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 (neprilysin or NEP, EC 3.4.24.11) is a zinc metallo-endopeptidase expressed in many eukaryotic cell types and displaying several important physiological roles. In the brain (and central nervous system), this enzyme is involved in the molecular mechanism of pain by its action in the degradation of enkephalin molecules. In the kidney, NEP is implicated in the degradation of regulatory factors involved in the control of arterial pressure, including atrial natriuretic peptide and bradykinin. In this study we assessed the potential of the fission yeast Schizosaccharomyces pombe to overproduce rabbit NEP and secreted NEP (sNEP, a soluble derivative of this integral membrane protein). Both recombinant NEP and sNEP were produced at high levels (5 mg/l) in this system. Enzymic studies revealed that these recombinant proteins were fully active and exhibit kinetic parameters similar to those of the bona fide enzyme. Immunofluorescence microscopy and enzymic assays demonstrated that recombinant NEP is correctly targeted to the cell membrane. Furthermore, co-immunoprecipitation studies showed that folding intermediates of NEP and sNEP, produced in S. pombe, interact in the endoplasmic reticulum (ER) with binding protein (BiP) and calnexin (Cnx1p). The amount of sNEP coprecipitated with both BiP and Cnx1p augmented when cells were subjected to various stresses causing the accumulation of unfolded proteins in the ER. The interactions of NEP with BiP and Cnx1p were, however, more refractive to the same stresses.
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PMID:Interaction of mammalian neprilysin with binding protein and calnexin in Schizosaccharomyces pombe. 1035 68

Enkephalins have been implicated in the regulation of mood, anxiety, reward, euphoria and pain. One of the major enzymes for enkephalin degradation is neutral endopeptidase [enkephalinase, membrane metalloendopeptidase (MME)]. We identified a dinucleotide polymorphism in the 5' region of the MME gene. Subjects were placed into three genotypes, 3/3, 3/x, and x/x since the 3 allele was the most common of the six alleles. Using one-way analysis of variance, we examined the association of these genotypes with the mean SCL-90 scores for anxiety, depression, obsessive-compulsive and phobic anxiety symptoms in 120 Caucasian males from an addiction treatment unit. There was a significant association between the MME genotypes and the SCL-90 scores for phobic anxiety, obsessive-compulsive and anxiety at a Bonferroni corrected alpha value of 0.0125. These results support a role of genetic variants of enkephalin metabolism in anxiety.
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PMID:Association of the neutral endopeptidase (MME) gene with anxiety. 1099 48

The endogenous ligand for the orphan NOR receptor (earlier named ORL1) was recently discovered. This ligand, nociceptin/orphanin FQ is involved in a number of pharmacological actions in the CNS, including modulation of pain and cognition. However, its specific physiological role remains to be determined. Two major pathways of metabolism have been identified; the action of aminopeptidase(s) that prominently occurs in plasma, and endopeptidase activity that successively generates the N-terminal 1-13 and 1-9 fragments. Both pathways result in fragments that are inactive at the NOR receptor. However, short N-terminal fragments appear to be active in blocking the release of substance P from primary afferent C-fiber terminals in the dorsal spinal cord. The same endopeptidase(s) may also be involved in the fragmentation of dynorphin A since the inhibitor profile is similar. Enzyme activity is upregulated by morphine using either peptide as substrate that may lead to pharmacological interactions.
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PMID:Nociceptin/orphanin FQ metabolism and bioactive metabolites. 1099 25

Botulinum toxin is the most neurotoxic substance known, with a specific action at cholinergic synapses. Acting as a zinc endopeptidase, botulinum toxin cleaves specific proteins involved in vesicle fusion, thereby preventing release of acetylcholine. The therapeutic effect of the toxin taken up presynaptically at the neuromuscular junction is to weaken muscle. Botulinum toxin type A (BTX-A) has been shown to be safe and effective in the treatment of cervical dystonia (CD; also known as spasmodic torticollis). In patients with CD, injections of botulinum toxin dampen or eliminate involuntary muscle activity and improve control of neck movement, pain, and range of motion. To successfully use botulinum toxin as a therapeutic modality, targeting the dystonic muscles, injecting a sufficient quantity of toxin and minimizing diffusion into uninvolved muscle collectively provide the best outcome with the fewest adverse reactions. EMG guidance may allow more precise injections. To maintain responsiveness to the toxin over repeated injections, using the lowest dose at the longest dosing interval has been suggested.
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PMID:Use of botulinum toxin type A in the treatment of cervical dystonia. 1118 79

