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)

Three distinct peptidyldipeptidases (exopeptidases releasing carboxyl terminal dipeptide residues) can be solubilized from nerve terminal membrane fractions from whole rat brain or striatum, and separated by ion exchange chromatography. Brain angiotensin-converting enzyme (PDP-1) cleaves Hip-His-Leu, but not 80 nM [3H-Tyr1, Leu5]-enkephalin, and is markedly inhibited by several specific inhibitors such as captopril, teprotide, and MK-422. Enkephalinase (PDP-2) cleaves 80 nM [3H-Tyr1, Leu5]-enkephalin, but not Hip-His-Leu; it is not inhibited by any of the standard competitive inhibitors of angiotensin-converting enzyme (all analogs of carboxyl-terminal peptide sequences Phe-Ala-Pro or Ala-Pro), but is strongly inhibited by captopril analogs such as thiorphan (Phe-Gly analog). A third peptidyldipeptidase (PDP-3) cleaves Hip-His-Leu, but not 80 nM [3H-Tyr1, Leu5]-enkephalin; it is inhibited by dipeptide analog inhibitors such as captopril and thiorphan, but not by longer peptides such as teprotide or tripeptide analog inhibitors such as MK-422. Both PDP-2 (enkephalinase) and PDP-3 are apparently present in nerve terminal membranes predominantly as inactive proenzyme precursors, which elute from DEAE-cellulose at high salt concentration, and are activated very slowly by a process involving one or more trypsin-like enzymes. Rechromatography of activated PDP-2 and PDP-3 achieves a nearly complete separation of the two enzymes, both markedly purified, since each is much less acidic than its proenzyme precursor. Purified enkephalinase does not appear to have any significant endopeptidase activity. It cleaves Hip-Phe-Arg 200 times more effectively than Hip-Phe-Arg-NH2, and appears to be quite selective for cleaving the terminal dipeptide residue, Phe-Arg, from bradykinin, with no release of the second dipeptide and no cleavage of the Gly4-Phe5 interior peptide bond.
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PMID:Purification and characterization of enkephalinase, angiotensin converting enzyme, and a third peptidyldipeptidase from rat brain. 631 70

A microvillar fraction was prepared from human kidney cortex. This fraction was seven to 10 times enriched in aminopeptidases N and A, gamma-glutamyltransferase, dipeptidyl peptidase IV, neutral endopeptidase and alkaline phosphatase. Dipeptidyl peptidase IV activity of human renal microvilli could be inhibited by di-isopropylphosphorofluoridate and neutral endopeptidase activity by phosphoramidon. Nearly all the activity of aminopeptidases A and N could be removed from the membrane by treatment with papain, but only 19% and 33% of dipeptidyl peptidase IV and gamma-glutamyltransferase activities were released under the same conditions. Neutral endopeptidase and alkaline phosphatase were not solubilized by papain. Treatment with elastase gave results similar to papain, except that gamma-glutamyltransferase was not released. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis under reducing conditions of microvilli revealed 36 polypeptide bands, 12 of which contained carbohydrate. A band of apparent Mr 130 000 was labelled with [3H]di-isopropylphosphorofluoridate and hence identified as dipeptidyl peptidase IV. Antibodies raised to human kidney microvilli produced 11 precipitates with detergent solubilized proteins and six with papain released proteins. Several of the precipitates were identified histochemically. Microvilli prepared from human kidney are very similar to microvilli from pig and rabbit kidney with respect to enzymology, response to papain treatment, sodium dodecyl sulphate-polyacrylamide gel patterns and immunochemistry.
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PMID:Proteins of the kidney microvillar membrane; analysis by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and crossed immunoelectrophoresis. 661 1

Neutral endopeptidase (EC 3.4.24.11) from pig kidney hydrolyses [125I]iodo-insulin B-chain and leucine-enkephalin. Both activities were equally sensitive to inhibition by phosphoramidon [N-(alpha-L-rhamnopyranosyloxyhydroxyphosphinyl)-L-leucyl-L-tryptophan] and thiorphan [N-(DL-2-benzyl-3-mercaptopropionyl)glycine]. Thermolysin hydrolysis of insulin B-chain was also sensitive to both inhibitors. The hydrolysis of the Gly3-Phe4 bond of Leu-enkephalin by synaptic membranes prepared from pig brain was partially inhibited by phosphoramidon and thiorphan. Synaptic membranes appear to contain another endopeptidase activity that is insensitive to these reagents. These observations suggest that enzymes similar to the kidney endopeptidase may play a general role in neuropeptide metabolism.
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PMID:Kidney neutral endopeptidase and the hydrolysis of enkephalin by synaptic membranes show similar sensitivity to inhibitors. 705 59

