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)

In addition to the cholinergic and adrenergic nervous systems, a new noncholinergic and nonadrenergic nervous system has recently been described, involving the afferent sensory nerves in the airways. Many irritants (dusts, chemicals) stimulate these sensory nerves to release neuropeptides. Among these neuropeptides, the "tachykinins" exist in sensory nerves of airways (substance P, neurokinin A). These tachykinins have the ability to affect multiple cells in the airways and to provoke many responses including smooth muscle contraction, mucus secretion, plasma extravasation and neutrophil adhesion. This series of effects is termed "neurogenic inflammation". Using the respiratory tract as experimental model, it has been shown that: a) substance P (SP) is widely distributed in afferent fibers in the vagus, b) SP-immunoreactivity has been demonstrated in the epithelium, in airway smooth muscle, near blood vessels and submucosal glands, c) substance P and other tachykinins are released from sensory nerve terminals during stimulation electrically and by capsaicin, d) local administration of substance P mimics the effect of sensory nerve stimulation, e) smooth muscle contraction, gland secretion and plasma leakage, normally induced by nerve stimulation or noxious stimulus, are absent in tissues pretreated with the substance P depleting agent capsaicin or with tachykinin antagonists. These findings indicate that peptidergic nerve fibers are involved in the local regulation of tone of smooth muscle, regulation of blood flow, vascular permeability, and mucus secretion. We released that degradative mechanisms could play an important role in modulating tachykinin effects, just as acetylcholinesterase modulates effects of acetylcholine released from nerve terminals. We discovered that a membrane-bound enzyme called enkephalinase (also called neutral endopeptidase, EC 3, 4, 24, 11), located on specific cells that contain tachykinin receptors, modulate the action of tachykinins by cleaving and thus inactivating them. Our studies demonstrate that viral infection or cigarette smoke potentiate various effects of tachykinins by decreasing tissue enkephalinase activity. Thus, down-regulation of enkephalinase activity in specific tissues can modify the extent of neurogenic inflammation, and this modification could be important in the pathogenesis of diseases in airways and other tissues that contain tachykinins.
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PMID:[The role of enkephalinase (neutral endopeptidase) in neurogenic inflammation of the respiratory tract]. 134 Apr 78

Studies in the rabbit retina have shown that infusion of exogenous acetylcholine (ACh) into the vitreal chamber leads to an increase in the amount of substance P (SP) immunoreactivity (Goebel and Pourcho, submitted). This increase was determined to be independent of new peptide synthesis, suggesting that the elevated level of SP is the result of ACh inhibition of an SP-degrading protease. This phenomenon has now been confirmed in vitro in both tissue slice and retinal homogenate assays. These studies have shown that ACh decreases the rate of SP hydrolysis in a concentration dependent manner. Recovery of SP hydrolytic activity following ACh inhibition was found to be directly proportional to the amount of acetylcholinesterase (AChE) activity in the membrane fraction. Specific protease inhibitors were used to determine the relative contributions of membrane associated retinal enzymes to SP-hydrolysis. In the presence of 1 mM 1,10-phenanthroline or p-chloromercuribenzenesulfonic acid all SP-hydrolytic activity was abolished, indicating that the enzyme(s) responsible for the degradation of the peptide is a metallopeptidase. The ACh sensitive retinal enzyme was found to be concentrated in the membrane fraction where it accounts for approximately 70% of the SP hydrolytic activity. Although the precise identity of this enzyme remains to be determined, the present evidence indicates that it shares many of the characteristics of the enzyme substance P-degrading endopeptidase (Endo et al. 1988, 1989). Enkephalinase activity was also found, contributing to 28% of the hydrolytic activity in the membrane fraction. However, the activity of this enzyme was insensitive to elevated levels of ACh. After initial cleavage of SP by the primary hydrolytic enzymes, further degradation of the fragments appears to be carried out by membrane associated serine protease(s). The activity exhibited by this class of enzymes was inhibited by DFP treatment and was not sensitive to ACh. Although AChE does not make a major contribution to the hydrolysis of SP, it does participate in peptide degradation via its esterase activity which controls the level of ACh, thereby modulating the primary SP-hydrolytic enzyme.
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PMID:Hydrolysis of substance P in the rabbit retina: II. The role of a membrane-associated acetylcholine-sensitive metalloendopeptidase. An in vitro study. 137 Nov 83

