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)

Neutral endopeptidase (NEP, EC 3.4.24.11), angiotensin-converting enzyme (ACE, EC 3.4.15.1) and carboxypeptidase N (CPN, EC 3.4.17.3) are potentially important enzymes which regulate the degradation of neuropeptides, such as bradykinin (BK) and substance P (SP), in the respiratory mucosa. Some neuropeptides are also degraded by these enzymes in vitro and in vivo. We investigated the localization of these enzymes in the human nasal mucosa by an indirect immunohistochemical technique (immunogold silver staining). NEP-immunoreactive areas were present in the epithelium, the serous cells of the submucosal glands, and the endothelial cells of small vessels. The epithelium and the serous cells were the predominant areas of NEP immunoreactivity in the nasal mucosa. ACE-immunoreactive areas were seen in the outer layer of the epithelium, the endothelial cells of vessels, and widely distributed in the superficial lamina propria. The endothelial cells of the vessels showed maximum positive intensity to ACE. CPN-immunoreactive areas were observed in the epithelium, the endothelium of vessels and the superficial lamina propria, except for the gland cells. The superficial lamina propria exhibited maximum immunoreactivity for CPN. We observed that the enzymes were widely distributed in the nasal mucosa. The epithelium, including the epithelial cells and glycocalyx, contains all three enzymes. These enzymes play an important role in the mucosal immunity of the respiratory mucosa by degrading active neuropeptides. These results show that NEP secretion is regulated by a glandular, cholinergic control. On the other hand, ACE and CPN secretion are regulated by vascular permeability.
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PMID:Immunological localization of neuropeptide-degrading enzymes in the nasal mucosa. 783 83

Synthesis of angiotensin-converting enzyme is induced during its chronic inhibition. Like angiotensin-converting enzyme, neutral endopeptidase (EC 3.4.24.11) is a plasma membrane peptidase. We studied changes of the two enzymes in lung, kidney and serum in a coronary ligation model of experimental congestive heart failure, and during chronic inhibition of the enzymes. Coronary-ligated rats (n = 19) and sham-operated controls (n = 18) were given SCH 34826 [(S)-N-[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy]carbonyl]-2-phenylethyl]-L-phenylalanine]-beta-alanine], a specific neutral endopeptidase inhibitor (n = 13), captopril (n = 12), or vehicle (n = 12) for 4 days, and exsanguinated. Pulmonary angiotensin-converting enzyme was induced both by captopril (52% compared to vehicle) and by SCH 34826 (21%). Serum angiotensin-converting enzyme was induced by captopril (44%). Neutral endopeptidase was induced in lung by captopril (73%), and in kidney by SCH 38426 (32%). Compared to controls, the relative heart weight of rats with heart failure was increased by 29%, and the plasma level of atrial natriuretic peptide elevated by 74%, but enzyme activities were not different. We conclude that, in the rat, separate inhibition of either angiotensin-converting enzyme or neutral endopeptidase induces both enzymes, and that the induction varies in different tissues. Alterations in the substrates of the two enzymes, e.g. in bradykinin, might cause these changes.
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PMID:Inhibition of either angiotensin-converting enzyme or neutral endopeptidase induces both enzymes. 785 75

Neutral endopeptidase inhibition (NEP-I) and angiotensin converting enzyme inhibition (ACE-I) act synergistically to produce acute beneficial hemodynamic effects in models of heart failure. Blockade of the formation of angiotensin II (Ang II) acting together with potentiation of the natriuretic peptides, bradykinin and other vasoactive peptides may mediate the interaction of dual enzyme inhibition. In this study, the potential roles of Ang II repression and bradykinin potentiation were evaluated in conscious cardiomyopathic hamsters with compensated heart failure. The Ang II AT1 receptor antagonist, SR 47436 (BMS-186295), was administered at 30 mumol/kg, i.v. followed by i.v. infusion at 1 mumol/kg/min in combination with NEP-I (SQ-28603 at 30 mumol/kg i.v.). Cardiac preload (left ventricular end diastolic pressure) and afterload (left ventricular systolic pressure) decreased significantly more after the combination of Ang II blockade and NEP-I than after either treatment alone. This indicated that repression of Ang II contributes importantly to the NEP-I/ACE-I interaction. Bradykinin B2 receptor antagonism by Hoe 140 at 100 micrograms/kg, i.v. significantly blunted the decrease in left ventricular end diastolic pressure but not the decrease in left ventricular systolic pressure after dual NEP-I/ACE-I (SQ-28603 and enalaprilat each at 30 mumol/kg, i.v.). This suggests that bradykinin potentiation contributes to the preload-reducing, but not the afterload-reducing, acute effects of NEP-I/ACE-I. Hence, both Ang II repression and bradykinin potentiation are factors contributing to the synergistic hemodynamic effects of combined NEP-I and ACE-I in hamsters with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Repression of angiotensin II and potentiation of bradykinin contribute to the synergistic effects of dual metalloprotease inhibition in heart failure. 785 75