We review three new classes of antihypertensive drugs: imidazolines, monatepil, and neutral endopeptidase inhibitors. Imidazolines are a new generation of central acting drugs. Because of their greater affinity for imidazoline receptors rather than alpha 2-adrenoreceptors, they cause less fatigue and dry mouth than the older central acting drugs. Monatepil is a single drug with both calcium antagonist and peripheral alpha 1-antagonist properties. This agent not only lowers blood pressure but also lowers serum cholesterol, an effect mediated by its alpha-antagonism, and has anti-lipid peroxidation properties. Monatepil might become an effective antiatherosclerosis drug. Neutral endopeptidase inhibitors lower blood pressure by inhibiting the metabolism of atrial natriuretic peptide and other vasoactive peptides.
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PMID:Newer antihypertensive drugs. 749 51

We describe the development of a new ELISA for the detection of neural endopeptidase 3.4.24.11 (NEP). Neutral endopeptidase 3.4.24.11 was determined in preparations of human granulocytes, mononuclear cells (MNC), and in serum. Human recombinant NEP was used as reference. Specificity of the mAbs was tested using APAAP, FACS analysis, and Western blot analysis. Lysis of the blood cells was performed by incubating the cells with 0.4% Tween-20 and repeated freezing cycles. The minimal detectable dose for recombinant NEP was 15 pg/ml. The recovery was 94 +/- 9%. The NEP was detectable in 15 out of 20 serum samples of 20 volunteers (mean +/- SEM, 245 +/- 88 pg/ml, n = 20)) and in all granulocyte preparations (1176 +/- 138 pg/10(7) cells, n = 20)). The results were reproducible among replicates (CV = 3 +/- 1%, n = 40), dilutions (CV = 8 +/- 2%, n = 5), and assays (CV = 12 +/- 4%, n = 5). With this new ELISA, a simple and reproducible method for the measurement of NEP 3.4.24.11 is described.
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PMID:ELISA for the neuropeptide degrading endopeptidase 3.4.24.11 in human serum and leukocytes. 752 44

Neutral endopeptidase (NEP; EC 3.4.24.11), an enzyme which metabolizes several peptides (including oxytocin and endothelins) implicated in the control of uterine function, was found to be localized in the ovine uterus throughout the oestrous cycle and in the uterus and conceptus during early pregnancy, using immunohistochemical techniques. Positive NEP immunoreactivity was found in the endometrium principally in stromal cells, in the vasculature in endothelial and vascular smooth muscle cells, and also weakly in some glandular epithelial cells. In a layer of stromal fibroblasts several cells in thickness underlying the luminal epithelium, staining was much weaker than that in the deeper stromal cells throughout the period examined. NEP staining was also present in smooth muscle cells of the myometrium at all times, and was most intense in the layer of cells adjacent to the endometrium. In the conceptus, NEP immunohistochemical staining was found in uninucleate cells, but not in binucleate trophoblast cells, in epithelial cells of the allantois and amnion, and in the heart and brain of the Day-20 embryo. In ovariectomized ewes treated with oestrogen or progesterone separately or remaining untreated, immunohistochemical staining of NEP was stronger when compared with intact ewes, in caruncular and intercaruncular stroma and epithelia, in glands, in the vasculature and in myometrium. The staining was less intense in all cell types in ewes receiving oestrogen plus progesterone. The expression of NEP and its specific regionalization within the uterus indicate a mechanism by which the availability of biologically important peptides involved in the regulation of the oestrous cycle and implantation, including oxytocin and endothelin, can be controlled by regulation of their metabolism.
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PMID:Localization of neutral endopeptidase in the ovine uterus and conceptus during the oestrous cycle and early pregnancy. 756 53

