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)

"Enkephalinase," a membrane-bound peptidase hydrolyzing the Gly3-Phe4 amide bond of enkephalins, initially characterized in brain, was purified from a rat kidney microsomal fraction. After differential solubilization with Triton X-100, the use of DEAE-Sephadex, concanavalin A, and hydroxylapatite chromatography led to a 2000-fold purification, close to homogeneity. Renal enkephalinase appears to be a glycoprotein Mr = 92,000-95,000 with catalytic properties and sensitivity to chelating agents and inhibitors (Thiorphan, phosphoramidon) very similar to those of the cerebral enzyme. The enzyme co-purified until the final step with "renal brush-border neutral proteinase" (EC 3.4.24.11) activity assayed with 125I-insulin B chain as substrate and displaying similar sensitivity to inhibitors. The specificity of the purified enkephalinase has been studied using either peptides derived from the enkephalins or model peptides of general formula (Ala)m-Tyr-(Ala)n as substrates. In all cases the bond cleaved was that involving the amino group of an aromatic residue, specificity being also defined by the nature of the neighboring residue on the COOH-terminal side. A free carboxyl in the latter residue was essential in the two series of substrates, indicating that enkephalinase more efficiently functions as a dipeptidyl carboxypeptidase than as an endopeptidase.
 ...
PMID:Enkephalinase from rat kidney. Purification, characterization, and study of substrate specificity. 638 47

1. We investigated the role of angiotensin converting enzyme (ACE) in the cardiovascular effects of N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), a peptidase inhibitor selective for metalloendopeptidase (EP) E.C. 3.4.24.15. 2. In conscious rabbits, cFP (5 mg kg-1, i.v.) markedly slowed the degradation of [3H]-bradykinin, potentiated the depressor response to right atrial administration of bradykinin (10-1000 ng kg-1), and inhibited the pressor response to right atrial angiotensin I (10-100 ng kg-1). In each of these respects, the effects of cFP were indistinguishable from those of the ACE inhibitor, captopril (0.5 mg plus 10 mg kg-1h-1 i.v.). Furthermore, the effects of combined administration of cFP and captopril were indistinguishable from those of captopril alone. 3. In experimentally naive anaesthetized rats, cFP administration (9.3 mg kg-1, i.v.) was followed by a moderate but sustained fall in arterial pressure of 13 mmHg. However, in rats pretreated with bradykinin (50 micrograms kg-1) a more pronounced fall of 30 mmHg was observed. Captopril (5 mg kg-1) had similar hypotensive effects to those of cFP, and cFP had no effect when it was administered after captopril. 4. CFP displaced the binding of [125I]-351A (the p-hydroxybenzamidine derivative of lisinopril) from preparations of rat plasma ACE and solubilized lung membrane ACE (KD = 1.2 and 0.14 microM respectively), and inhibited rat plasma ACE activity (KI = 2.4 microM). Addition of phosphoramidon (10 microM), an inhibitor of a range of metalloendopeptidases, including neutral endopeptidase (E.C.3.4.24.11), markedly reduced the potency of cFP in these systems. 5. Taken together these findings suggest that the actions of cFP in vivo are attributable to inhibition of ACE rather than EP 24.15. Given that cFP is a poor inhibitor of ACE in the presence of phosphoramidon in vitro, it is likely that cFP is cleaved by a phosphoramidon-sensitive metallopeptidase in vivo to liberate N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala, a potent ACE inhibitor.
 ...
PMID:Role of angiotensin converting enzyme in the vascular effects of an endopeptidase 24.15 inhibitor. 762 Jul 8

Four angiotensin I-converting enzyme (EC 3.4.15.1) (ACE) inhibitory peptides C105, C107, C111, and C112 were isolated from bonito bowels. C111 was obtained from liver, while the others were from intestine. Their amino acids were sequenced as Ser-Val-Ala-Lys-Leu-Glu-Lys for C105, Ala-Leu-Pro-His-Ala for C107, Gly-Val-Tyr-Pro-His-Lys for C111, and Ile-Arg-Pro-Val-Gln for C112. Their ACE inhibition activities were measured for synthetic peptides. The IC50 of these peptides were estimated to be 82, 79, 1.6, and 1.4 microM, respectively. Carboxyl-terminal amino acid(s) were considered to be essential for their expression of ACE inhibition for C105, C107, and C111, while the amino terminal tripeptide Ile-Arg-Pro of C112 was presumed to inhibit ACE after the removal of a dipeptide from C112 with ACE digestion. Presumed original proteins of these peptides are discussed.
 ...
PMID:Isolation and characterization of angiotensin I-converting enzyme inhibitory peptides derived from bonito bowels. 776 72