Inter- and intralobular mammary fibroblasts have been separated from normal human breast tissue and cultured to study the differential expression of ectoenzymes present within the stroma of the normal gland and associated with breast cancers. Specific ectoenzymes were identified by indirect immunofluorescence and quantified by flow cytometry and semi-quantitative PCR. A consistent difference was noted between the two fibroblast sub-populations at early passage in respect of dipeptidyl peptidase IV (DPP IV) and aminopeptidase N (APN) expression. Early passage intralobular fibroblasts were positive for APN but negative for DPP IV, as seen in the intact tissue. However, with continued sub-culture they gradually began to express DPP IV, until at later passages they became indistinguishable from the interlobular fibroblasts, which were APN and DPP IV-positive at all stages in culture, as they are in intact tissue. Neutral endopeptidase (NEP/CALLA/CD10) is not expressed by normal adult breast fibroblasts but is found in the stroma associated with over 60% of breast cancers. It was up-regulated in vitro on both inter- and intralobular fibroblasts, with final levels that were significantly (< 14 times) higher on the former in all pairs of preparations from individual donors analysed. This difference persisted with continued passage, and levels of the ectoenzyme and its messenger RNA were further up-regulated by hydrocortisone in both populations. These results demonstrate that phenotypically distinct cultures of human mammary fibroblast sub-populations can be used to study the regulation of these stromal ectoenzymes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ectoenzyme regulation by phenotypically distinct fibroblast sub-populations isolated from the human mammary gland. 787 58

Neutral endopeptidase is a cell surface zinc metal-lopeptidase that regulates the action of a variety of physiologically active peptides. The enzyme exhibits a wide tissue distribution, being most abundant in kidney and lung. Three rat neutral endopeptidase cDNAs with unique 5'-untranslated sequences were isolated. Distribution of the corresponding mRNAs in rat tissues was analyzed by RNase protection assays and by in situ hybridization. In kidney, the type 2b transcript was the major species. In lung and testis, type 1 and type 2b transcripts were expressed in approximately equal amounts, while in brain and spinal cord the type 1 mRNA was the major transcript. These findings were extended by in situ hybridization studies. All three mRNAs were expressed in the proximal tubule of the kidney, with the type 2b transcript giving the strongest signal. In the frontoparietal cortex, expression of the neutral endopeptidase mRNA subtypes was cell- and region-specific. The type 1 transcript was localized to neurons, type 2b mRNA was not detectable, while type 3 mRNA was localized to the oligodendrocytes of the corpus callosum. These results clearly demonstrate that expression of the three neutral endopeptidase mRNAs can be regulated in a cell-specific manner.
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PMID:Tissue-specific expression of rat neutral endopeptidase (neprilysin) mRNAs. 789 Jun 99

The existence of neutral endopeptidase (Enkephalinase, NEP, E.C.3.4.24.11) in membranes of nerve endings in the rat median eminence suggests that some neuropeptides have paracrine and/or autocrine actions in this region. In vitro, neutral endopeptidase is capable of hydrolysing a variety of regulatory peptides but in vivo, many works indicate that in the central nervous system this enzyme is highly implicated in the biological inactivation of enkephalins and tachykinins. In addition there is evidence that NEP is also involved in the inactivation of neurotensin in vivo. The modulation of the release of gonadotrophin releasing hormone (GnRH) is one of the documented actions of enkephalins within the median eminence. However, it is at present unclear whether enkephalins act on dopamine endings, on GnRH endings or on both. As the technical parameters and particularly the tissue fixation used to detect neutral endopeptidase are compatible with immunocytochemical detection of GnRH and tyrosine-hydroxylase (the rate limiting enzyme in the synthesis of catecholamines), two double immunolabelings were realised at the ultrastructural level to determine if GnRH and dopamine nerve endings have the enzyme inserted within their plasma membrane. Our study shows the presence of neutral endopeptidase on tyrosine-hydroxylase-immunoreactive nerve endings while presence of the enzyme on GnRH-immunoreactive nerve endings is not demonstrated. Consequently, our results provide morphological arguments for possibilities of paracrine and/or autocrine actions by neuropeptides inactivated by neutral endopeptidase on tuberoinfundibular dopaminergic nerve endings. Conversely, action of the same peptides on GnRH boutons seems more unlikely.
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PMID:Detection of neutral endopeptidase (NEP, enkephalinase, E.C.3.4.24.11) in relation to dopaminergic and gonadoliberinergic nerve endings in the median eminence of the male rat: a double labeling ultrastructural study. 789 68

