Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The parent diacid (N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro of MK-421 inhibited hog plasma angiotensin converting enzyme (ACE) by 50% (I50) at a concentration of 1.2 nM and was 17 times more potent than captopril. In vitro the I50 for MK-421, an ethyl ester, was 1200 nM because de-esterification did not occur. Similarly in the guinea-pig ileum, the diacid inhibitor and MK-421 potentiated the contractile effects of bradykinin at an AC50 of 77 pM and 18 nM, respectively. Inhibition of the pressor effects of angiotensin I by the diacid ACE inhibitor occurred at an ID50 of 8.2 micrograms/kg i.v. in rats and 6.4 micrograms/kg i.v. in dogs. Thus, the diacid was approximately 12 times more potent than captopril. The ID50 for MK-421 was 14 and 278 micrograms/kg i.v. in rats and dogs, respectively, because of differences in the rates of de-esterification. Oral ACE inhibitory activity was determined by blockade of the pressor effects of angiotensin I in conscious rats and dogs. In rats, but not in dogs, the diacid inhibitor was poorly absorbed, whereas MK-421 was well absorbed in both species. MK-421 inhibited the pressor effects of angiotensin I at 0.1 to 3.0 mg/kg p.o. for at least 6 hr in rats and dogs, and compared to captopril was 8.6 times more potent in rats and 4.6 times more potent in dogs. These data demonstrate that MK-421 and its parent diacid are potent, long-lasting orally active inhibitors of ACE. In addition, the low activity of MK-421 in vitro contrasts with its substantial in vivo activity, and supports the hypothesis that MK-421 is a prodrug that first must be de-esterified to permit full expression of its significant in vivo pharmacological activity.
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PMID:Effect of N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro and its ethyl ester (MK-421) on angiotensin converting enzyme in vitro and angiotensin I pressor responses in vivo. 625 22

1. A thiol proteinase from human pituitaries was purified approximately 400 fold and shown to have different chromatographic properties from that of calf brain. Among substrates cleaved were myelin basic protein, histones, beta-lipotropin, neurophysin, and Substance P. 2. The enzyme showed properties associated with a cathepsin-B like enzyme: dependence on -SH groups, pH optimum of 6.5, inhibition by leupeptin and a synthetic analog, Boc-D-Phe-Pro-arginal, and cleavage of dipeptidyl arylamides with basic residues adjacent to or penultimate to the chromatographic grouping. 3. Membranes present in the P2 fraction of rat brain contained three or more enkephalinases when submitted to DEAE-cellulose chromatography. Further purification on an IgG-Sepharose affinity column prepared with antibody to lung angiotensin converting enzyme indicated the presence of dipeptidyl carboxypeptidase(s) with properties distinct from those of ACE. In addition, the DEAE-cellulose fractions contained various aminopeptidase activities when tested with Leu-Gly-Gly, Leu-Nap, and Ala-Ala-Nap as substrates.
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PMID:Peptide processing in the central nervous system. 625 8

The degradation of des-Arg9-brady kinin and its analogues by highly purified preparations of hog lung and kidney kininase II (angiotensin-converting enzyme; peptidyldipeptide hydrolase, EC 3.4.15.1) was studied. The degradative peptides fragments were separated and isolated by high performance liquid chromatography and identified by amino acid analysis. Both enzymes released C-terminal tripeptides from des-Arg9-bradykinin, des-Arg9-(Leu8)-bradykinin, Pro-Pro-Gly-Phe-Ser-Pro-Phe, Pro-Gly-Phe-Ser-Pro-Phe, Gly-Phe-Ser-Pro-Phe, Bz-Gly-Ser-pro-Phe and Bz-Gly-Ala-Pro-Phe. Hydrolysis of Phe-Ser-Pro-Phe, Bz-Gly-His-Pro-Phe, Bz-Gly-Phe-Pro-Phe and Bz-Gly-Gly-Pro-Phe by both enzymes was negligible. These data indicate that kininase II can release C-terminal tripeptides of substrates having a proline residue in the penultimate position such as des-Arg9-bradykinin and its analogues, and that this enzyme is able not only to act as a dipeptidyl carboxypeptidase but also acts as a tripeptidyl carboxy-peptidase. The tripeptidyl carboxypeptidase enzyme was sensitive to inhibition by kininase II inhibitors.
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PMID:Tripeptidyl carboxypeptidase activity of kininase II (angiotensin-converting enzyme). 627 13

