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

The effects of the endopeptidase 24.11 ('enkephalinase') inhibitor thiorphan, the aminopeptidase inhibitor bestatin and a novel metallopeptidase inhibitor JMV 390-1 on the K(+)-evoked release of immunoreactive neurotensin and neuromedin N (iNT and iNN) from mouse hypothalamic slices were examined. (JMV 390-1 inhibits several metallopeptidases including endopeptidases 24.11, 24.15 and 24.16, and aminopeptidase N equipotently with Ki values around 50 nM.) Thiorphan increased the recovery of released iNT nearly 2-fold and had no effect on iNN. Bestatin produced a 4-fold increase in iNN recovery and was inactive on iNT. Finally, iNT and iNN recoveries were increased up to 4- and 5-fold, respectively, by JMV 390-1. These results show that in the mouse hypothalamus endopeptidase 24.11 participates with other metalloendopeptidases to the degradation of endogenously released NT while endogenously released NN is principally degraded by aminopeptidase(s).
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PMID:Effects of thiorphan, bestatin and a novel metallopeptidase inhibitor JMV 390-1 on the recovery of neurotensin and neuromedin N released from mouse hypothalamus. 145 16

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide secreted by endothelial cells. We investigated whether polymorphonuclear neutrophils (PMN) were able to destroy this peptide by enzymatic hydrolysis produced either by the membrane-bound endopeptidase 24.11 or by lysosomal proteinases released in the medium by activated cells. Resting and activated PMN were incubated with 125I-labelled ET-1 and the degradation fragments were analyzed by HPLC. A marked degradation of ET-1 was observed only in the presence of the stimulated cells, leading to the generation of seven radiolabelled peaks. Addition of phosphoramidon had no effect on the appearance of these metabolites, while soybean trypsin inhibitor abolished almost completely the degradation of the peptide, suggesting a role of cathepsin G in ET-1 hydrolysis. Among the purified leukocyte enzymes tested, cathepsin G hydrolyzed 125I-labelled ET-1 at the higher rate and gave rise to two radiolabelled peaks already observed in the presence of activated PMN. Incubation of unlabelled ET-1 with purified cathepsin G allowed to identify a major cleavage site corresponding to the His16-Leu17 bond, leading to the formation of inactive [1-16] fragments and the C-terminal pentapeptide. This mechanism of ET-1 inactivation could play a role in acute inflammatory reaction where PMN adhere to the vascular endothelial cells.
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PMID:Enzymatic degradation of endothelin-1 by activated human polymorphonuclear neutrophils. 147 5

Atrial natriuretic peptide (ANP), a 28-residue peptide with cardiovascular and renal effects, is rapidly cleared from the circulation. Beside renal clearance, an extra-renal metabolism by the enzyme neutral endopeptidase-24.11 (NEP-24.11) has been proposed, since specific NEP-24.11-inhibitors increase endogenous plasma-ANP. NEP-24.11 is present in rat lung but its significance for ANP hydrolysis within the lung is unclear. The aim of this study was to investigate a possible degradation of rat ANP in a membrane preparation from rat lung. Hydrolysis products of ANP were separated by HPLC and further characterized by a pulmonary artery bioassay, by radioimmunoassay with different antisera, by peptide sequencing and by masspectrometry. Rat pulmonary membranes degraded ANP to one main metabolite lacking biological activity and with poor cross-reactivity to an antiserum recognising the central ring-structure of the peptide. Formation of the hydrolysis product was prevented by the NEP-24.11-inhibitor phosphoramidon (1 microM). Peptide sequencing of the metabolite revealed a cleavage between Cys7 and Phe8, which was confirmed by mass-spectrometry. The metabolite had an HPLC elution time identical to that of the product formed by purified porcine NEP-24.11. These findings suggest that ANP is metabolized and inactivated by endopeptidase-24.11 in rat lungs, the first organ exposed to ANP released from the heart.
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PMID:Degradation and inactivation of rat atrial natriuretic peptide 1-28 by neutral endopeptidase-24.11 in rat pulmonary membranes. 147 9

The activation of procollagenase and prostromelysin by mechanisms that might be functional in vivo has been investigated. Studies with cell monolayers plated onto collagen films have indicated key roles for plasmin and TIMP in these processes. Prostromelysin activation could be rapidly effected by fibroblast monolayers in the presence of plasminogen, with identical kinetics to plasminogen-streptokinase generated plasmin. Procollagenase activation by plasmin was shown to be poor, although an M(r) shift of 11,000 occurred. Activation was enhanced ten-fold by the presence of active stromelysin even at a very low molar ratio. A tumour cell line secreting procollagenase but not stromelysin was found to be dependent upon the addition of both stromelysin and plasminogen to effect degradation of collagen films. Biochemical studies of metalloproteinase activation were carried out using other purified proteinases synthesized by connective tissue cells including endopeptidase 24.11, endopeptidase-2, cathepsin B and cathepsin L. None was a particularly effective activator relative to plasmin, but cathepsin B was shown to activate stromelysin. By use of both cell model systems and biochemical studies of purified enzymes we have found that the role of plasmin as the major metalloproteinase activator in normal connective tissue cells remains unchallenged.
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PMID:Physiological mechanisms for metalloproteinase activation. 148 31

