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)

Peptidases play an important role in the regulation of peptide-mediated effects. Modulation of peptidase activity may therefore be a major mechanism to control peptide actions. Our aim was to analyse the effects of cytokines and glucocorticoids on peptidases expressed by human bronchial epithelial cells, which have been shown to be an important site for peptidase activity. The effects of cytokines [interleukin 1 beta (IL-1 beta), tumour necrosis factor alpha (TNF-alpha), IL-4, interferon gamma (INF-gamma), and epidermal growth factor (EGF)] and/or dexamethasone (DEX) on both expression and activity of neutral endopeptidase (NEP) and aminopeptidase N (APN) by BEAS 2B cells were determined using flow cytometry and activity assays, respectively. IL-1 beta, and to a lesser extent, TNF-alpha and IL-4 increased NEP activity and expression, whereas IFN-gamma decreased NEP. The effect of IL-1 beta was mediated, at least in part, via a cAMP-dependent pathway which did not involve prostaglandin E2 synthesis. APN was increased after 24-h stimulation with IFN-gamma, whereas other stimuli had no effect. DEX strongly increased NEP and APN expression and activity, both in the absence and in the presence of cytokines. We conclude that cytokines and glucocorticoids are able to modulate the activity of NEP and APN on BEAS 2B cells. Our results suggest a role for the human bronchial epithelium in the control of inflammation and indicate that one beneficial effect of glucocorticoids on asthma may be upregulation of peptidases expressed by bronchial epithelial cells.
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PMID:Cytokines and glucocorticoids modulate human bronchial epithelial cell peptidases. 950 46

It is known that aminopeptidase N (APN) and neutral endopeptidase (NEP) in the central nervous system (CNS) regulate opioid peptides, leading to pain modulation. To examine whether these enzymes located on human neutrophils (PMNs) play a role in several modalities of pain, we measured the activity of these enzymes located on PMNs derived from patients with chronic pain and compared this with that of healthy volunteers. APN activity in the group of patients with chronic pain was significantly increased compared with that in group of healthy volunteers (4.25 +/- 0.17, n = 36 vs 3.53 +/- 0.21, n = 24, nmol.min-1.10(6) cells, P > 0.05, mean +/- SE). But NEP activity showed no differences in two groups. These results suggest that APN located on PMNs from patients with chronic pain may act as an indicator of continuous painful condition and there may be a pain-modulating system in the blood.
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PMID:[Changes in aminopeptidase N located on neutrophils derived from patients with chronic pain]. 951 26

Inhibition of aminopeptidase N and neutral endopeptidase-24.11, two zinc metallopeptidases involved in the inactivation of the opioid peptides enkephalins, produces potent physiological analgesic responses, without major side-effects, in all animal models of pain in which morphine is active. Dual inhibitors of both enzymes could fill the gap between opioid analgesics and antalgics. Until now, attempts to find a compound with high affinity both for neutral endopeptidase and aminopeptidase N have failed. We report here the design of dual competitive inhibitors of both enzymes with KI values in the nanomolar range. These have been obtained by selecting R1, R2, and R3 determinants in aminophosphinic-containing inhibitors: NH2---CH(R1)P(O)---(OH)CH2---CH(R2)CONH---CH(R3)COOH, for optimal recognition of the two enkephalin inactivating enzymes, whose active site peculiarities, determined by site-directed mutagenesis, have been taken into account. The best inhibitors were 10x more potent than described dual inhibitors in alleviating acute and inflammatory nociceptive stimuli in mice, thus providing a basis for the development of a family of analgesics devoid of opioid side effects.
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PMID:Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes: a class of central analgesics. 975 84

Because mesangial cells (MC) are a target and a degradation site for angiotensin II (ANG II), we characterized the degrading enzymes and receptors of ANG IV, a metabolite of ANG II, on these cells. ANG IV was metabolized into its NH2-terminal deleted peptides, ANG II-(4-8), ANG II-(5-8), and ANG II-(6-8) by rat MC. Total protection of ANG IV was obtained only when PC-18, a specific aminopeptidase N (APN) inhibitor, and JFH-27A, a mixed inhibitor of dipeptidylaminopeptidase (DAP) and neutral endopeptidase (NEP), were simultaneously added. In contrast, thiorphan, an NEP inhibitor, was inactive. These results demonstrate the exclusive role of APN and DAP in ANG IV degradation. 125I-labeled ANG IV binding was studied in the presence of PC-18 and JFH-27A to suppress ligand degradation. Under these conditions, ANG IV-specific receptors could be demonstrated with a KD of 1.8 nM and a density of 55 fmol/mg. In contrast with MC, no evidence for ANG IV receptors could be obtained in freshly isolated glomeruli. ANG IV stimulated cytosolic calcium concentration in MC, whereas its NH2-terminal deleted metabolites were inactive. Therefore, ANG IV must be protected from degradation by APN and DAP in studies on the nonimmediate biological effects of this peptide.
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PMID:Characterization of angiotensin IV-degrading enzymes and receptors on rat mesangial cells. 975 25

