmonary passage in anesthetized rabbits (n = 4), cats (n = 3) and pigs (n = 4). However, percent metabolism of 3H-APPB ranged from 54 to 63% in anesthetized rats (n = 6). In all experiments, the substrate remained within the vascular space and was thus accessible to endothelial and blood AmP only. At the same time, single-pass transpulmonary percent metabolism of [14C]benzoyl-Ala-Gly-Pro by endothelial-bound angiotensin converting enzyme was remarkably similar among rabbits, cats, rats and pigs (60-65%). In culture, Vmax/Km of AmP was 3 to 10 x 10(-4) min-1 for human basal arterial and rabbit and bovine pulmonary arterial endothelial cell monolayers (2 x 10(5) cells). AmP activity in the supernatant of lung and kidney tissue (homogenized in saline containing 1-o-n-octyl-beta-glucopyranoside) from rabbit, cat, pig and rat expressed as Vmax/Km(min-1) per (g wet tissue/ml) was 0.74, 2.25, 3.91 and 185.8 (lung), and 1.0, 3.7, 8.4 and 438.3 (kidney), respectively. Similarly, Vmax/Km values of AmP in plasmas of cat, dog, rabbit, pig, calf (serum), human and rat were 0, 0.016, 0.025, 0.068, 0.191, 0.237 and 3.53 min-1. These results suggest that 1) there are large interspecies variations in AmP activities of plasma, lung and kidney; 2) of the species studied, the rat contains the largest activities of AmP; and 3) AmP appears to be located on the luminal surface of the rat pulmonary endothelium.
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PMID:Species variation in pulmonary endothelial aminopeptidase P activity. 176 77

Captopril ((2S)-1-(3-mercapto-2-methyl-propionyl)-L-proline) inhibited the bifunctional, Zn(2+)-containing enzyme leukotriene A4 hydrolase/aminopeptidase reversibly and competitively with Ki = 6.0 microM for leukotriene B4 formation and Ki = 60 nM for L-lysine-p-nitroanilide hydrolysis at pH 8. Inhibition was independent of pH between pH 7 and 8, the optimum range for each catalytic activity. Half-maximal inhibition of leukotriene B4 formation by intact erythrocytes and neutrophils required 50 and 88 microM captopril, respectively. In neutrophils and platelets neither 5(S)-hydroxyeicosatetraenoic acid, 12(S)-hydroxyeicosatetraenoic acid, nor leukotriene C4 formation were reduced, indicating selective inhibition of leukotriene A4 hydrolase/aminopeptidase, not 5-lipoxygenase, 12-lipoxygenase, or leukotriene C4 synthase. In whole blood, captopril inhibited leukotriene B4 formation with an accompanying redistribution of substrate toward formation of cysteinyl leukotrienes. The decrease in leukotriene B4 was more substantial than the corresponding increase in cysteinyl leukotrienes suggesting that nonenzymatic hydration predominates over transcellular metabolism of leukotriene A4 by platelets during selective inhibition of leukotriene A4 hydrolase. Enalapril dicarboxylic acid and Glu-Trp-Pro-Arg-ProGln-Ile-Pro-Pro which inhibit angiotensin-converting enzyme: angiotensin I, bradykinin, and N-[3-(2-furyl)acryloyl]Phe-Gly-Gly which are substrates; and chloride ions which activate angiotensin-converting enzyme did not modulate leukotriene A4 hydrolase/aminopeptidase activity. The results indicate that: (i) the sulfhydryl group of captopril is an important determinant for inhibition of leukotriene A4 hydrolase/aminopeptidase, probably by binding to an active site Zn2+; (ii) aminopeptidase and leukotriene A4 hydrolase display differential susceptibility to inhibition; (iii) there is minimal functional similarity between angiotensin-converting enzyme (peptidyl dipeptidase) and leukotriene A4 hydrolase/aminopeptidase; (iv) captopril may be a useful prototype to identify more potent and selective leukotriene A4 hydrolase inhibitors.
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PMID:Inhibition of leukotriene A4 hydrolase/aminopeptidase by captopril. 188 82