Several neuropeptides, including neurotensin, somatostatin, bradykinin, angiotensin II, substance P, and luteinizing hormone-releasing hormone but not vasopressin and oxytocin, were actively metabolized through proteolytic degradation by cultivated astrocytes obtained from rat cerebral cortex. Because phenanthroline was an effective degradation inhibitor, metalloproteases were responsible for neuropeptide fragmentation. Neurotensin was cleaved by astrocytes at the Pro10-Tyr11 and Arg8-Arg9 bonds, whereas somatostatin was cleaved at the Phe6-Phe7 and Thr10-Phe11 bonds. These cleavage sites have been found previously with endopeptidases 24.16 and 24.15 purified from rat brain. Addition of specific inhibitors of these proteases, the dipeptide Pro-Ile and N-[1-(RS)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-4-aminobenzoate, significantly reduced the generation of the above neuropeptide fragments by astrocytes. The presence of endopeptidases 24.16 and 24.15 in homogenates of astrocytes could also be demonstrated by chromatographic separations of supernatant solubilized cell preparations. Proteolytic activity for neurotensin eluted after both gel and hydroxyapatite chromatography at the same positions as found for purified endopeptidase 24.16 or 24.15. In incubation experiments or in chromatographic separations no phosphoramidon-sensitive endopeptidase 24.11 (enkephalinase) or captopril-sensitive peptidyl dipeptidase A (angiotensin-converting enzyme) could be detected in cultivated astrocytes. Because astrocytes embrace the neuronal synapses where neuropeptides are released, we presume that the endopeptidases 24.16 and 24.15 on astrocytes are strategically located to contribute significantly to the inactivation of neurotensin, somatostatin, and other neuropeptides in the brain.
 ...
PMID:Endopeptidases 24.16 and 24.15 are responsible for the degradation of somatostatin, neurotensin, and other neuropeptides by cultivated rat cortical astrocytes. 790 52

As part of a search for potent and long-lasting angiotensin converting enzyme (ACE) inhibitors, various types of N-[(1S)-1-carboxy-5-(4-piperidyl)pentyl]-L-alanine derivatives (7a, 8-11) were prepared. The key synthetic intermediate, N-[(1S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1- ethoxycarbonylpentyl]-L-alanine (17a), was synthesized by asymmetric reduction of the alpha-oxoester (13) with Lactobacillus paracasei subsp. paracasei followed by a substitution reaction with tert-butyl L-alaninate (15) and subsequent treatment with hydrogen chloride. Compounds 7a and 8-11 showed potent and long-lasting ACE-inhibitory activity in rats.
 ...
PMID:Synthesis and angiotensin converting enzyme-inhibitory activity of N-[(1S)-1-carboxy-5-(4-piperidyl)pentyl]-L-alanine derivatives. 800 3

A novel fluorogenic peptide, dansyl-Gly-(p-NO2) Phe-beta Ala (DGNPA), was synthesized as a selective substrate for neutral endopeptidase 24.11, an enzyme involved in enkephalin and atrial natriuretic peptide degradation and a marker of differentiation (CD10) on the surface of lymphohematopoietic cells. Cleavage of the substrate Gly-(p-NO2)Phe amide bond leads to an increase in fluorescence related to the disappearance of the intramolecular quenching of the dansyl fluorescence by the nitrophenyl residue. This new fluorogenic substrate is an improvement over the commercially available dansyl-D-Ala-Gly-(p-NO2)Phe-Gly, as the Gly4 residue of the latter has been replaced by a beta-alanine, therefore eliminating a residual sensitivity of the peptide toward angiotensin converting enzyme. Moreover, deletion of the D-Ala2 residue was shown to increase the quenching efficiency, thus raising the sensitivity of the assay, which was further improved by stopping the reaction with dioxane. The present substrate has improved affinity (Km = 37 microM, V = 0.72 mumol min-1 mg protein-1), selectivity, and sensitivity over its precursor and was used in automated assays using 96-well microplates and a fluorescence plate reader.
 ...
PMID:Dns-Gly-(p-NO2)Phe-beta Ala, a specific fluorogenic substrate for neutral endopeptidase 24.11. 805 59

