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)

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

Proteolytic hydrolysis rates of neurotensin and acetyl-neurotensin-(8-13) by brush-border membranes from various rat intestinal segments were as follows: jejunum > duodenum approximately jejunoileal junction > ileum > caecum. The rank order of endopeptidase-24.11 activity along the intestine was jejunum > duodenum approximately jejunoileal junction > ileum > caecum. Angiotensin converting enzyme (ACE) had a similar distribution profile as endopeptidase-24.11. Activities of these two enzymes were lower in the distal intestine. Distribution of endopeptidase-2 activity along the intestine was different: ileum > duodenum approximately jejunum approximately jejunoileal junction > caecum. The profiles of differential hydrolysis of neurotensin and acetylneurotensin-(8-13) within the gut corresponded to the distribution of endopeptidase-24.11 and ACE. Moreover, effects of enzyme inhibitors confirm that these two enzymes initiated proteolysis of neurotensin and acetylneurotensin-(8-13). These results suggest that the regional differences in the activities of key brush-border membrane peptidases will affect site-dependent stability of peptide drugs.
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PMID:Influences of regional differences in activities of brush-border membrane peptidases within the rat intestine on site-dependent stability of peptide drugs. 841 76

Antisera from lambs immunised with the Haemonchus contortus integral membrane protein complex, Haemonchus galactose-containing glycoprotein (H-gal-GP), the lambs being refractory to subsequent challenge, were used to identify several clones from an adult H. contortus lambda gt11 cDNA library. Using gene-specific oligonucleotide primers in conjunction with primers directed to a conserved nematode Spliced Leader (SL) sequence and to the polyA+ tail of mRNA, the remaining 5' and 3' sequences of one of these clones, metallopeptidase-1 (MEP1), were amplified. The 2.4 kb full-length coding sequences was subsequently amplified in a single reaction. Sequence analysis identified MEP1 as encoding a putative zinc metallopeptidase, which shared limited homology with the mammalian type II integral membrane protein neutral endopeptidase (NEP). Southern blotting indicated that MEP1 belonged to a multigene family. MEP1 was expressed in bacteria as a glutathione-S-transferase (GST) fusion protein, and a specific antiserum raised in sheep. This antiserum recognised several polypeptide components of H-gal-GP. Immunolocalisation studies showed that MEP1 encoded a protein located on the luminal surface of the nematode gut. Both MEP1 mRNA and protein are developmentally regulated with expression being limited to the blood-feeding stages of H. contortus.
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PMID:Molecular cloning and characterisation of a developmentally regulated putative metallopeptidase present in a host protective extract of Haemonchus contortus. 910 50

Membrane metalloendopeptidase EC 3.4.24.11 (Enkephalinase, neutral endopeptidase, NEP) is a cellular ectoenzyme, immunophenotypically identified as the leukocyte cluster of differentiation CD10 or CALLA (common acute lymphoblastic leukemia antigen). Immunological, biochemical and molecular biology techniques have identified tis cell membrane feature in various organs: brain, cardiovascular system, lung, placenta, kidney etc. The CD10 immunophenotype is a common feature of lymphoblasts in acute lymphoid leukemia not expressing the T- or B-markers. The enzymatic activity of CD10/NEP possibly influences normal lymphocyte ontogeny by proteolytic cleavage of the regulatory peptides. The substrates of CD10/NEP in the kidneys are (see the list of abbreviations) ANP, adrenomedullin and PAMP; in the brain, the substrates are enkephalins and oxytocin; in the lung, bombesin, BLP, GRP, neuromedin C, substance P and neurokinin A; in the cardiovascular system, angiotenisin II, bradykinin and CGRP; in the gut, VIP; on the neutrophil membrane, fMLP etc. Some substrates are not strictly tissue-specific, e.g. substance P. Preclinical and clinical trials explore possibilities of therapeutic application of the inhibitors of neutral endopeptidase, such as thiorphan in the management of pain, diarrhoea, depression, arterial hypertension and asthma. Other possibilities of application include the treatment of hyalinomembranous disease and prevention of neurotoxicosis in tetanus and botulism.
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PMID:[Membrane metalloendopeptidase (CD10/CALLA): distribution, physiologic and pathophysiologic functions and its inhibitors]. 974 92

