Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonadrenergic, noncholinergic contractile responses of guinea pig hilar bronchi to transmural electrical stimulation (TES) have been suggested to be due to release of endogenous tachykinins from capsaicin-sensitive neurons (C-fibers). Thiorphan and phosphoramidon, inhibitors of neutral endopeptidase (NEP, the major enzyme responsible for degrading tachykinins), were found to potentiate contractile responses of this isolated airway segment to TES and exogenously applied capsaicin, substance P and neurokinin A. However, the magnitude of potentiation by either inhibitor was smaller for TES and capsaicin (less than 10-fold leftward shift) than for the substrate agonists (about 100-fold leftward shift). This quantitative difference in potentiation by NEP inhibitors does not appear to be due to an influence of vasoactive intestinal peptide or calcitonin gene-related peptide, two endogenous peptides that might be released concomitantly by TES. Neither peptide caused marked effects on contractile responses to TES or tachykinins when applied to the isolated tissues. Addition of inhibitors of serine proteases, aminopeptidases, acetylcholinesterase and angiotensin-converting enzyme failed to further potentiate responses to TES in the presence of thiorphan. Therefore, the contractile response does not appear to be further modified by the activity of these peptidases. Neuropeptide gamma, but not neuropeptide K, was potentiated by thiorphan. The data suggest that peptides that are not substrates for NEP (for example, neuropeptide K) may also be released by TES from capsaicin-sensitive neurons to cause contraction. This may, at least in part, explain the quantitative difference in potentiation by NEP inhibitors of contractile responses to TES and to exogenously applied NEP-sensitive tachykinins in the guinea pig hilar bronchus.
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PMID:Pharmacologic studies on the differential influence of inhibitors of neutral endopeptidase on nonadrenergic, noncholinergic contractile responses of the guinea pig isolated hilar bronchus to transmural electrical stimulation and exogenously applied tachykinins. 239 13

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

To study the roles of substance P and endogenous neutral endopeptidase in mediating cough, we measured cough responses in awake guinea pigs in response to exogenous substance P and capsaicin aerosols in the presence and absence of the neutral endopeptidase inhibitors leucine-thiorphan and phosphoramidon. Substance P stimulated cough in very low concentrations (10(-17)-10(-16) M). In a second study where the investigator did not know whether substance P or diluent alone was aerosolized, substance P (10(-16) M) caused cough. Leucine-thiorphan (10(-5) M) and phosphoramidon (10(-5) M) potentiated substance P-induced cough; NEP inhibitors also potentiated capsaicin-induced cough significantly. These findings suggest that substance P is a potent stimulator of cough responses, that capsaicin-induced cough is mediated by substance P or another similar neuropeptide, and that cough responses are modulated by endogenous neutral endopeptidase.
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PMID:Neutral endopeptidase inhibitors potentiate substance P- and capsaicin-induced cough in awake guinea pigs. 246 67

We have previously reported that the amino acid sequence of the common acute lymphoblastic leukemia antigen (CALLA, CD10) translated from a normal human kidney cDNA clone is identical to that of neutral endopeptidase (NEP, EC 3.4.24.11). In this study, we show that by flow cytometry, a monoclonal antibody (135A3) produced against rabbit NEP reacted selectively with leukemia and melanoma cell lines expressing CALLA on their surface. A glycoprotein of apparent Mr 100,000 was immunoprecipitated from surface labeled NALM-1 leukemia or Mel-1477 melanoma cells with monoclonal antibodies to NEP (135A3) or CALLA (44C10). mRNAs hybridizing to a NEP-specific probe were present in CALLA+ leukemia and melanoma cell lines, but absent from CALLA- lines. NEP enzymatic activity was detected on intact cells from CALLA+ lines, but not CALLA- lines. The activity was blocked by two selective inhibitors of NEP, thiorphan and phosphoramidon. CALLA antigen purified from the NALM-6 leukemic cell line by affinity to 44C10-IgG Sepharose retained a peptidase activity that was completely blocked by thiorphan and phosphoramidon. Thus the CALLA antigen present at the surface of leukemia and melanoma cell lines is an enzymatically active neutral endopeptidase.
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PMID:Common acute lymphoblastic leukemia antigen expressed on leukemia and melanoma cell lines has neutral endopeptidase activity. 252 92