Neutral endopeptidase 24.11, a membrane-bound metallopeptidase, cleaves, and degrades vasoactive peptides such as atrial natriuretic peptide, endothelin, angiotensin I, substance P, and bradykinin. Therefore, the presence of this metallopeptidase may contribute to the regulation of vascular tone and local inflammatory responses in the vascular endothelium and elsewhere. We determined neutral endopeptidase in cultured human endothelial cells from different vascular beds and studied its regulation by protein kinase C. Neutral endopeptidase was detected in all cultured endothelial cell types. Lowest concentrations were measured in human endothelial cells from umbilical veins (360 +/- 14 pg/mg protein), followed by pulmonary and coronary arteries; higher concentrations were found in endothelial cells from the cardiac microcirculation (1099 +/- 73 pg/mg protein). Neutral endopeptidase content increased during cell growth but was not affected by endothelial cell growth factor or modifications of the growth medium. Stimulation of protein kinase C with 1-oleoyl-2-acetyl-rac-glycerol (0.1 to 1 mumol/L) and phorbol 12-myristate 13-acetate (0.01 to 0.1 mumol/L) induced a time- and concentration-dependent increase of endothelial cells that was inhibited by cycloheximide (5 mumol/L), an inhibitor of protein synthesis. Incubation with phospholipase C (1 mumol/L) and thrombin (10 IU/mL) induced upregulation of neutral endopeptidase, resulting in 158 +/- 26% and 150 +/- 22% increases, respectively, compared with controls. The thrombin effect was inhibited by calphostin C (1 mumol/L), an inhibitor of protein kinase C. Endothelial neutral endopeptidase is constitutively expressed in endothelial cells from different origins and is inducible by thrombin via activation of the protein kinase C pathway.
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PMID:Regulation and differential expression of neutral endopeptidase 24.11 in human endothelial cells. 763 30

Neutral endopeptidase (E.C.3.4.24.11) was visualized at the ultrastructural level in the external zone of the rat median eminence by using 125I-labelled IgG of a monoclonal serum. A precise analysis of the localization of the immunolabelling, which appears in the form of individual stray silver grains, was undertaken. Among the 1,045 grains counted, 82% were localized over membrane appositions involving nerve endings only and nerve endings plus tanycytes. The difference between the real and a randomly generated population of grains was statistically significant. Our results provide morphological arguments in support of the view of a paracrine action of neuropeptides present in the median eminence especially enkephalins but possibly, substance P, angiotensin, cholecystokinin and neurotensin. These neuropeptides are known to be inactivated by neutral endopeptidase. The action of these peptides may be exerted on nerve endings (autocrine or paracrine) but an intervention on tanycytes cannot be excluded.
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PMID:Radioimmunocytochemical distribution of neutral endopeptidase (enkephalinase E.C.3.4.24.11) at the ultrastructural level in the rat median eminence. 768 59

Neutral endopeptidase (NEP; EC. 3.4.24.11) is a type 2 cell surface metalloprotease known by a variety of eponyms, including enkephalinase, common acute lymphoblastic leukemia antigen, and CD10. Identified substrates are largely neural or humoral oligopeptide agonists, and the enzyme functions to terminate signaling by degrading the ligand, analogously to acetylcholine/acetylcholinesterase. Targeted disruption of the NEP locus in mice results in enhanced lethality to endotoxin shock with a pronounced gene dosage effect. The site(s) of action appears downstream from release of tumor necrosis factor and interleukin-1 since NEP-deficient animals demonstrate increased sensitivity to these mediators as well. This unexpected finding indicates an important protective role for NEP in septic shock.
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PMID:Neutral endopeptidase modulation of septic shock. 776 13

Oxidants have been implicated in the pathogenesis of many inflammatory airway diseases. Neutral endopeptidase (also called enkephalinase, EC 3.4.24.11) is a peptidase that is involved in the degradation of several proinflammatory peptides, such as tachykinins and kinins. Indirect evidence suggests that airway neutral endopeptidase is inactivated by oxidants. To determine whether hydrogen peroxide inactivates neutral endopeptidase, we studied the activity of this peptidase in washed crude preparations of membranes from guinea pig lungs. Washed crude membrane preparations were exposed to increasing concentrations of hydrogen peroxide (1.25-25 mM) in the presence or absence of two different concentrations of catalase (300 and 700 U/mL). Neutral endopeptidase activity was inhibited by hydrogen peroxide in a concentration-dependent fashion (p = .0001). Addition of catalase prevented, in a concentration-dependent fashion, the inhibition of neutral endopeptidase induced by hydrogen peroxide (p = .0001). Mannitol (40 mM) and L-methionine (20 mM) did not prevent inhibition of neutral endopeptidase induced by hydrogen peroxide (2.5 mM). It can be concluded that neutral endopeptidase is inactivated by hydrogen peroxide, an effect that is prevented by catalase. Hydrogen peroxide-induced inactivation of neutral endopeptidase is not mediated by spontaneous generation of either hydroxyl radical or hypochlorous acid in the membrane preparation. Our results suggest that neutral endopeptidase inactivation may occur in airway diseases associated with exposure to or production of oxidants.
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PMID:Hydrogen peroxide inhibits lung neutral endopeptidase. 777 26


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