Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Bradykinin (BK) instilled directly into the airway lumen caused bronchoconstriction in anaesthetized, mechanically ventilated guinea-pigs in the presence of propranolol (1 mg kg-1 i.v.). The geometric mean dose of BK required to produce 100% increase in airway opening pressure (PD100) was 22.9 nmol (95% c.i. 11.7-44.6 nmol). 2. The dose-response curve for the effect of instilled BK was significantly shifted to the left by the angiotensin converting enzyme (ACE) inhibitor, captopril (5 and 50 nmol instillation, PD100 = 3.0, 95% c.i. 0.98-8.9, and 2.0 nmol, 95% c.i. 0.65-6.2 nmol, respectively). 3. The neutral endopeptidase (NEP) inhibitor, phosphoramidon (5 and 50 nmol instillation) also shifted the dose-response curve for the effect of instilled BK; the PD100 values = 2.2 (95% c.i. 0.40-11.7) and 1.8 nmol (95% c.i. 0.87-3.5 nmol), respectively. 4. After pretreatment with captopril (50 nmol) and phosphoramidon (50 nmol) in combination, the dose-response curve for the effect of instilled BK (PD100 = 1.1 nmol, 95% c.i. 0.37-3.2 nmol) was similar to that obtained in the presence of each inhibitor used alone. 5. The kinase I inhibitor, DL-2-mercaptomethyl-3-guanidinoethylthiopropionic acid (50 nmol instillation) failed to alter the dose-response curve to instilled BK (PD100 = 14.6 nmol, 95% c.i. 6.7-32.0 nmol). 6. These data suggest that both ACE and NEP degrade BK in the airway lumen, but that kininase I is not involved.
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PMID:The effect of peptidase inhibitors on bradykinin-induced bronchoconstriction in guinea-pigs in vivo. 228 70

Carboxypeptidase M, a plasma membrane-bound enzyme, is present in many human organs and differs from other carboxypeptidase that cleave basic COOH-terminal amino acids. Cultured Madin-Darby canine kidney (MDCK) distal tubular cells contain a kininase I-type enzyme that inactivates bradykinin by releasing Arg9. We found the properties of this kininase to be identical with carboxypeptidase M. In fractionated cells, carboxypeptidase activity sediments with membranes; and detergents, trypsin, and phosphatidylinositol-specific phospholipase C solubilize it, similar to results with human placental carboxypeptidase M. Ten microM 2-mercaptomethyl-3-guanidinoethylthiopropanoic acid and 1 mM o-phenanthroline inhibit, whereas 1.0 mM CoCl2 activates the enzyme. It has a neutral pH optimum and cleaves COOH-terminal Arg or Lys in bradykinin and in shorter peptides. The relative hydrolysis rates of peptides in the presence or absence of 1 mM CoCl2 were similar to those obtained with human carboxypeptidase M. The carboxypeptidase in MDCK cells (54 kDa) cross-reacts with antibodies to human carboxypeptidase M in Western blotting, but not with antibodies to plasma carboxypeptidase N. The enzyme is a glycoprotein; chemical deglycosylation reduced the size to 48 kDa. The presence of the enzyme on the cell membrane of MDCK cells was also shown with transmission electron microscopy using immunogold, which indicated that the enzyme is on the apical side. In addition, MDCK cells contain neutral endopeptidase 24.11 (enkephalinase) and prolylcarboxypeptidase (angiotensinase C) activities. Partitioning of solubilized carboxypeptidase M into Triton X-114 and water indicates that trypsin and phospholipase C remove a hydrophobic tail, while detergent solubilization leaves the hydrophobic moiety intact. Labeling of MDCK cells with [3H]ethanolamine resulted in the synthesis of radiolabeled carboxypeptidase M as determined by immunoprecipitation and fluorography. Thus, MDCK cells contain membrane-bound carboxypeptidase M, which is anchored to the plasma membrane via phosphatidylinositol-glycan. As a major kininase of the distal tubules, it may regulate salt and water excretion.
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PMID:Carboxypeptidase M in Madin-Darby canine kidney cells. Evidence that carboxypeptidase M has a phosphatidylinositol glycan anchor. 239 13