In recent years, studies of the regulation of the airways have focused to an increasing degree on the roles of neuropeptides. Several peptides have been shown to be present in airways and mediate such diverse responses as ion transport, mucus secretion, bronchospasm or relaxation, edema, cough, changes in vascular permeability, and neutrophil chemotaxis. More recently, studies have described the roles of peptidases, most notably neutral endopeptidase (NEP, also known as enkephalinase, or E.C. 3.4.24.11) and kininase II (also known as angiotensin-converting enzyme, or E.C. 3.4.15.1) in modulating peptide-induced responses. The enzymes cleave a wide variety of peptides, generating metabolites that are inactive in the systems studied to date. Thus inhibitors of NEP potentiate responses to peptides that are cleaved by it. Therefore, NEP plays roles in modulating peptide-induced effects analogous to the role of acetylcholinesterase in modulating cholinergic neurotransmission. In several experimental respiratory diseases, the activity of neutral endopeptidase is decreased, resulting in increased responses to peptides. The therapeutic application of recombinant NEP protects the airways from the adverse actions of stimuli that release inflammatory peptides, and induction of the NEP gene expression by glucocorticoids suggest a possible mechanism for the action of these steroids in treating airway diseases such as asthma, chronic bronchitis, or cystic fibrosis.
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PMID:Roles of neutral endopeptidase in airways. 201 45

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

To determine the role of endogenous neutral endopeptidase (NEP), also called enkephalinase (EC 3.4.24.11), in regulating tachykinin-induced contraction of gut smooth muscle, we studied the effects of NEP inhibitors on the contractile responses to substance P (SP) in isolated longitudinal strips of ileum or duodenum in rats and ferrets. Leucine-thiorphan and phosphoramidon shifted the concentration-response curves of SP to lower concentrations in all tissues studied, but the sensitivity to SP was greater and the effect of leucine-thiorphan was less in the ferret, a finding that correlated with the observation that the ferret ileum contained substantially less NEP activity than rat ileum. Captopril, bestatin, MGTA, leupeptin, and physostigmine did not alter contractile responses to SP, suggesting that kininase II, aminopeptidases, carboxypeptidase N, serine proteinases, and acetylcholinesterase do not modulate the SP-induced effects. These studies suggest that, in the ileum and duodenum, NEP modulates the actions of SP and, furthermore, that the sensitivity of tissues may be determined, at least in part, by the amount of enzymatically active NEP present.
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PMID:Neutral endopeptidase inhibitors potentiate substance P-induced contraction in gut smooth muscle. 246 69

Endopeptidase-24.11 ("enkephalinase") appears to play a key role in the metabolism of a number of neuropeptides at cell surfaces. It has been previously mapped in the central nervous system, but some doubt has been expressed concerning the identity of the cell type expressing this peptidase. Primary cell cultures derived from striata of new-born piglets were set up and cells were characterized by immunocytochemistry using antibodies to neurofilament protein, a glial fibrillary acidic protein and a neuronal antigen recognized by a monoclonal antibody BM88 and by histochemistry for acetylcholinesterase. Some cultures were set up in which neurons were selectively enriched. Cells which were thus morphologically defined as neurons were recognized by an affinity-purified polyclonal antibody to endopeptidase-24.11. The staining for the peptidase, which was punctate in appearance, was shown to be at the cell surface and extended to the perikaryon and all neurites. Compared with the number of neurofilament protein-positive cells, relatively few cells were positive for endopeptidase-24.11. No glial cells, immunochemically defined by glial fibrillary acidic protein, were stained by the antibody to endopeptidase-24.11. We conclude that endopeptidase-24.11 is expressed on the surface of a set of neurons derived from the striatum in primary culture and not by any glial cells in these cultures.
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PMID:Immunocytochemical localization of endopeptidase-24.11 in cultured neurons from pig striatum. 277 Oct 59