1 The effect of the angiotensin converting enzyme inhibitor, MK 421 (N-((S)-1-(ethoxycarbonyl)-3-phenylpropyl)L-Ala-L-Pro), on the blood pressure of two-kidney Goldblatt hypertensive rats has been investigated in relation to he initial plasma renin activity (PRA) and the initial blood pressure of the individual animals. 2 Blood pressure was monitored by an indirect tail-cuff method at 1, 3, 6 and 24 h after dosing. MK 421 produced a fall in blood pressure in the majority of animals, but the extent of this reduction varied considerably between individuals. 3 The change in blood pressure showed a significant correlation with both the initial PRA and the initial blood pressures of the animals. However, only a modest correlation was found between the initial PRA and the degree of hypertension. 4 MK 421 (10 mg/kg, orally) produced a mean blood pressure change which was statistically significant (P less than 0.001) at all times tested. 5 It is concluded that the degree of antihypertensive activity of MK 421 is related to the degree of activity of the renin-angiotensin system which, in this model at least, is reflected by the PRA.
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PMID:Relation of plasma renin activity to the antihypertensive effect of MK 421 in the rat. 628 72

N alpha-Phosphoryl-L-alanyl-L-proline is a reversible competitive inhibitor of angiotensin converting enzyme with a Ki of 1.4 nM. Alkylation of one phosphate oxygen with methyl, ethyl, or benzyl does not change the Ki. The high activity of the O-alkylated inhibitors demonstrates that the two phosphate oxygen anions do not constitute a bidentate ligand of the active site zinc ion. Substitution of valyltryptophan, glycylglycine, or delta-aminovaleric acid for alanylproline in the phosphoramidate raises the Ki to 12 nM, 25 microM, and 178 microM, respectively. Methylation of the alanine nitrogen in phosphorylalanylproline raises the Ki to 29 microM. Polyphosphates inhibit converting enzyme with the following Ki's: phosphate, approximately 300 mM; pyrophosphate, 2 mM; tripolyphosphate, 18 microM; tetrapolyphosphate, 150 microM. The inhibition by tripolyphosphate appears to be competitive and is unaffected by the addition of excess zinc ion. Since the Ki of tripolyphosphate is nearly 10-fold lower than that of N-phosphoryl-delta-aminovaleric acid and is near that of N alpha-phosphorylglycylglycine, its terminal phosphates may bind the zinc site and the cationic site on the enzyme, thus spanning the S1' and S2' sites.
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PMID:Inhibition of angiotensin converting enzyme by phosphoramidates and polyphosphates. 629 38

Anion activation of pulmonary angiotensin converting enzyme has been examined by using 23 furanacryloyl- and 3 benzoyl-tripeptides as substrates. Chloride stimulates hydrolysis of all substrates at least 24-fold. However, the kinetic mechanism, the amount of chloride required, and the effect of pH on activation, plus the relative activating potencies of various anions, are all strongly dependent on the substrate employed. Three substrate classes have been identified. Class I substrates appear to be hydrolyzed at pH 7.5 by an ordered bireactant mechanism in which anion must bind before substrate. The apparent activation constant (KA') for Cl- ranges from 75 to 150 mM at pH 7.5, doubles at pH 9.0, and decreases to about 3 mM at pH 6.0. Class II substrates, in contrast, are hydrolyzed by a nonessential activator mechanism. The kinetically determined KA' for Cl- at pH 7.5 ranges from 2.9 to 5.0 mM and changes only slightly with pH. Class III substrates are also hydrolyzed by a nonessential kinetic mechanism but one different from that followed by class II peptides. KA' values for Cl- at pH 7.5 measured with class III substrates are 18-30 mM. Class II substrates have Arg or Lys at the ultimate or penultimate position. The features distinguishing class I and III peptides are less clear, although all class III substrates identified have penultimate alanine residues. Possible explanations for this substrate dependence are offered.
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PMID:Anion activation of angiotensin converting enzyme: dependence on nature of substrate. 631 Dec 53

The compounds N-[1 (S)-carboxy-5-amino-pentyl]-L-phenylalanylglycine and N-[1 (S)-carboxy-5-aminopentyl]-DL-alanyl-L-proline were synthesized and explored as potential ligands for the affinity chromatography of angiotensin converting enzyme (dipeptidyl carboxypeptidase, EC 3.4.15.1) (ACE), a membrane-bound zinc metalloprotease. The N-alkylated Ala-Pro derivative has an apparent Ki less than 1 nM (at pH 7.5, 0.50 M NaCl) while the Phe-Gly derivative is a much less potent competitive inhibitor with an apparent Ki = 0.20 microM under the same conditions and thus more suitable for use as an affinity ligand. Immobilization of these compounds via a 28-A spacer to agarose yields resins with binding capacities of greater than 7 mg of enzyme/mL of resin, while spacers of 22 A or less result in binding capacities at least 350 times smaller. Immobilized N-[1 (S)-carboxy-5-amino-pentyl]-L-Phe-Gly is superior to the Ala-Pro derivative because elution can be affected by raising the pH to 8.9 with 98% yields compared with only 20% from the latter. Thus, a three-step process involving detergent extraction, concentration by ammonium sulfate precipitation, and affinity chromatography on the resin-immobilized Phe-Gly derivative provides 30 mg of homogeneous ACE from 640 g of rabbit lung tissue. An ACE-like metalloprotease has also been isolated from testicular tissue by this same technique.
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PMID:Affinity chromatographic purification of angiotensin converting enzyme. 632 55