1. Phosphoramidon (10 microM) markedly increased the contractile response to endothelin-3 in human and rabbit bronchus in vitro. In human tissue the contractile response to 0.3 microM endothelin-3 was significantly increased from 54 +/- 12% to 137 +/- 34% (of the response to 1 nM acetylcholine) in the presence of phosphoramidon. Similarly, in rabbit isolated bronchus, the endothelin-3-induced response was increased from 34 +/- 5% to 61 +/- 7%. 2. In addition, the potency (as measured by EC30 values) of this peptide in human and rabbit airways was significantly augmented in the presence of the enzyme inhibitor. The geometric mean EC30 value was decreased from 53 nM (95% CI:15, 190) to 8 nM (95% CI:3, 23) in human bronchus and from 150 nM (95% CI:89, 250) to 23 nM (95% CI:11, 50) in rabbit tissue. 3. Neither the potency nor the response (at 0.3 microM) to endothelin-3 in canine bronchial rings was altered after incubation of the tissue in phosphoramidon. 4. A previous study carried out in human airways has implied that the difference in potency between endothelin-1 and endothelin-3 may be attributed to a heterogeneous endothelin receptor population. The results of our study, while also demonstrating this difference in potency, have shown that this marked difference, as well as that obvious in rabbit airway tissue can be abolished in the presence of phosphoramidon. 5. Phosphoramidon produced no change in the cumulative concentration-response curve for endothelin-1 in airway tissue from the three species studied. 6. These results suggest that a phosphoramidon-sensitive enzyme (probably neutral endopeptidase) found in lung, may be responsible for local degradation of endothelin-3, but not endothelin-l in human and rabbit isolated bronchus.
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PMID:Phosphoramidon potentiates the contractile response to endothelin-3, but not endothelin-1 in isolated airway tissue. 150 19

Hydrolysis of endothelin 1 by rat kidney membranes was investigated using a reverse-phase HPLC and an automated gas-phase protein sequencer. Endothelin 1 was hydrolyzed into four major fragments which were detected by HPLC. Phosphoramidon, an inhibitor of neutral endopeptidase 24,11, almost completely suppressed the production of three fragments, but one fragment was not affected by the inhibitor. Analysis of N-terminal sequences of the degradation products revealed that the phosphoramidon-sensitive fragments were generated by cleavage at the Ser5-Leu6 bond of endothelin 1 that was identical with its cleavage site by purified rat endopeptidase 24,11, reported previously. The phosphoramidon-insensitive fragment was produced by cleavage at Leu17-Asp18, which was distinct from the sites by endopeptidase 24,11, but corresponded to that by a phosphoramidon-insensitive metallo-endopeptidase recently isolated from rat kidney membranes by us [(1992) Eur. J. Biochem. 204, 547-552]. Kinetic determination of endothelin 1 hydrolysis by the isolated enzyme yielded values of Km = 71.5 microM and kcat = 1.49 s-1, giving a ratio of kcat/Km = 2.08 x 10(4) s-1.M-1. The Km value was much higher and the kcat/Km value was much lower than those for rat endopeptidase 24,11 reported previously. Thus, endopeptidase 24,11 appears to hydrolyze endothelin 1 more efficiently than the isolated enzyme does. Both enzymes may play physiological roles in the metabolism of endothelin 1 by rat kidney membranes in vivo.
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PMID:Endothelin 1 hydrolysis by rat kidney membranes. 151 1

A novel metallo-endopeptidase from human neuroblastoma NB-OK-1 cells was partially purified and characterized. This enzyme activity was detected in the culture medium and could be detached from intact cells by gentle washing, suggesting a peripheral localization of the enzyme. This endopeptidase inactivated Atrial Natriuretic Peptide (ANP) by a unique and selective cleavage of the Ser123-Phe124 bond. It also produced hydrolysis at the Xaa-Phe, Xaa-Leu, or Xaa-Ile bonds of other peptide hormones such as bradykinin, somatostatin 14, litorin, substance P, neuromedin C and angiotensin II. The substrate selectivity and inhibition profile of the enzyme showed obvious similarities with the peptide hormone inactivating endopeptidase (PHIE) recently purified from Xenopus laevis skin secretions and indicated a thermolysin-like activity distinct from neutral endopeptidase (EC 3.4.24.11) and from angiotensin converting enzyme (EC 3.4.15.1).
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PMID:A new metallo- endopeptidase from human neuroblastoma NB-OK-1 cells which inactivates atrial natriuretic peptide by selective cleavage at the Ser123-Phe124 bond. 153 Oct 11