The objective of this study was to examine the effects of protease inhibitors on the absorption of calcitonin from different regions of the intestine in rats. The absorption experiments were investigated by in-situ use of closed intestinal loops in rats and stability of calcitonin was examined in mucosal homogenates and intestinal fluids. The intestinal absorption of calcitonin was evaluated by measurement of its hypocalcaemic effect. No substantial hypocalcaemic response was observed when calcitonin was administered into the jejunum or colon. A slight hypocalcaemic effect was observed after administration of calcitonin into the ileum. Of the co-administered protease inhibitors, bacitracin (20mM) strongly promoted calcitonin absorption from the jejunum, ileum and colon. A significant hypocalcaemic effect was also obtained after intestinal administration of calcitonin with soybean trypsin inhibitor (10mgmL(-1)), camostat mesylate (20mM) or aprotinin (2mgmL(-1)). In the stability experiment, bacitracin reduced the degradation of calcitonin in the different intestinal homogenates. Soybean trypsin inhibitor significantly reduced the degradation of calcitonin in the fluids of the small intestine. We also examined the different endopeptidases in gut luminal fluids and the different exopeptidases in gut mucosal homogenates of rats. The ranking order for the total endopeptidase activity of the intestinal fluids was jejunum > ileum > colon. That for total exopeptidase activity of the intestinal mucosa was jejunum > ileum > colon. These results suggest that endo- and exopeptidases might be responsible for the hydrolysis of calcitonin and that protease inhibitors might usefully improve absorption of calcitonin to the systemic circulation from the large intestine.
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PMID:Use of protease inhibitors to improve calcitonin absorption from the small and large intestine in rats. 975 57

A novel recurrent translocation t(11;14)(p11;q32) was found in three patients with splenic marginal zone B cell lymphoma (MZBCL). Fluorescence in situ hybridization (FISH) studies with IgH probes revealed in all cases involvement of the IgH locus, with breakpoint downstream of the IGVH sequences. Partner genes at 11p11 were not identified. The translocation defined the stem line in two patients, who carried additional cytogenetic aberrations, including a 17p deletion, present in both cases. In one patient a 7q- chromosome was the primary cytogenetic defect, the t(11;14) having been found in four out of 11 abnormal metaphase cells at the time of transformation into high-grade MZBCL. Hematological features in all cases included splenomegaly with peripheral blood (PB) involvement by a monoclonal B cell population consisting of lymphocytes with villous projections and several blast-like cells. The immunophenotype was CD19+; CD22bright+; CD23-, CD10-, CD5-, surface Igbright+. A bone biopsy in one patient revealed an interstitial infiltration with an intrasinusoidal pattern of growth. Histological studies on spleen specimens in two patients showed an expanded marginal zone, with small lymphocytes and several blast-like cells. One patient had a therapy-demanding disease, with partial, short-term responses to cytotoxic treatment; one patient transformed into a high-grade MZBCL involving the gut, the PB and the bone marrow 2 years after diagnosis; one patient was unresponsive to cytotoxic treatment and underwent splenectomy. The t(11;14)(p11;q32) may define a subset of splenic MZBCL with a high-grade component and a relatively aggressive clinical behavior.
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PMID:A novel recurrent translocation t(11;14)(p11;q32) in splenic marginal zone B cell lymphoma. 1148 May 69

Efforts are being undertaken to control tick infestations that cause important economic losses. A cathepsin L-like endopeptidase of Boophilus microplus was expressed in Escherichia coli; the recombinant enzyme was capable of hydrolysing gelatin, tick vitellin and bovine haemoglobin. In this paper we focus on the expression and local of synthesis of this enzyme in the tick. RT-PCR experiments showed that this endopeptidase is transcribed in the gut of partially engorged tick females. In immunoblotting, polyclonal antibodies against the recombinant enzyme reacted with proteins of larvae older than 5 days, of fully and partially engorged female gut. In immunolocalization experiments the enzyme was localized in probable secretory cells of the gut. Based on our findings we postulate that BmCL1 may be involved in haemoglobin degradation in the B. microplus gut. This enzyme may be used as target for the control of this parasite.
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PMID:Expression and immunolocalization of a Boophilus microplus cathepsin L-like enzyme. 1214 97