We examined the relative contribution of renin-angiotensin system blockade and bradykinin potentiation to the renal hemodynamic effect of the angiotensin converting enzyme inhibitor enalaprilat in sodium-deprived dogs. Six conscious dogs instrumented for monitoring of blood pressure (BP) and renal blood flow (RBF) were employed in five groups of experiments. In group 1, enalaprilat alone was administered, and it decreased BP by -24 +/- 3 mm Hg and increased RBF by 135 +/- 15 ml/min. During a constant intravenous infusion of saralasin (group 2), enalaprilat decreased BP by -7 +/- 3 mm Hg and increased RBF by 84 +/- 7 ml/min (delta BP and delta RBF, p less than 0.01 vs. group 1 by analysis of variance). During a constant intrarenal arterial infusion of saralasin (group 3), the respective changes in BP and RBF after enalaprilat were -10 +/- 3 mm Hg and 69 +/- 12 ml/min, and these results did not differ from those of group 2. The infusion of saralasin intravenously or intrarenal arterially decreased BP slightly and increased RBF. In the presence of an intravenous infusion of a specific bradykinin antagonist, D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg.TFA (B5630) (group 4), enalaprilat decreased BP by -28 +/- 4 mm Hg and increased RBF by 82 +/- 24 ml/min (delta RBF, p less than 0.01 vs. group 1).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bradykinin contribution to renal blood flow effect of angiotensin converting enzyme inhibitor in the conscious sodium-restricted dog. 215 61

The angiotensin I-converting enzyme (peptidyl-dipeptide hydrolase, EC 3.4.15.1) inhibitor, ramiprilat (2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-Ala]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid), is shown to exist in tow conformational isomers, cis and trans, which interconvert around the amide bond. The two conformers were separated by reversed-phase high-performance liquid chromatography. The conformers were identified by nuclear Overhauser effect measurements. From line shape analysis the isomerization rate constants were determined to be kcis----trans = 15 s-1 and ktrans----cis = 5 s-1 at 368 K in [2H]phosphate buffer (p2H 7.5). By enzyme kinetic studies using 3-(2-furylacryloyl)-L-Phe-Gly-Gly as substrate, the trans conformer was found to be the most potent enzyme inhibitor, whereas the cis conformer had a very low inhibitory effect. A new inhibition mechanism is presented for this type of slow, tight-binding inhibitors that contain an amide bond. This mechanism involves an equilibrium between the two conformers and the enzyme-bound inhibitor complex.
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PMID:Cis-trans isomerization of an angiotensin I-converting enzyme inhibitor. An enzyme kinetic and nuclear magnetic resonance study. 217 61

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

The interaction of angiotensin converting enzyme (ACE) with ramiprilat was studied at pH 7.5 in the presence of 300 mmol/l sodium chloride with furanacryloyl-Phe-Gly-Gly as substrate. Ramiprilat inhibits ACE with a Ki value of 7 pmol/l. It is both a slow- and tight-binding inhibitor; the mode of inhibition is fully competitive. Binding of ramiprilat to ACE proceeds by a two-step mechanism E + I in equilibrium EI in equilibrium EI* in which the inhibitor rapidly binds to enzyme to form an initial enzyme-inhibitor complex, which then undergoes a slow isomerization. The interaction of ramiprilat with ACE is compared to that of two other potent inhibitors, captopril and enalaprilat.
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PMID:Kinetic properties of the angiotensin converting enzyme inhibitor ramiprilat. 248 60

Taking advantage of the recently demonstrated identity of common acute lymphoblastic leukemia antigen (CALLA) and neutral endopeptidase EC.24.11 (NEP) the presence of this ectoenzyme on lymphoid cells has been reassessed using highly sensitive assays (cleavage of [3H]-D-Ala2-leucine-enkephalin and binding of the inhibitor [3H]HACBO-Gly. NEP activity was found not only on already classified CALLA + ve cells but also on numerous cells (including mature B and polyclonal T cells) previously considered as CALLA-ve. This suggests that CALLA/NEP is expressed all along the differentiation pathway in B and T cell lineage. Moreover substantial ACE-like activity was also detected in three tested cells, all of the pre-B phenotype. The availability of specific inhibitors for these enzymes should help clarify their role in cell-differentiation.
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PMID:Neutral endopeptidase 24.11 and angiotensin converting enzyme like activity in CALLA positive and CALLA negative lymphoid cells. 254 97