In this study, we examined the influence of morphine and naloxone on the enzymatic activity of different ecto-peptidases located on the surface of endothelial cells. Morphine increased in a concentration dependent manner the degradation of Leu-enkephalin in cultivated bovine aortic endothelial cells. Naloxone, a morphine antagonist, did not prevent this effect, but caused it as well. The enhanced Leu-enkephalin degradation was due to an increase in the activity of angiotensin-converting enzyme (ACE), whereas the activity of other ecto-peptidases (aminopeptidase N and neutral endopeptidase) was not influenced. Despite a high non-specific binding of [3H]-morphine, no specific opioid receptor binding on the endothelial cells could be detected. Autoradiographic investigations with native, cryostat-sectioned cells demonstrated that [3H]-morphine was nearly exclusively located within the nuclei. The present results suggests that the morphine effect concerning ACE activity is not mediated via opioid receptors but presumably by interactions within the cell nucleus.
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PMID:Stimulation of endothelial angiotensin-converting enzyme by morphine via non-opioid receptor mediated processes. 977 Feb 11

During the course of a productive infection, human cytomegalovirus (HCMV) has a sophisticated relationship with its host cell. An increasing number of virus-encoded genes are being identified which act specifically to usurp or modulate functions in the host cell associated with transcriptional control, cell signalling, and protein synthesis. While HCMV infection is associated with a general upregulation of cellular gene expression, the expression a small subset of cellular proteins, including the MHC-1 heavy chain and fibronectin, is downregulated. This study now identifies two additional cellular proteins, aminopeptidase N (CD13) and neutral endopeptidase (CD10), that are downregulated during HCMV infection. While aminopeptidase N and neutral endopeptidase exhibit no significant sequence homology, both are expressed on the cell surface and have very similar enzymatic properties. HCMV infection was associated with reduced surface expression and enzyme activity of CD13 and CD10, an apparent decrease in the rate of synthesis of both proteins in metabolic-labelling experiments, and inhibited glycosylation of the nascent CD13 and CD10 polypeptide chains that were synthesized. Levels of CD10 poly A+ RNA were suppressed efficiently at all stages of virus infection; however, the reduction in CD13 poly A+ RNA levels was much less pronounced. This differential effect suggests that HCMV may be downregulating expression of CD10 and CD13 by independent mechanisms. Indeed, treatment of cells with an inhibitor of viral DNA synthesis blocks downregulation of CD13, whilst downregulation of CD10 is unaffected. While it is not yet clear what advantage is bestowed on the virus by downregulating expression of CD13 and CD10, aminopeptidases are known to have a role in peptide processing in both the MHC class I the MHC class II antigen presentation pathways.
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PMID:Human cytomegalovirus infection downregulates expression of the cellular aminopeptidases CD10 and CD13. 979 45

The regulatory mechanisms responsible for malignant transformation, tumor progression and metastasis in renal cell cancer (RCC) are still unclear, but there is some evidence that biologically active peptides might have regulatory effects on the behavior of this malignancy. Tumor cells can change local concentrations of active peptides by modulating their cell-surface enzymes. Using immunohistochemistry and enzyme-histochemistry, the expression of various membrane peptidases was examined in RCC and adjacent noninvaded renal parenchyma (n = 44). We describe the down-regulation of neutral endopeptidase 24.11 (NEP) protein expression in RCC of the clear cell/chromophilic type when compared with renal parenchyma, and show for the first time the lack of enzyme activity of NEP in RCC. The strongest expression could be found for dipeptidyl peptidase IV (DPIV) which is only decreased in RCC of the chromophobe cell type and is even present in oncocytoma. Aminopeptidase N (APN) and aminopeptidase A (APA) show attenuated expression in up to one third of clear cell/ chromophilic RCC. Chromophobe RCC and oncocytomas do not express APN, APA, NEP and gamma-glutamyltranspeptidase.
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PMID:Endopeptidase 24.11/CD10 is down-regulated in renal cell cancer. 985 25