This report summarizes the recent rapid development of research on neutral endopeptidase 24.11 (enkephalinase; NEP) and on two other metalloenzymes, meprin and endopeptidase 24.15. NEP cleaves a variety of active peptides, including enkephalins, at the amino side of hydrophobic amino acids. The cDNA for human, rat, and rabbit NEP has been cloned and the deduced protein sequences revealed a high degree of homology (93-94%). Site-directed mutagenesis proved that an active site glutamic acid is involved in catalysis and two active site histidines are responsible for binding the zinc cofactor. Although NEP was originally discovered in the kidney, it is widely distributed in the body including specific structures in the central nervous system, lung, male genital tract, and intestine and in neutrophils, fibroblasts, and epithelial cells. In tissues and cells NEP is bound to plasma membrane through a hydrophobic membrane-spanning domain near the NH2 terminus, but it is present in soluble form in urine and blood. In addition to enkephalins, NEP cleaves kinins, chemotactic peptide, atrial natriuretic factor (ANF), and substance P in vivo. NEP in the lung is a major inactivator of substance P, which constricts the airway smooth muscles. Because of the possible involvement of NEP in the metabolism of opioid peptides and the cardiac hormone ANF, orally active inhibitors have been synthesized. Compounds that inhibit both aminopeptidase and NEP were reported to prolong the analgesic effects of enkephalins. Other inhibitors given per os prolonged the renal effects of exogenous ANF. A newly synthesized specific inhibitor of NEP was also active in animal experiments as an analgesic. Studies on the structure and function of NEP should lead to further development of therapeutically applicable inhibitors.
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PMID:Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones. 252 10

We have previously isolated a cDNA clone encoding the common acute lymphoblastic leukemia antigen (CALLA) from a normal human kidney library. Analysis of the amino acid sequence deduced from nucleotide sequencing of this cDNA established that CALLA is identical to the recently cloned human neutral endopeptidase (NEP; E.C. 3.4.24.11). Southern blot analysis of SacI fragments of DNA from human-rodent somatic cell hybrids using a 1.6-kb CALLA cDNA probe showed that the CALLA-NEP gene is located on human chromosome 3.
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PMID:The common acute lymphoblastic leukemia antigen (neutral endopeptidase-3.4.24.11) gene is located on human chromosome 3. 252 24

Several established human glioma cell lines have been previously shown to express the common acute lymphoblastic leukemia antigen (cALLa, CD 10), an important marker in the diagnosis of human acute lymphocytic leukemia (ALL). The amino acid sequence of cALLa is identical to that of neutral endopeptidase (NEP,E.C.3.4.24.11), and cALLa expressed on leukemia and melanoma cell lines is enzymatically active NEP. In the present study, we investigated whether cALLa expressed on glioma cell lines is active NEP. We detected cALLa on 10 out of 13 glioma cell lines using 2 different anti-cALLa MAbs (A12-G4 and FAH99). NEP antigen, as detected by immunostaining with an anti-NEP MAb (135A3), was expressed on the same 10 lines. cALLa-positive, but not cALLa-negative cell lines displayed an endopeptidase activity. This activity could be blocked by phosphoramidon, a specific inhibitor of NEP. Furthermore, mRNAs hybridizing to an NEP-specific probe were present in cALLa-positive glioma cells but not in cALLa-negative cells. Taken together, the results provide strong evidence that cALLa-positive glioma cell lines express endopeptidase activity on the cell surface.
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PMID:Human glioma cell lines expressing the common acute lymphoblastic leukemia antigen (cALLa) have neutral endopeptidase activity. 253 Nov 22