Endopeptidase-24.11 (sometimes referred to as 'enkephalinase') is a key cell-surface enzyme in the metabolism of neuropeptides. A previous immunohistochemical study mapped the enzyme in pig brain and indicated a striosomal ordering of the enzyme within the striatum. This point has now been confirmed by staining adjacent sections for acetylcholinesterase (by histochemistry) and endopeptidase-24.11 (by an immunoperoxidase method). While there were some general similarities in the mapping of these two hydrolases, e.g. in the caudate-putamen, globus pallidus, olfactory tubercle, substantia nigra and striatonigral tract, there were differences in intensity and in the microscopic distribution, e.g. as in striosomes for which acetylcholinesterase was diminished. Two other membrane peptidases, peptidyl dipeptidase A ('angiotensin converting enzyme') and aminopeptidase N, were also mapped by the same immunohistochemical method. Peptidyl dipeptidase A had some similarities with endopeptidase-24.11, e.g. in its concentration within the striatal nuclei, but clear differences were also apparent, in particular the absence of staining of the former in the globus pallidus and olfactory tubercle. Immunostaining for aminopeptidase N, in contrast to the other peptidases, was observed as a diffuse staining throughout the gray matter. At the microscopic level, two important differences were that staining for aminopeptidase N and peptidyl dipeptidase A was very intense throughout the vasculature of the brain and that striatal efferent bundles of unmyelinated fibres staining positively for endopeptidase-24.11 were depleted of the other two peptidases. All three peptidases were identified in the pia mater. Thus, endopeptidase-24.11, unlike peptidyl dipeptidase A and aminopeptidase N, is a marker for a set of striatal efferent fibres in pig brain.
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PMID:Endopeptidase-24.11 is striosomally ordered in pig brain and, in contrast to aminopeptidase N and peptidyl dipeptidase A ('angiotensin converting enzyme'), is a marker for a set of striatal efferent fibres. 290 57

Acetylcholinesterase (EC 3.1.1.7) has been shown to possess an intrinsic peptidase activity. [Chubb et al. (1983), Neuroscience 10, 1369-1383]. To examine this activity further, the breakdown of a model hexapeptide (leu-trp-met-arg-phe-ala) LWMRFA was studied. Affinity-purified eel acetylcholinesterase rapidly cleaved the hexapeptide in a trypsin-like manner to produce two peptides (LWMR and FA). Acetylcholinesterase more slowly cleaved the C-terminal alanine residue from the peptide to yield LWMRF. Although the enzyme showed preference for cleaving the hexapeptide at its C-terminal, it was also able to cleave the N-terminal leucine residue form the tryptic product LWMR. Hydrolysis of the peptide at the tryptic site (arg4-phe5) was strongly inhibited by the trypsin inhibitor diisopropylfluorophosphate. Cleavage of the C-terminal alanine was only poorly inhibited by diisopropylfluorophosphate, but more strongly inhibited by metal-ion chelating agents, and it was increased in the presence of Zn2+ and Co2+. The pH optimum for cleavage at the tryptic site was 6, while that for the carboxypeptidase site was 8-9. These results show that acetylcholinesterase can hydrolyse peptides like a trypsin-like endopeptidase and a Zn2+- or Co2+-dependent exopeptidase, and they suggest that these two peptidase activities are associated with two separate active sites on the acetylcholinesterase molecule. As both peptidase activities eluted with acetylcholinesterase from a TSK 4000SW column when it was chromatographed by high-performance liquid chromatography, it is unlikely that the presence of either peptidase activity could be attributable to a contaminant in the acetylcholinesterase preparation. We suggest that acetylcholinesterase may be involved in the breakdown of bioactive peptides or their precursors in neuroendocrine cells.
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PMID:Acetylcholinesterase exhibits trypsin-like and metalloexopeptidase-like activity in cleaving a model peptide. 330 51

In addition to its ability to hydrolyze acetylcholine, purified eel acetylcholinesterase possesses a trypsin-like endopeptidase activity. The tryptic activity is associated with a serine residue at a site that is distinct from the esteratic site. To label both the esteratic and tryptic sites, the enzyme was incubated with the serine hydrolase inhibitor [3H]diisopropyl fluorophosphate. This compound labelled the protein in a biphasic manner, with both slow and rapid labelling kinetics. The time course of the rapid phase was similar to the time course of inactivation of the esteratic activity. The time course of the slow phase was similar to the time course of inactivation of the tryptic activity. Labelling of the nonesteratic site was inhibited by the trypsin inhibitor N alpha-p-tosyl-L-lysine chloromethyl ketone. The total number of sites labelled by [3H]diisopropyl fluorophosphate on eel acetylcholinesterase was 2.6 mol/280,000 g protein, whereas the number of tryptic sites was less (0.52 mol/280,000 g). The results suggest that a subpopulation of acetylcholinesterase molecules may possess tryptic activity. Extensive chromatography of the purified enzyme by ion-exchange and gel filtration failed to separate the labelled tryptic component from acetylcholinesterase. On sodium dodecyl sulfate-polyacrylamide gels, the labelled tryptic component comigrated with a polypeptide of 50,000 molecular weight, which is a major proteolytic digestion product derived from the intact acetylcholinesterase monomer. Because of its localization in many noncholinergic peptide-containing cells, acetylcholinesterase could act as a neuropeptide processing enzyme in these cells.
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PMID:Identification of a trypsin-like site associated with acetylcholinesterase by affinity labelling with [3H]diisopropyl fluorophosphate. 337 13

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


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