Aminopeptidase M (EC 3.4.11.2), an enzyme present on the cell surface of vascular endothelium and/or smooth muscle, rapidly hydrolyzes leucyl- and arginyl-2-naphthylamides and a number of vasoactive peptides at physiologic pH. Utilizing both thin-layer chromatography and high pressure liquid chromatography, it was found that vascular aminopeptidase M converted kallidin to bradykinin and inactivated des(Asp1)angiotensin I, angiotensin III, hepta(5-11)substance P and hexa(6-11)substance P. Aminopeptidase M did not, however, hydrolyze bradykinin, angiotensin I, angiotensin II, saralasin, vasopressin, oxytocin or any form of substance P containing a component of the Arg-Pro-Lys-Pro sequence. Both the naphthylamidase and peptidase activities were inhibited similarly by known amino-peptidase M inhibitors including o-phenanthroline, amastatin, bestatin and puromycin. However, inhibitors of angiotensin I converting enzyme (captopril), carboxypeptidase N (MERGETPA), neutral endopeptidase (phosphoramidon), post proline cleaving enzyme and dipeptidyl(amino)peptidase IV (diisopropylphosphofluoridate, DFP) were without effect. These results demonstrate that vascular, cell surface aminopeptidase M can selectively metabolize vasoactive peptides and may play a role in modulating their levels in the circulation and/or within the vessel wall.
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PMID:Vascular, plasma membrane aminopeptidase M. Metabolism of vasoactive peptides. 240 81

Angiotensin I converting enzyme (ACE) and neutral endopeptidase ("enkephalinase"; NEP), were purified to homogeneity from human renal membranes. NEP hydrolyzed substance P (SP) at Gln6-Phe7, Phe7-Phe8, and Gly9-Leu10 and neurotensin (NT) at Pro10-Tyr11 and Tyr11-Ile12. ACE cleaved SP at Phe8-Gly9 and Gly9-Leu10 to release C-terminal tri- and dipeptide (ratio = 4:1). The hydrolysis was dependent on chloride ion and inhibited by captopril. Modification of arginine residues in ACE with cylcohexanedione or butanedione inhibited hydrolysis of SP, bradykinin and Bz-Gly-Phe-Arg (80-93%) indicating an active site arginine is required for hydrolysis of SP. ACE cleaved NT at Tyr11-Ile12 to release Ile12-Leu13. These studies indicate that ACE and NEP, two enzymes which are widely distributed in the body, may be involved in the metabolism of SP and NT.
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PMID:Characterization of the metabolism of substance P and neurotensin by human angiotensin I converting enzyme and "enkephalinase". 241 54

Microvillar membranes derived from the brush border of the renal proximal tubule are very rich in peptidases. Pig kidney microvilli contain endopeptidase-24.11 associated with a battery of exopeptidases. The manner by which some neuropeptides are degraded by the combined attack of the peptidases of this membrane has been investigated. The contribution of individual peptidases was assessed by including inhibitors (phosphoramidon, captopril, amastatin and di-isopropyl fluorophosphate) with the membrane fraction when incubated with the peptides. Substance P, bradykinin and angiotensins I, II and III and insulin B-chain were rapidly hydrolysed by kidney microvilli. Oxytocin was hydrolysed much more slowly, but no products were detected from [Arg8]vasopressin or insulin under the conditions used for other peptides. The peptide bonds hydrolysed were identified and the contributions of the different peptidases were quantified. For each of the susceptible peptides, the main contribution came from endopeptidase-24.11 (inhibited by phosphoramidon). Peptidyl dipeptidase A (angiotensin-I-converting enzyme) was of less importance, even in respect of angiotensin I and bradykinin. When [2,3-Pro3,4-3H]bradykinin was also investigated at a lower concentration (20 nM), the conclusions in regard to the contributions of the two peptidases were unchanged. The possibility that endopeptidase-24.11 might attack within the six-residue disulphide-bridged rings of oxytocin and vasopressin was examined by dansyl(5-dimethylaminonaphthalene-1-sulphonyl)ation and by reduction and carboxymethylation of the products after incubation. Additional peptides were only observed after prolonged incubation, consistent with hydrolysis at the Tyr2-Ile3 and Tyr2-Phe3 bonds respectively. These results show that a range of neuropeptides are efficiently degraded by microvillar membranes and that endopeptidase-24.11 plays a key role in this process.
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PMID:Metabolism of neuropeptides. Hydrolysis of the angiotensins, bradykinin, substance P and oxytocin by pig kidney microvillar membranes. 243 10