A series of trifluoromethyl-containing analogs of captopril as well as analogs and homologs of enalaprilat were synthesized and evaluated for inhibition of angiotensin converting enzyme (ACE). It was found that direct substitution of trifluoromethyl for methyl produced a very potent captopril analog with an IC50 of 3 x 10(-10) M in vitro. Hydrophobicity and conformational effects of trifluoromethyl group are among the reasons accounting for this activity. Structure-activity relationship is studied based on molecular mechanics calculations using a II-SCF-molecular mechanics program (PIMM) as well as SYBYL molecular mechanics program. It was found that simultaneous incorporation of trifluoromethyl and an indoline residue unexpectedly yielded a less potent captopril analog (IC50 = 8 x 10(-8) M). Enalaprilat analogs derived from replacement of the alanine residue with trifluoronorvaline and trifluoronorleucine residues gave moderately potent compounds (IC50 = 2-6 x 10(-8) M). The structure-activity relationship for these fluoroenalaprilat analogs is discussed in comparison with known analogs.
 ...
PMID:Design, synthesis and enzyme inhibitory activities of new trifluoromethyl-containing inhibitors for angiotensin converting enzyme. 807 3

N-[1(R,S)-Carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate (cFP-AAF-pAB) is a potent, substrate-related, specific inhibitor of endopeptidase 24.15, an enzyme involved in the metabolism of bioactive peptides including bradykinin, neurotensin, and proenkephalin, and prodynorphin-derived enkephalin precursors. The observation that this inhibitor causes a pronounced decrease in blood pressure after intravenous infusion into normotensive rats posed the question of the mechanism of this hypotensive response. It was suggested previously that cFP-AAF-pAB is an inhibitor of angiotensin converting enzyme (ACE) and that this function can account for the hypotensive response to the inhibitor. We present here evidence that cFP-AAF-pAB has no intrinsic ACE-inhibitory activity. The previously observed inhibition is shown to be dependent on cleavage of the Ala-Phe bond in the inhibitor by endopeptidase 24.11 (enkephalinase, EC 3.4.24.11), a contaminant of some ACE preparations.
 ...
PMID:Evidence that enzymatic conversion of N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate, a specific inhibitor of endopeptidase 24.15, to N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala is necessary for inhibition of angiotensin converting enzyme. 813 8

Guinea pig serum angiotensin converting enzyme (ACE) activities exceed ACE activities of other mammalian sera by as much as two magnitudes. To examine the possibility that guinea pig ACE has a superior catalytic efficiency, we purified it to apparent homogeneity and compared it to highly purified forms of ACE from human seminal plasma, rat lungs and rabbit lungs. The first 24 amino acid residues of guinea pig and rat ACE forms were 96% identical with the sequence of human ACE. Second order rate constants (kcat/Km) for guinea pig, human and rabbit forms of ACE on reaction with benzoyl-Phe-Ala-Pro were identical (1.6E-09 M-1 min-1). Their dissociation constants on reaction with the ACE inhibitor RAC-X-65 were within a narrow range (10-16 pM). Thus, the high ACE activity of guinea pig serum is owing to high enzyme concentration and not to superior catalytic efficiency.
 ...
PMID:A comparison of guinea pig serum angiotensin converting enzyme with forms of angiotensin converting enzyme from human, rat and rabbit tissues. 824 Mar 21

N-[1-(R,S)-carboxyl-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate (cFP-AAF-pAB), an active-site-directed inhibitor of metalloendopeptidase-24.15, has been shown to lower blood pressure, increase cardiac output and renal blood flow, and potentiate the intravenous bradykinin-induced vasodepressor response. Because in vivo cFP-AAF-pAB can be converted to N-[1-(R,S)-carboxyl-3-phenylpropyl]-Ala-Ala (a compound with angiotensin converting enzyme inhibitory activity) by metalloendopeptidase-24.11, it is possible that some of its effects are due to angiotensin converting enzyme inhibition. In the present study, we questioned (1) whether cFP-AAF-pAB inhibits angiotensin converting enzyme in vivo and (2) whether cFP-AAF-pAB has renal effects that are independent of its conversion to an angiotensin converting enzyme inhibitor. cFP-AAF-pAB alone (3 mumol in 300 microL per rat) almost abolished the blood pressure response to angiotensin I, suggesting that in vivo it inhibits angiotensin converting enzyme. In rats pretreated with a high dose of enalaprilat (1 mg/kg), cFP-AAF-pAB had no further effect on blood pressure, renal blood flow, or potentiation of the vasodepressor response to bradykinin but still increased glomerular filtration rate by 44 +/- 9% (P < .01); urine volume increased by 118 +/- 10% (P < .001), urinary sodium excretion by 230 +/- 31% (P < .001), urinary potassium excretion by 68 +/- 14% (P < .01), and urinary cyclic GMP by 55 +/- 18% (P < .01). All of these changes were significant compared with enalaprilat/vehicle-treated rats. Fractional excretion of sodium and potassium did not differ from controls.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Effects of a metalloendopeptidase-24.15. Inhibitor on renal hemodynamics and function in rats. 828 66


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>