Peptidases are essential for the establishment and survival of the medically important parasite, Schistosoma mansoni. This helminth expresses a number of gut-associated peptidases that degrade host blood proteins, including hemoglobin, as a means of nutrition. Using irreversible affinity probes, we demonstrate that S. mansoni cathepsin B-like endopeptidase 1 (SmCB1) is the most abundant papain family cysteine peptidase in both the parasite gut and somatic extracts. SmCB1 zymogen (SmCB1pm) was functionally expressed in Pichia pastoris (4-11mgl(-1)). Monospecific and immunoselected antibodies raised against SmCB1pm localized the enzyme exclusively to the gut lumen and surrounding gastrodermis of adult worms. Recombinant SmCB1pm was unable to catalyze its activation, even at low pH. However, recombinant S. mansoni asparaginyl endopeptidase (SmAE), another gut-associated cysteine peptidase, processed and activated SmCB1pm in trans. Consistent with the known specificity of AEs, processing occurred on the carboxyl side of an asparagine residue, two residues upstream of the start of the mature SmCB1 sequence. The remaining pro-region dipeptide was removed by rat cathepsin C (dipeptidyl-peptidase I)-an action conceivably performed by an endogenous cathepsin C in vivo. The activated recombinant SmCB1 is biochemically identical to the native enzyme with respect to dipeptidyl substrate kinetics and pH profiles. Also, the serum proteins, hemoglobin, serum albumin, IgG, and alpha-2 macroglobulin were efficiently degraded. Further, a novel application of an assay to measure the peptidyl carboxypeptidase activity of SmCB1 and other cathepsins B was developed using the synthetic substrate benzoyl-glycinyl-histidinyl-leucine (Bz-Gly-His-Leu). This study characterizes the major digestive cysteine peptidase in schistosomes and defines novel trans-processing events required to activate the SmCB1 zymogen in vitro which may facilitate the digestive process in vivo.
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PMID:Functional expression and characterization of Schistosoma mansoni cathepsin B and its trans-activation by an endogenous asparaginyl endopeptidase. 1296 13

Current control of gastrointestinal nematodes relies primarily on the use of synthetic drugs and encounters serious problems of resistance. Oral administration of plant cysteine proteinases, known to be capable of damaging nematode cuticles, has recently been recommended to overcome these problems. This prompted us to examine if plant cysteine proteinases like the four papaya proteinases papain, caricain, chymopapain, and glycine endopeptidase that have been investigated here can survive acidic pH conditions and pepsin degradation. The four papaya proteinases have been found to undergo, at low pH, a conformational transition that instantaneously converts their native forms into molten globules that are quite unstable and rapidly degraded by pepsin. As shown by activity measurements, the denatured state of these proteinases which finally results from acid treatment is completely irreversible. It is concluded that cysteine proteinases from plant origin may require to be protected against both acid denaturation and proteolysis to be effective in the gut after oral administration.
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PMID:Structural characterization of the papaya cysteine proteinases at low pH. 1643 27

Botulinum neurotoxins are multifaceted molecules, which are truly unique not only in their mode of action, but also their utility as a drug carrier either across the gut wall or to the nerve terminals. The molecule is divided in clear functional domains that can operate independently. This feature can be used to employ them as cargo carrier by linking other drugs or vaccines with the binding and translocation domains of BoNT. While the domain structures are largely independent of each other, the dynamic structure of these domains, especially that of the enzymatic domain (L chain), is quite different from the reported crystal structures for several BoNT serotypes and their enzymatic domain. This review discusses the comparative structures of BoNT in crystal and solution for their relevance to the molecular mechanism of BoNT action, especially in view of our recent discovery that the enzymatically active structure of the BoNT exists as a molten-globule and that of the endopeptidase domain as a novel PRIME conformation. Finally, a non-exhaustive discussion has been included to explain the long-lasting biological effects of certain serotypes of BoNT, based on the current knowledge of the structure-function of different serotypes of botulinum neurotoxins.
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PMID:Botulinum neurotoxin structure, engineering, and novel cellular trafficking and targeting. 1678 3


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