Endopeptidase-2, the second endopeptidase in rat kidney brush border [Kenny & Ingram (1987) Biochem. J. 245, 515-524] has been further characterized in regard to its specificity and its contribution to the hydrolysis of peptides by microvillar membrane preparations. The peptide products were identified, after incubating luliberin, substance P, bradykinin and angiotensins I, II and III with the purified enzyme. The bonds hydrolysed were those involving a hydrophobic amino acid residue, but this residue could be located at either the P1 or P1' site. Luliberin was hydrolysed faster than other peptides tested, followed by substance P and bradykinin. Human alpha-atrial natriuretic peptide and the angiotensins were only slowly attacked. Oxytocin and [Arg8]vasopressin were not hydrolysed. No peptide fragments were detected on prolonged incubation with insulin, cytochrome c, ovalbumin and serum albumin. In comparison with pig endopeptidase-24.11 the rates for the susceptible peptides were, with the exception of luliberin, much lower for endopeptidase-2. Indeed, for bradykinin and substance P the ratio kcat./Km was two orders of magnitude lower. Since both endopeptidases are present in rat kidney microvilli, an assessment was made of the relative contributions to the hydrolysis of luliberin, bradykinin and substance P. Only for the first named was endopeptidase-2 the dominant enzyme; for bradykinin it made an equal, and for substance P a minor, contribution.
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PMID:The metabolism of neuropeptides. Hydrolysis of peptides by the phosphoramidon-insensitive rat kidney enzyme 'endopeptidase-2' and by rat microvillar membranes. 246 6

In previous studies, neutral endopeptidase (NEP) hydrolyzed the Cys105-Phe106 bond of atrial natriuretic peptides (ANP) in vitro. Three such ring-opened peptides derived from ANP 99-126, 103-126, and 103-123 were inactive in conscious rats. In conscious spontaneously hypertensive rats (SHR) in the present study, 100 mumol/kg, intravenously (i.v.) of the NEP inhibitor, SQ 29,072 (7-[[2-(mercaptomethyl)-1-oxo-3-phenyl-propyl]amino]heptanoic acid), significantly increased the area over the curve (AOC) of the depressor response to 3 nmol/kg of ANP 103-126 from 165 +/- 36 to 792 +/- 350, 1,515 +/- 374, and 828 +/- 164 mm Hg.min at 15, 30, and 60 min after inhibitor treatment. Thirty minutes after 3, 10, 30, and 100 mumol/kg of SQ 29,072, the AOC of 3 nmol/kg of ANP 99-126 increased from 175 +/- 59 mm Hg.min in vehicle-treated rats to 296 +/- 100, 318 +/- 34, 632 +/- 194 (p less than 0.05) and 656 +/- 151 (p less than 0.05) mm Hg.min. Furthermore, 100 mumol/kg of SQ 29,072 potentiated the AOC of human ANP 99-126 and 105-126 and rat ANP 99-126, 103-126, and 103-123, suggesting that the exocyclic N-terminal residues and the C-terminal tripeptide did not influence ANP potentiation by SQ 29,072. In contrast, inhibitors of aminopeptidase, angiotensin-converting enzyme (ACE), and serine protease and an arginine vasopressin (AVP) antagonist did not substantially affect the AOC of 3 nmol/kg ANP 99-126. Finally, SQ 29,072 did not alter the activities of bradykinin, AVP, or angiotensin I or II. In conclusion, NEP may inactivate ANP in vivo by cleavage of susceptible bonds within the ANP ring.
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PMID:Potentiation of the depressor responses to atrial natriuretic peptides in conscious SHR by an inhibitor of neutral endopeptidase. 247 91

The common acute lymphoblastic leukemia antigen (CALLA) is a 749-amino acid type II integral membrane protein expressed by most acute lymphoblastic leukemias, certain other lymphoid malignancies with an immature phenotype, and normal lymphoid progenitors. A computer search against the most recent GenBank release (no. 56) indicates that human CALLA cDNA encodes a protein nearly identical to the rat and rabbit neutral endopeptidase 24.11 ("enkephalinase;" EC 3.4.24.11). This zinc metalloendopeptidase, which has been shown to inactivate a variety of peptide hormones including enkephalin, chemotactic peptide, substance P, neurotensin, oxytocin, bradykinin, and angiotensins I and II, had not been identified in lymphoid cells. To determine whether CALLA cDNA derived from human acute lymphoblastic leukemia cells (Nalm-6 cell line) encodes functional neutral endopeptidase activity, we generated CALLA+ stable transfectants in the CALLA- murine myeloma cell line J558 and analyzed them for enzymatic activity in a fluorometric assay based upon cleavage of the substrate glutaryl-Ala-Ala-Phe 4-methoxy-2-naphthylamide at the Ala-Phe bond. Total lysates as well as whole-cell suspensions of the Nalm-6 line and of the CALLA+ transfectants, but not of the CALLA- J558 cells, possessed neutral endopeptidase activity. This enzymatic activity was associated with the cellular membrane fraction and was abrogated by the specific neutral endopeptidase inhibitor phosphoramidon. The unequivocal identification of CALLA as a functional neutral endopeptidase provides insight into its potential role in both normal and malignant lymphoid function.
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PMID:Common acute lymphoblastic leukemia antigen (CALLA) is active neutral endopeptidase 24.11 ("enkephalinase"): direct evidence by cDNA transfection analysis. 252 88