The polymorphonuclear neutrophils (PMN) possess sufficient potential to affect both immune response and inflammation, however it has not been yet described in the course of multiple sclerosis (MS). We have studied binding of fluorescein isothiocyanate (FITC)- stained TNF-alpha by PMN, the expression of CD11a, CD11b, and CD18 molecules of beta2-integrines and the expression of CD10 (neutral endopeptidase-NEP) and of CD13 (aminopeptidase N; APN) antigens on PMN in three different groups of MS patients. The control group included neurological patients (OND) with noninflammatory diseases. The obtained results have proved that during MS exacerbation and in the course of chronic progressive MS, PMN reveal several forms of preactivation, including significantly higher stained-TNF-alpha binding, higher expression of CD11b and CD18, as well as CD10 and CD13 antigens, in comparison with MS remission or OND. We suggest that the increased expression of these molecules on PMN of MS patients in exacerbation of the disease and to a lower degree in the course of CP-MS is a result of PMN priming, and directly prove the PMN involvement in the disease pathogenesis.
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PMID:The immunoregulatory abilities of polymorphonuclear neutrophils in the course of multiple sclerosis. 1070 82

There is little data available regarding the extent of peptide metabolism encountered following inhalation to the lung. We have studied the activity of five ectopeptidases in primary rat alveolar epithelial cells, A549 cells and pulmonary macrophages. Peptidase activity was assayed in the plasma membrane fractions (PMF) of primary type II alveolar epithelial cells (ATII cells) after 2 days in culture and after 7 days in culture when they had formed monolayers of type I-like cells (ATI-like cells). Dipeptidyl peptidase IV (DPP) activity fell from 36.65 mU/mg protein to 16.29 mU/mg protein between day 2 and day 7 in culture, aminopeptidase N (AMN) activity increased from 16.16 mU/mg protein to 23.99 mU/mg protein, angiotensin-converting enzyme (ACE) activity was lost (4.29 mU/mg protein at day 2, not detected at day 7), and carboxypeptidase M (CPM) activity was acquired (not detected at day 2, 5.20 mU/mg protein at day 7). The profile of exopeptidase expression in A549 cells was similar to that of primary rat alveolar cells at day 7 in culture (DPP 24.24 mU/mg protein, AMN 47.74 mU/mg protein, CPM 4.28 mU/mg protein, ACE not detected). Macrophages expressed high levels of aminopeptidases (DPP 46.85 mU/mg protein, AMN 28.28 mU/mg protein) but carboxypeptidase activity was not detected. Low neutral endopeptidase 24.11 (NEP) activity was found in all cell types studied (0.96-2.41 mU/mg protein). The qualitative and quantitative changes in the peptidase activity of primary cultured rat alveolar cells between day 2 and day 7 in culture has implications for the use of alveolar cell monolayers as drug absorption models to investigate peptide absorption from the lung. Ectopeptidase activity in cultured alveolar cells can be used to infer the peptide-metabolising capacity of the surface of the alveolar epithelium. The aminopeptidase activity in particular, if representative of enzyme activity in vivo, would offer a significant metabolic barrier to systemic delivery of peptides via the lung.
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PMID:Temporal dependence of ectopeptidase expression in alveolar epithelial cell culture: implications for study of peptide absorption. 1037 Jan 93

Through the development of a new chemical strategy, aminophosphinic peptides containing a pseudoglutamyl residue (Glu Psi(PO2-CH2)Leu-Xaa) in the N-terminal position were synthesized and evaluated as inhibitors of aminopeptidase A (APA). The most potent inhibitor developed in this study, Glu Psi(PO2-CH2)Leu-Ala, displayed a Ki value of 0.8 nM for APA, but was much less effective in blocking aminopeptidase N (APN) (Ki = 31 microM). The critical role of the glutamyl residue in this phosphinic peptide, both in potency and selectivity, is exemplified by the P1 position analogue, Ala Psi(PO2-CH2)Leu-Ala, which exhibited a Ki value of 0.9 microM toward APA but behaved as a rather potent inhibitor of APN (Ki = 25 nM). Glu Psi(PO2-CH2)Leu-Xaa peptides are poor inhibitors of angiotensin converting enzyme (Ki values higher than 1 microM). Depending on the nature of the Xaa residue, the potency of these phosphinic peptides toward neutral endopeptidase 24-11 varied from 50 nM to 3 microM. In view of the in vivo role of APA in the formation of brain angiotensin III, one of the main effector peptides of the renin angiotensin system in the central nervous system, highly potent and selective inhibitors of APA may find important therapeutic applications soon.
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PMID:Potent and selective inhibition of zinc aminopeptidase A (EC 3.4.11.7, APA) by glutamyl aminophosphinic peptides: importance of glutamyl aminophosphinic residue in the P1 position. 1065 62


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