Neuropeptides such as substance P are implicated in inflammation mediated by sensory nerves (neurogenic inflammation), but the roles in disease of these peptides and the peptidases that degrade them are not understood. It is well established that inflammation is a prominent feature of several airway diseases, including viral infections, asthma, bronchitis, and cystic fibrosis. These diseases are characterized by cough, airway edema, and abnormal secretory and bronchoconstrictor responses, all of which can be elicited by substance P. The effects of substance P and other peptides that may be involved in inflammation are decreased by endogenous neutral endopeptidase (NEP; also called enkephalinase, EC 3.4.24.11), which is a peptidase that degrades substance P and other peptides. In the present study, we report that rats with histories of infections caused by common respiratory tract pathogens (parainfluenza virus type 1, rat corona-virus, and Mycoplasma pulmonis) not only have greater susceptibility to neurogenic inflammatory responses than do pathogen-free rats but also have a lower activity of NEP in the trachea. This reduction in NEP activity may cause the increased susceptibility to neurogenic inflammation by allowing higher concentrations of substance P to reach tachykinin receptors in the trachea. Thus decreased NEP activity may exacerbate some of the pathological responses in animals with respiratory tract infections.
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PMID:Neutral endopeptidase and neurogenic inflammation in rats with respiratory infections. 254 62

The distributions of the neutral endopeptidase 24.11 (NEP; enkephalinase) and of mu and delta opioid receptors have been studied by autoradiography in the human spinal cord during ontogenesis, mu and delta sites were assessed by using [3H]DAGO and [3H]DTLET respectively and NEP was labelled by [3H]HACBO-Gly, a NEP inhibitor. Labelling by the three markers was found at an early stage of development of the central nervous system (14 weeks) and was mainly localized in the gray matter, with highest densities in the superficial layers of the dorsal horn. Moreover [3H]DAGO also diffusely labelled the ventral motor areas. NEP and delta binding sites were localized transiently in the fasciculus gracilis at the cervical level at a fetal age of 24 weeks, an area where no enkephalin-like immunoreactivity (ELI) has been found. Conversely no opioid binding sites or NEP were observed at a fetal age of 18 weeks in the intermediolateral region where ELI fibres and cells were detected transiently. In general, a better correlation between the distribution of NEP and that of delta opioid sites was observed. Meninges contained a very high density of [3H]HACBO-Gly sites. This labelling appeared almost simultaneously with that in the spinal cord tissue and increased with maturation. An increase in labelling by the three markers appeared slightly earlier than the clustering of ELI fibres in the substantia gelatinosa. Our data show that in the human spinal cord, structural and biochemical elements involved in enkephalinergic transmission appear almost simultaneously and early in ontogeny.
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PMID:Ontogeny of mu and delta opioid receptors and of neutral endopeptidase in human spinal cord: an autoradiographic study. 255 52

The possible changes in neutral endopeptidase EC 3.4.24.11 ("enkephalinase", NEP), mu and delta opioid binding sites, were investigated using in vitro quantitative radioautography in various regions of the central nervous system of the Freund's adjuvant-induced arthritic rat, a model of chronic pain. Enkephalinase was labeled by a specific tritiated inhibitor, [3H]N-[(2RS)-3-hydroxyaminocarbonyl-2-benzyl-1-oxopropyl]glycine ([3H]HACBO-Gly), while mu and delta opioid binding sites were selectively labelled with [3H]Tyr-D-Ala-Gly-(Me)Phe-Gly-ol ([3H]DAGO) and [3H]Tyr-D-Thr-Gly-Phe-Leu-Thr ([3H]DTLFT), respectively. As compared to controls, no significant modifications were found in NEP, mu or delta binding sites at both supraspinal and spinal levels of arthritic rats. These results suggest that the enhanced efficiency of exogenous opioids or endogenous enkephalins, reported to occur in this model of chronic inflammatory pain, are not directly related to changes in mu and delta opioid binding sites or steady state levels of NEP.
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PMID:Lack of significant changes in mu, delta opioid binding sites and neutral endopeptidase EC 3.4.24.11 in the brain and spinal cord of arthritic rats. 255 47


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