Mutants of Salmonella typhimurium deficient in dipeptidyl carboxypeptidase have been isolated by screening for clones unable to use N-acetyl-L-alanyl-L-alanyl-L-alanine (AcAla3) as the sole nitrogen source. An insertion of the transposable element Tn10 near dcp (the locus coding for dipeptidyl carboxypeptidase) has been isolated and used to map the locus in the interval between purB and trp, an otherwise genetically silent region of the S. typhimurium map. All dcp mutants could still grow using N-acetyl-L-alanyl-L-alanyl-L-alanyl-L-alanine (AcAla4) as the sole nitrogen source. Crude extracts from the dcp mutants failed to hydrolyze AcAla3 but retained approximately 80% of the wild-type activity toward AcAla4. Several lines of evidence indicate that hydrolysis of AcAla4 in the dcp mutant results from the action of a new peptidase distinct from dipeptidyl carboxypeptidase. A mutant strain lacking dipeptidyl carboxypeptidase in addition to peptidases N, A, B, and D showed reduced protein breakdown during carbon starvation compared with a strain lacking only peptidases N, A, B, and D.
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PMID:Dipeptidyl carboxypeptidase-deficient mutants of Salmonella typhimurium. 633 91

An oligopeptidase that hydrolyzes N-acetyl-L-alanyl-L-alanyl-L-alanyl-L-alanine (AcAla4) has been identified in extracts of Salmonella typhimurium. Mutants lacking this activity have been isolated in dcp mutant strains by screening extracts of mutagenized clones for failure to hydrolyze AcAla4 or by screening colonies for inability to use AcAla4 as a nitrogen source. Double mutants (dcp optA) lacking both oligopeptidase A and dipeptidyl carboxypeptidase cannot use AcAla4 as a nitrogen source, although dcp+ optA and dcp optA+ strains grow on this peptide. The mutations responsible for the loss of activity map at a locus (optA) between asd (75 map units) and xylA (78 map units). Oligopeptidase A hydrolyzes certain N-blocked tetrapeptides, unblocked pentapeptides, and unblocked hexapeptides, usually but not always liberating the C-terminal tripeptide. These two activities seem to be responsible for the production of a large fraction of the dipeptides that accumulate during protein breakdown in a pepN pepA pepB pepD strain.
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PMID:Oligopeptidase-deficient mutants of Salmonella typhimurium. 633 92

A thermolysin-like metalloendopeptidase, optimally active at a neutral pH, was identified in human serum. The enzyme cleaves the synthetic substrate glutaryl-Ala-Ala-Phe-2-naphthylamide at the Ala-Phe bond. Activity was determined by measuring the rate of formation of Phe-2-naphthylamide in a coupled enzyme assay in the presence of excess aminopeptidase M. 2-Naphthylamine released during the reaction was determined by a diazotization procedure. Enzyme activity is not affected by inhibitors of serine, thiol, or carboxyl proteases, but is sensitive to inhibition by metal chelators such as EDTA and o-phenanthroline. Dialysis against EDTA leads to loss of activity, which can be fully restored by zinc and cobalt ions. The serum enzyme closely resembles a membrane-bound metalloendopeptidase (EC 3.4.24.11) abundant in lung, spleen, and kidney in that both enzymes are inhibited by the same active-site-directed inhibitors. In addition, an antiserum obtained against the metalloendopeptidase from rabbit kidney shows strong cross-reactivity with the serum enzyme. Metalloendopeptidase activity was measured in 150 controls and in 95 patients with sarcoidosis; the two groups had significantly different enzyme activities (p less than 0.001). The mean enzyme activity in the sarcoidosis group was more than threefold higher than that of the control group. The mean enzyme activity for patients with active disease was more than double that of patients with inactive disease and more than four times that of controls (p less than 0.001). This is noteworthy because angiotensin converting enzyme, a zinc-dipeptidyl carboxypeptidase with a mechanism of action similar to that of the metalloendopeptidase, has also been reported to be increased in the serum of patients with active sarcoidosis. Enzyme activity in patients with active tuberculosis, primary pulmonary neoplasms, and idiopathic interstitial pulmonary fibrosis did not differ significantly from that of controls.
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PMID:Identification of a thermolysin-like metalloendopeptidase in serum: activity in normal subjects and in patients with sarcoidosis. 636 93


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