We have examined pulmonary effects of bradykinin (Bk) in vivo and in vitro in guinea pigs and their potential inhibition by antagonists of Bk B1 and B2 receptors. Bk was a potent bronchoconstrictor in vivo and caused contractions of isolated, epithelium-denuded trachealis. D-Arg[Hyp3,D-Phe7]-Bk (NPC567) and D-arg[Hyp3,Thi5,8,D-Phe7]-Bk (NPC349), B2 receptor antagonists, were weak inhibitors of Bk-induced bronchoconstriction in vivo and were virtually inactive as antagonists of Bk-induced airway smooth muscle contraction. Several other B2 antagonists as well as B1 antagonist, des-Arg9-[Leu8]-Bk, did not inhibit Bk-induced tracheal contraction. The B1 receptor agonist des-Arg9-Bk was without effect on tracheal tone. Tracheal responses to Bk were unaffected by antagonists of muscarinic, histamine, serotonin, and catecholamine receptors. The inability of the antagonists to inhibit Bk is unlikely to be due to their degradation, because NPC567 was only weakly active in the presence of inhibitors of kininase I (EC 3.4.11.2), kininase II (EC 3.4.15.1), and neutral endopeptidase (EC 3.4.24.11). These studies were corroborated by ligand binding experiments in guinea pig and ovine airways. In [3H]Bk binding, the Bk antagonists had no effect in guinea pig trachea, slightly displaced [3H]Bk in ovine trachea, and inhibited approximately 60% of total specific binding in lung. des-Arg9-[Leu8]-Bk and several other agents, including atropine, neurokinin A, substance P, and vasoactive intestinal peptide, had no effect on lung Bk binding. Bk and its analogs were not degraded during the binding assay. These data suggest that pulmonary tissue, particularly in the large airways, contains a novel Bk binding site, a B3 receptor, which may be involved in Bk-induced bronchoconstriction.
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PMID:Evidence for a pulmonary B3 bradykinin receptor. 254 44

Arterial plasma kinins and mean arterial pressure were measured in intact and bilaterally nephrectomized rats infused with vehicle or bradykinin to study the role of 1) angiotensin converting enzyme (ACE) and other peptidases and 2) the kidney (a kininase-rich organ) in the metabolism of kinins in vivo. Before the infusion, rats were pretreated with vehicle, enalaprilat (an ACE inhibitor), or a cocktail of kininase inhibitors containing 1) enalaprilat, 2) DL-2-mercaptomethyl-3-guanidinoethyl-thiopropanoic acid (MGTA), a carboxypeptidase N inhibitor, 3) phosphoramidon, a neutral endopeptidase 24.11 inhibitor, and 4) bestatin, an aminopeptidase B inhibitor. In the rats with vehicle (n = 8), the cocktail did not significantly increase endogenous kinins (from 31 +/- 6 to 41 +/- 9 pg/ml, p = 0.94). In the rats infused with bradykinin (peptidase substrate), plasma kinins increased threefold in the group pretreated with the vehicle, 21-fold in the enalaprilat group, and 22-fold in the cocktail group. These increases were doubled by nephrectomy but were not affected by ureteral ligation. In the groups pretreated with the cocktail or enalaprilat, the hypotensive effect of bradykinin was correlated with plasma kinin concentration (r = 0.75, p less than 0.001). After bradykinin infusion was stopped, plasma kinins decreased by half in 10-12 seconds in the rats pretreated with vehicle, enalaprilat, or cocktail. We concluded that ACE and the kidney are important to the metabolism of circulating kinins while carboxypeptidase N, neutral endopeptidase 24.11 and aminopeptidase B are not. We also concluded that other tissue peptidases, not affected by either the above inhibitors or nephrectomy, play an important role in kinin metabolism.
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PMID:Role of angiotensin converting enzyme and other peptidases in in vivo metabolism of kinins. 254 61


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