Botulinum neurotoxin type A is one of the most toxic substances known to man (LD(50) for mouse 0.1 ng/kg). It is also an effective therapeutic drug against involuntary muscle disorders and for pain management. BoNT/A is a Zn(2+) endopeptidase which selectively cleaves SNAP-25 (synaptosomal-associated protein of 25 kDa), a critical component of the exocytotic machinery. Based on nucleotide sequence, BoNT/A is a 145 kDa protein, which appears as a 145 kDa protein band on sodium dodecyl sulfate--polyacrylamide gel electrophoresis. We have examined the structure of BoNT/A in aqueous solution, and found the structure in aqueous solution differs dramatically from that resolved by X-ray crystallography, both at secondary and at quaternary levels. In terms of secondary structure, BoNT/A in aqueous solution has about 47% beta-sheet structure as revealed by infrared spectroscopy, while X-ray crystallography revealed only 17% beta-sheet structure. In terms of quaternary structure, the estimated molecular mass of the native BoNT/A in aqueous solution ranged between 230 and 314 kDa, based on results from different chemical and biophysical techniques (native gel electrophoresis, chemical cross-linking, size exclusion chromatography, and fluorescence anisotropy). These results indicate that BoNT/A exists as a dimer in aqueous solution, which contrasts with the reported monomeric structure of BoNT/A based on X-ray crystallography. The dimeric form of BoNT/A can self-dissociate into the monomeric form at a concentration lower than 50 nM. This concentration-dependent structural change has a significant impact on the endopeptidase activity of BoNT/A: the catalytic efficiency of the monomeric BoNT/A is about 4-fold higher than that of its dimeric form. This difference implies a sterically restricted catalytic site of BoNT/A in the dimeric form of BoNT/A.
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PMID:A correlation between differential structural features and the degree of endopeptidase activity of type A botulinum neurotoxin in aqueous solution. 1129 37

Botulinum toxin A (BoNT-A) develops its muscle-relaxing effect by the inhibition of acetylcholine (ACh) release. This toxin is also known to relieve muscular pain in different disorders. Conspicuously, pain in some patients responds earlier and sometimes even better than muscle tension, indicating that the effect of BoNT-A on pain is not only due to inhibition of ACh release. A questionnaire was distributed to 88 patients suffering from cervical dystonia (CD). Thirty-five completed questionnaires could be used for data analysis. After intramuscular injections of BoNT-A, patients with CD experience significant reductions in pain which sometimes occur significantly earlier than the improvements in head posture. In the iris sphincter muscle of the rabbit and in dorsal root ganglion cells (DRG) of the rat, inhibition of the release of substance P by BoNT-A has been shown experimentally, and BoNT-C has been proven to develop endopeptidase activity toward substance P (SP) in vitro. Findings in the current literature and our observations allow the conclusion that alleviation of muscle pain by BoNT-A may also be due to an effect on the release of nociceptive neuropeptides, among which SP seems to have a key function.
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PMID:[Reduction of pain and muscle spasms by botulinum toxin A]. 1132 Aug 66

Members of the neutral endopeptidase (NEP, also known as MME for membrane metallo-endopeptidase in the Human Gene Nomenclature database) family play significant roles in pain perception, arterial pressure regulation, phosphate metabolism, and homeostasis. In this paper, we report the cloning of a new human member of the NEP family that we named MMEL2 for membrane metallo-endopeptidase-like 2. The MMEL2 protein has the structural characteristics of type II transmembrane proteins, although the presence of a furin-like cleavage site in the ectodomain suggests that it may be released into the medium following proteolytic cleavage. The MMEL2 protein contains the zinc-binding consensus sequence HEXXH and all the residues known to be essential for the enzymatic activity of other members of the family. The MMEL2 mRNA was detected predominantly in testis, but weak expression also was observed in brain, kidney, and heart. The human MMEL2 gene was mapped to 1p36 by fluorescence in situ hybridization. It will be important to test whether MMEL2 defects are associated with diseases such as hereditary motor sensory neuropathy 2A, Schwartz-Jampel-Aberfeld syndrome, or neuroblastoma, which all map to this locus.
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PMID:Molecular cloning, tissue distribution, and chromosomal localization of MMEL2, a gene coding for a novel human member of the neutral endopeptidase-24.11 family. 1156 Jul 81