The effects of a neutral endopeptidase (NEP) inhibitor, SCH 39.370, and a clearance receptor ligand, C-atrial natriuretic factor-(4-23) [C-ANF-(4-23)] on the plasma concentration of atrial natriuretic peptide (ANP) and hemodynamics under basal conditions and during increased circulating ANP levels produced by acute volume loading in conscious rats were studied. Measurements of plasma immunoreactive N-terminal fragment of pro-ANP (IR-NT-ANP) concentrations were used to characterize the endogenous secretion of the biologically active peptide in response to drug infusions and volume expansion. Infusion of SCH 39.370 increased plasma IR-ANP levels dose-dependently in conscious normotensive Wistar rats; maximal increases of 17% (P less than 0.02) after the dose of 3 mg/kg, iv, and 67% (P less than 0.002) after the dose of 10 mg/kg, iv, SCH 39.370 were noted. Similarly, infusion of C-ANF-(4-23) alone (30 micrograms/kg, iv bolus, followed by infusion of 3 micrograms/kg.min for 30 min) increased plasma IR-ANP levels by 37% (P less than 0.001). Given in combination, SCH 39.370 and C-ANF-(4-23) produced a greater increase in plasma IR-ANP concentration (83%; P less than 0.001) than when either substance was infused alone. Neither SCH 39.370 nor C-ANF-(4-23), alone or in combination, had any effect on basal plasma IR-NT-ANP concentrations. The combination reduced mean arterial pressure (8 +/- 2 mm Hg; P less than 0.01) and right atrial pressure (0.67 +/- 0.20 mm Hg; P less than 0.01), while administration of SCH 39.370 or C-ANF-(4-23) alone had no effect on mean arterial pressure, heart rate, or right atrial pressure in conscious rats. Acute volume expansion with 0.9% saline (1.1 ml/100 g BW) resulted in an increase in right atrial pressure (2.7 +/- 0.2 mm Hg; P less than 0.001) as well as in plasma IR-ANP (55%; P less than 0.001) and IR-NT-ANP concentrations (24%; P less than 0.03). Volume expansion in rats pretreated with SCH 39.370 resulted in a greater increase in plasma IR-ANP concentrations than in control animals; the relative ANP increases corresponding to the 2.5-mm Hg increase in right atrial pressure were 1.48-, 1.69-, and 2.28-fold in control, 3 mg/kg SCH 39.370-treated, and 10 mg/kg SCH 39.370-treated groups, respectively. When the relation between changes from control in plasma IR-ANP and right atrial pressure in response to acute volume expansion was analyzed in the presence of C-ANF-(4-23), no difference was noted between control and treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Basal and volume expansion-stimulated plasma atrial natriuretic peptide concentrations and hemodynamics in conscious rats: effects of SCH 39.370, an endopeptidase inhibitor, and C-ANF-(4-23), a clearance receptor ligand. 153 Nov 29

To explore the mechanisms for the natriuretic effects of a neutral endopeptidase inhibitor, candoxatril, the concentration of atrial natriuretic peptide (ANP) and its molecular forms in the urine of Dahl salt-sensitive (S) rats were examined. Candoxatril-induced natriuresis (+120%, p less than 0.05) was associated with a marked increase in the urinary ANP excretion (+1200%, p less than 0.05). Analysis by Sephadex G-50 gel filtration revealed that molecular weight of the major fraction of immunoreactive (ir-) ANP in the plasma of candoxatril-treated Dahl S rats was 3K, whereas that in the urine was 2.5 K. Further analysis by reverse phase high performance liquid chromatography showed that ir-ANP in the plasma of Dahl S rats was alpha-rANP (1-28), while that in the urine from rats treated with candoxatril was alpha-rANP (1-25). These results indicate that candoxatril inhibits the complete degradation of ANP in the kidney, thereby increasing the amount of biologically active ANP reaching the distal nephron and contributing to natriuresis.
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PMID:Characterization of atrial natriuretic peptide in urine from rats treated with a neutral endopeptidase inhibitor. 153 53

The common acute lymphoblastic leukemia antigen (CALLA, CD10) has been identified as neutral endopeptidase-24.11 (NEP), a mammalian ectoenzyme involved in the inactivation of regulatory peptides, such as the enkephalins and atrial natriuretic peptide. Twenty monoclonal antibodies directed against the human antigen, were tested for their ability to inhibit the enzymatic activity of the human and rat peptidases expressed by cell lines. Six anti-CALLA antibodies were found to inhibit 50% or more of the hydrolysis of D-Ala2-leucine enkephalin by the neutral endopeptidase present on the human leukemic cell line Reh6 and, to a lesser extent, the hydrolysis of atrial natriuretic peptide. This may indicate that their binding may affect regions of the active site more important for the dipeptidylcarboxypeptidase activity of the enzyme. Only four antibodies cross-reacted with the peptidase from the rat epithelial cell line Rat2, as shown by membrane immunofluorescence, and these also partially inhibited enzyme activity. No antibody was able to inhibit completely the activity of the human and rat enzymes and all the active antibodies appeared to behave as non-competitive inhibitors of substrate cleavage. These monoclonal antibodies could be used in mapping studies of NEP.
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PMID:Effects of monoclonal antibodies raised against the common acute lymphoblastic leukemia antigen on endopeptidase-24.11 activity. 153 55


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