Angiotensin-converting enzyme (ACE; EC 3.4.15.1) is a zinc-containing dipeptidyl carboxypeptidase widely distributed in mammalian tissues and is thought to play a critical role in blood pressure regulation. Testis contains a unique, androgen-dependent ACE isozyme of unknown function. We have determined the cDNA sequence for human testicular ACE; it encodes a protein that is identical, from residue 37 to its C terminus, to the second half or C-terminal domain of the endothelial ACE sequence [Soubrier, F., Alhenc-Gelas, F., Hubert, C., Allegrini, J., John, M., Tregear, G. & Corvol, P. (1988) Proc. Natl. Acad. Sci. USA 85, 9386-9390]. The full-length human testis ACE cDNA was constructed from a composite of cloned cDNAs, obtained by a combination of (i) immunoscreening and hybridization screening of a human testicular cDNA library in lambda gt11 and (ii) hybridization screening of human testis cDNAs constructed with ACE-specific primers and amplified by the polymerase chain reaction. The protein sequence inferred consists of a 732-residue preprotein including a 31-residue signal peptide. The mature polypeptide has a molecular weight of 80,073. The testis enzyme contains the second of the two putative metal-binding sites (His-Glu-Met-Gly-His) identified in endothelial ACE. This indicates that the functionally active catalytic site is within the C-terminal domain of the endothelial enzyme, accounting for the previous finding that these two structurally dissimilar isozymes are virtually identical catalytically. Of 22 testis ACE cDNAs cloned and sequenced, 3 have unique 5' regions, consisting of inserted, deleted, or substituted sequences up to 328 base pairs long, which have apparently arisen by alternative pre-mRNA splicing.
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PMID:Molecular cloning of human testicular angiotensin-converting enzyme: the testis isozyme is identical to the C-terminal half of endothelial angiotensin-converting enzyme. 255 86

ACE (angiotensin-converting enzyme; peptidyl dipeptidase A; EC 3.4.15.1), cleaves C-terminal dipeptides from active peptides containing a free C-terminus. We investigated the hydrolysis of cholecystokinin-8 [CCK-8; Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] and of various gastrin analogues by purified rabbit lung ACE. Although these peptides are amidated at their C-terminal end, they were metabolized by ACE to several peptide fragments. These fragments were analysed by h.p.l.c., isolated and identified by comparison with synthetic fragments, and by amino acid analysis. The initial and major site of hydrolysis was the penultimate peptide bond, which generated a major product, the C-terminal amidated dipeptide Asp-Phe-NH2. As a secondary cleavage, ACE subsequently released di- or tri-peptides from the C-terminal end of the remaining N-terminal fragments. The cleavage of CCK-8 and gastrin analogues was inhibited by ACE inhibitors (Captopril and EDTA), but not by other enzyme inhibitors (phosphoramidon, thiorphan, bestatin etc.). Hydrolysis of [Leu15]gastrin-(14-17)-peptide [Boc (t-butoxycarbonyl)-Trp-Leu-Asp-Phe-NH2] in the presence of ACE was found to be dependent on the chloride-ion concentration. Km values for the hydrolysis of CCK-8, [Leu15]gastrin-(11-17)-peptide and Boc-[Leu15]gastrin-(14-17)-peptide at an NaCl concentration of 300 mM were respectively 115, 420 and 3280 microM, and the catalytic constants were about 33, 115 and 885 min-1. The kcat/Km for the reactions at 37 degrees C was approx. 0.28 microM-1.min-1, which is approx. 35 times less than that reported for the cleavage of angiotensin I. These results suggest that ACE might be involved in the metabolism in vivo of CCK and gastrin short fragments.
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PMID:Novel activity of angiotensin-converting enzyme. Hydrolysis of cholecystokinin and gastrin analogues with release of the amidated C-terminal dipeptide. 255 81

The intestinal absorption mechanism of two nonsulfhydril lysyl-proline angiotensin converting enzyme (ACE) inhibitors, lisinopril (1) and SQ 29,852 (2; [(S)-1-[6-amino-2-[[hydroxy (4-phenylbutyl)-phosphinyl]oxy[-1-oxohexyl]-L-proline) were investigated in rats using a single-pass perfusion method. Compound 2 is well absorbed from rat jejunum, whereas lisinopril absorption is relatively low. The permeability of both ACE inhibitors is concentration dependent and is decreased by the dipeptide Tyr-Gly and by cephradine, indicating a nonpassive absorption mechanism via the peptide carrier-mediated transport system. Compound 2 is well absorbed by a nonpassive mechanism, in parallel with a small passive component. The estimated dimensionless carrier parameters for 2 are J*max = 0.16, Km = 0.08 mM, P*c = 2.0, and P*m = 0.25; for lisinopril, passive absorption is not significant and its absorption is nonpassive: J*max = 0.032, Km = 0.082 mM, and P*c = 0.39 (where J*max is the maximal flux, Km is the Michaelis constant, P*c is the carrier permeability, and P*m is the passive permeability). These results offer a mechanistic explanation for the prolonged ACE inhibition and the low oral bioavailability of lisinopril, and for the nonlinear pharmacokinetics of 2.
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PMID:Intestinal absorption mechanism of dipeptide angiotensin converting enzyme inhibitors of the lysyl-proline type: lisinopril and SQ 29,852. 255 91


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