Neutral endopeptidase (EC3.4.24.11, NEP, enkephalinase) is a zinc-metalloendopeptidase, cleaving a variety of substrates like enkephalins, substance P, and bradykinin. In the brain, NEP is a key enzyme in the degradation of enkephalins. Pharmacological inhibition of NEP-activity causes analgesia resulting from enhanced extracellular enkephalin concentrations. Recently, transgenic mice lacking the enzyme NEP have been developed (Lu, 1995). The present study was designed to investigate the nociceptive behavior of these NEP-knockout mice. Interestingly, NEP-deficient mice did not respond with decreased pain perception, but exhibited hyperalgesia in the hot-plate jump, warm-water tail-withdrawal, and mostnotablyin theacetic-acid writhing test. Inhibition of aminopeptidase N by bestatin reduced writhing in both strains, whereas NEP-inhibition by thiorphan reduced writhing selectively in wild-type mice. Naloxone increased writhing in wild-type but not in knockouts, whereas the bradykinin B2-receptor antagonist HOE140 reduced writhing selectively in NEP-knockouts. Similarly, the nitric oxide synthase inhibitor L-NAME reduced writhing in NEP-knockouts. These results indicate that genetic elimination of NEP, in contrast to pharmacological inhibition, leads to bradykinin-induced hyperalgesia instead of enkephalin-mediated analgesia. Nitric oxide (NO) is suggested to be involved in this process.
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PMID:Neutral endopeptidase knockout induces hyperalgesia in a model of visceral pain, an effect related to bradykinin and nitric oxide. 1193 42

Clostridial neurotoxins potently and specifically inhibit neurotransmitter release in defined cell types. Here we report that a catalytically active derivative (termed LH(N)/A) of the type A neurotoxin from Clostridium botulinum has been coupled to a lectin obtained from Erythrina cristagalli to form a novel conjugate. This conjugate exhibits an in vitro selectivity for nociceptive afferents compared with the anatomically adjacent spinal neurons, as assessed using in vitro primary neuronal culture systems to measure inhibition of release of neurotransmitters. Chemical conjugates prepared between E. cristagalli lectin and either natively sourced LH(N)/A or recombinant LH(N)/A purified from Escherichia coli are assessed, and equivalence of the recombinant material are demonstrated. Furthermore, the dependence of inhibition of neurotransmitter release on the cleavage of SNAP-25 is demonstrated through the use of an endopeptidase-deficient LH(N)/A conjugate variant. The duration of action of inhibition of neurotransmitter released by the conjugate in vitro is assessed and is comparable with that observed with Clostridium botulinum neurotoxin. Finally, in vivo electrophysiology shows that these in vitro actions have biological relevance in that sensory transmission from nociceptive afferents through the spinal cord is significantly attenuated. These data demonstrate that the potent endopeptidase activity of clostridial neurotoxins can be selectively retargeted to cells of interest and that inhibition of release of neurotransmitters from a neuronal population of therapeutic relevance to the treatment of pain can be achieved.
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PMID:Inhibition of release of neurotransmitters from rat dorsal root ganglia by a novel conjugate of a Clostridium botulinum toxin A endopeptidase fragment and Erythrina cristagalli lectin. 1210 93

We analyzed spinal metabolic pathway of nociceptin/orphanin FQ related to pain-transmission or modulation in the both in vitro and in vivo experiments. Nociceptin was degraded by spinal synaptic membranes. Major metabolites of nociceptin were free phenylalanine, nociceptin (1-13) and nociceptin (14-17). Both the degradation of nociceptin and the accumulation of the major cleavage metabolites, nociceptin (1-13) and nociceptin (14-17), were strongly inhibited by a metal chelator and also by specific inhibitors of endopeptidase-24.11, thiorphan and phosphoramidon. Furthermore, purified endopeptidase-24.11 hydrolyzed nociceptin at the cleavage site (Lys(13)-Leu(14) bond) identical to that by spinal synaptic membranes. Recently, we have found that nociceptin, injected intrathecally at small doses (fmol order) elicits a behavioral response consisting of scratching, biting and licking in mice. In the present study, we have examined the effect of peptidase inhibitors on the behavioral response elicited by intrathecal injection of nociceptin in mice. Phosphoramidon simultaneously injected with nociceptin additively enhanced nociceptin-induced behavioral response, whereas the nociceptin-induced behavioral response was unaffected by either bestatin, an aminopeptidase inhibitor or captopril, an angiotensin-converting enzyme inhibitor. However, the nociceptin effect was potentiated by combined injection of phosphoramidon and bestatin, indicating that inhibition of aminopeptidase may also contribute to inducing the behavioral response to nociceptin. These data suggest that endopeptidase-24.11 plays a major role in initial stage of nociceptin metabolism at the spinal cord level in mice.
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PMID:Degradation of nociceptin (orphanin FQ) by mouse spinal cord synaptic membranes is triggered by endopeptidase-24.11: an in vitro and in vivo study. 1223 9


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