We quantitated the level of activity of several peptidases to determine if enzymes involved in the post-translational processing and metabolism of peptides are detectable and are altered developmentally in specific regions of the rat brain. Carboxypeptidase H (EC 3.4.17.10), a processing enzyme, located in chromaffin secretory granules was expressed at high levels on postnatal day 0 (P 0, birth) in hypothalamus, cortex and cerebellum (3.48, 4.98, 4.29 pmol/mg/min, respectively). An increase of activity occurred from P 0 to P 7 in both hypothalamus and cortex (7.68, 6.94) with a decrease shown in cerebellum (3.89). After P 7, activity increased by P 90 (adult) in the hypothalamus (7.65), decreased to birth levels in the cortex (4.79) and decreased below birth levels in the cerebellum (2.76). This regional pattern of carboxypeptidase H activity may signify its involvement throughout the life of the rat in the synthesis of specific regional neuropeptides important in development. Enzyme activity for the degradative enzymes, neutral endopeptidase (EC 3.4.24.11) and metallo endopeptidase (EC 3.4.24.15) did not present the same developmental pattern as seen with the processing enzyme. Neutral endopeptidase activity doubled in the hypothalamus from P 0 to P 7 (3080 pmol/mg/min) and remained constant throughout the maturation of the animal. In the cortex, activity increased significantly from P 0 to P 30 (1171) and remained at that level to P 90. In the cerebellum, activity decreased from P 0 to P 30 (320) and remained at that level to P 90 (304). At birth, metallo endopeptidase activity was highest in cortex (2702 pmol/mg/min), intermediate in hypothalamus (1658) and lowest in cerebellum (1410).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The ontogeny of enzymes involved in post-translational processing and metabolism of neuropeptides. 795 37

Neutral endopeptidase (Endopeptidase 24.11; NEP; neprilysin), an integral membrane protein, and villin, a major microvillar cytoskeletal actin-binding protein, are both typically associated with brush border epithelia. In this study, cRNA probes were hybridized in situ to investigate the expression of NEP and villin genes in embryo and adult mouse enterocytes. During development, villin mRNAs were easily detected in the immature digestive tract well before establishment of the brush border. In 17-day-old embryos, a transient elevation of villin mRNA occurred just prior to a dramatic increase in microvilli length and density. NEP only appeared by day 17 as the embryonic gut began to become functional. It therefore appears that the onset of transcription of specialized cytoskeletal proteins from the brush border preceded that of intrinsic membrane-bound enzyme from microvilli. In the adult intestinal fold, both mRNAs were expressed along the whole length of the villus with maximal expression at its base. In contrast, both proteins were uniformly expressed along the whole crypt-villus axis. Quantitative analysis revealed an asymmetric intracellular distribution of both mRNAs that were differentially polarized in the apical cytoplasm of enterocytes.
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PMID:Comparative analysis of neutral endopeptidase (NEP) and villin gene expression during mouse embryogenesis and enterocyte maturation. 802 47

Neutral endopeptidase (NEP, EC 3.4.24.11) is a major ectoenzyme of the brush-border membrane. The ectodomain of NEP contains five putative N-glycosylation sites. In order to determine the role of the addition of sugar moieties on the activity and intracellular transport of NEP, we have used site-directed mutagenesis to remove all or some of the five potential sites of sugar addition in membrane-bound and secreted forms of the enzyme. Expression of NEP glycosylation mutants in COS-1 cells showed that all five sites are used for sugar addition. Immunoblotting of NEP in COS-1 cell extracts or culture media indicated that total expression of normal membrane-bound NEP was not affected by mutations at glycosylation sites, whereas this expression level appeared to be strictly dependent on the number of glycosylation sites retained on the soluble form. The transport to the cell surface was also reduced by decreased glycosylation, but again the phenomenon appeared more drastic in the case of the soluble form than for the membrane-bound enzyme. Enzyme activity was decreased by deglycosylation. However, the presence of either of two crucial sites (sites 1 and 5; numbered from the N-terminus of the protein) was sufficient to recover close-to-normal enzymic activities. Transport to the cell surface and enzyme activity of NEP are thus both dependent on sugar residues, probably through different conformational constraints. These constraints seem to be local for enzyme activity but more global for transport to the cell surface.
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PMID:Role of glycosylation in transport and enzymic activity of neutral endopeptidase-24.11. 809 97

Neutral endopeptidase (EC 3.4.24.11; NEP) is a membrane-bound zinc-metallopeptidase. The catalytic zinc ion is coordinated to three amino acid residues (His538, His587 and Glu646) and a water molecule. Here, we have systematically substituted potential metal-coordinating amino acid residues (His, Glu, Asp, Cys, Tyr, Ser) for each of the three zinc ligands of NEP using a recombinant polymerase chain reaction procedure. NEP mutants at positions 583 and 587 were devoid of catalytic activity. However, Glu587 NEP and Cys583 NEP were able to bind partially a tritiated inhibitor, the binding of which is dependent on the presence of the zinc atom. At position 646, the aspartate and cysteine mutants exhibited activity. For both mutants Km values were unaltered but kcat values were decreased by about 20-fold. Both mutants bound the tritiated inhibitor with Kd values similar to that of the wild-type enzyme. Our data suggest that neither histidine-583 nor -587 can be replaced by any other ligands. On the other hand, the glutamic acid at position 646 can be converted to an aspartic acid or a cysteine indicating the importance of a negative charge at this position.
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PMID:Substitution of potential metal-coordinating amino acid residues in the zinc-binding site of endopeptidase-24.11. 809 56


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