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:3.4.21.37 (neutrophil elastase)
4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chronic, progressively destructive bronchitis of patients with cystic fibrosis (CF) is characterized by an important imbalance between tissue destroying granulocyte proteases such as granulocyte elastase (GE) and its physiological inhibitors in bronchial secretions. Recent in vitro studies suggest, that proteases derived from bacteria or endogenous proteases may contribute to inactivation of physiological inhibitors of GE. Since only trypsin-unreactive alpha 1-proteinase inhibitor (alpha 1-PI) was detected in CF bronchial secretions, we attempted to identify the mechanism of inactivation of alpha 1-PI. We found a heat stable, serine protease-like enzymatic activity capable of degrading 125I-labelled alpha 1-PI extensively in 22 infected but not in one non-infected CF bronchial secretion. In infected secretions, only degraded alpha 1-PI, which did not migrate like oxidized alpha 1-PI in tandem-crossed immunoelectrophoresis, was detectable. We conclude, that free GE in excess as well as GE bound to bronchial mucosal inhibitor may partly account for the alpha 1-PI-cleaving activity, but that other yet unknown bacterial or host serine proteases also contribute to alpha 1-PI inactivation.
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PMID:Proteolytic inactivation of alpha 1-proteinase inhibitor in infected bronchial secretions from patients with cystic fibrosis. 202 37

The potent serine protease, neutrophil elastase (NE), is stored in neutrophil azurophilic granules, where it is available to degrade phagocytosed material and can be released by the cell to assist in tissue migration and help clear tissue debris. While neutrophils carry NE, they cannot produce it; the NE gene is expressed only in bone marrow granulocyte precursor cells. Protection of normal tissues from the destructive capacity of NE is provided by alpha 1-antitrypsin (alpha 1 AT), a 52-Kd serine antiprotease produced by hepatocytes and mononuclear phagocytes. In the context of the broad destructive capacity of NE, we evaluated the concept that human neutrophils may be able to modulate the extracellular activity of NE by synthesizing and secreting alpha 1AT. Immunocytochemical analysis demonstrated that the neutrophil contains alpha 1AT. Northern analysis and in situ hybridization with alpha 1AT-specific probes demonstrated the presence of alpha 1AT messenger RNA transcripts within neutrophils. [35S]methionine-labeling of neutrophils followed by immunoprecipitation of the supernatant with an anti-alpha 1AT antibody and sodium dodecyl sulfate-acrylamide gel analysis demonstrated that neutrophils can synthesize alpha 1AT de novo and secrete the synthesized molecule. In the presence of major neutrophil degranulation, the antiprotease effect of neutrophil alpha 1AT is overwhelmed, allowing the NE to act unopposed in the extracellular microenvironment. However, in conditions where small amounts of NE are released by neutrophils, at least some of the secreted newly synthesized alpha 1AT was capable of complexing with NE. Thus, despite the fact that the neutrophil cannot synthesize NE, it can synthesize and secrete alpha 1AT, the inhibitor of NE, ie, the neutrophil is capable, to some extent, of modulating NE activity in the local milieu without the help of antiproteases produced by other cells.
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PMID:Human neutrophils express the alpha 1-antitrypsin gene and produce alpha 1-antitrypsin. 204 69

Closely similar but nonidentical NH2-terminal amino acid sequences have been reported for a protein or proteins in human neutrophils whose bioactivities is/are diverse (as a serine protease, antibiotic, and Wegener's granulomatosis autoantigen) but that share(s) several features: localization in the azurophil granules, a molecular mass of approximately 29 kD, reactivity with diisopropylfluorophosphate, and the ability to degrade elastin. We previously purified one such entity, termed p29b. Using a monospecific antibody, we have cloned from human bone marrow a cDNA encoding the complete p29b protein in its mature form, along with pre- and pro-sequences. The predicted amino acid sequence agrees closely with the NH2-terminal sequence obtained previously from purified p29b, as well as with sequences newly obtained from CNBr fragments. The primary structure is highly homologous to elastase, cathepsin G, T cell granzymes, and other serine proteases, and shares both the catalytic triad and substrate binding pocket of elastase. Hybridization of the full-length cDNA with restriction enzyme digests of human genomic DNA revealed only one fragment. This suggests that the closely related species described previously are the same, and can be subsumed by the term used for the first-described activity, proteinase 3. Proteinase 3 is more abundant in neutrophils than elastase and has a similar proteolytic profile and specific activity. Thus, proteinase 3 may share the role previously attributed to neutrophil elastase in tissue damage, and has the potential to function as an antimicrobial agent.
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PMID:Cloning of cDNA for proteinase 3: a serine protease, antibiotic, and autoantigen from human neutrophils. 225 1

The chymotrypsin-like family of serine protease genes includes several members that are expressed exclusively in subsets of hematopoietic cells. For example, human neutrophil elastase and cathepsin G are expressed only in myelomonocytic precursors, and cytotoxic-T-cell serine proteases are found only in cytotoxic lymphocytes. We have used a cathepsin G cDNA probe to clone two cathepsin G-like genes (designated CGL-1 and CGL-2) from a human genomic library. We have determined that CGL-1 is identical to a previously identified gene (known as CCPI, CTLA I, or cytotoxic serine protease B) that is expressed only in activated cytotoxic T lymphocytes. We show here that cathepsin G, CGL-1, and CGL-2 are linked on an approximately 50-kilobase locus found on human chromosome 14 at band q11.2. This gene cluster maps to the same chromosomal band as the alpha and delta T-cell receptor genes; this region is involved in most chromosomal translocations and inversions that are specifically associated with T-cell malignancies.
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PMID:A cluster of hematopoietic serine protease genes is found on the same chromosomal band as the human alpha/delta T-cell receptor locus. 230 May 87

A variety of 7 alpha-methoxycephalosporin ester and amide sulfones were prepared and tested to determine the structure-activity relations for inhibition of human leukocyte elastase (HLE), a serine protease which has been implicated in several degenerative lung and tissue diseases. The most potent IC50 values were obtained with neutral, lipophilic derivatives, with the esters being more active than the amides. However, the best time-dependent inhibition in this series was observed with the p- and m-carboxybenzyl esters 7b and 7c. These results are discussed in terms of the proposed mechanism of inhibition as well as a molecular modeling study using the recently solved X-ray crystal structure of HLE.
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PMID:Inhibition of human leukocyte elastase. 2. Inhibition by substituted cephalosporin esters and amides. 239 92

Neutrophil elastase, a potent serine protease carried and released by activated neutrophils, is not synthesized by neutrophils, but by their bone marrow precursor cells. Using in situ hybridization with 35S-labeled antisense and sense neutrophil elastase cRNA probes, the present study demonstrates that expression of the neutrophil elastase gene is tightly controlled in bone marrow precursors and occurs during a very limited stage of differentiation of the neutrophil myeloid series, almost entirely at the promyelocyte stage. Neutrophil elastase mRNA transcript levels are detectable to a limited extent in blasts, increase markedly in the promyelocyte stage, and then disappear as promyelocytes further differentiate. Control probes specific for myeloperoxidase, lactoferrin, and beta-globin mRNA transcripts, respectively, demonstrated contrasting gene expression. Myeloperoxidase mRNA transcripts were also found almost exclusively at the promyelocyte stage, but myeloperoxidase mRNA levels disappeared earlier than do neutrophil elastase mRNA levels, suggesting that expression of these genes may be differently controlled. In comparison, lactoferrin mRNA transcripts were detected late in the neutrophil lineage, while beta-globin mRNA was detected only in cells of the erythroid lineage. Together these observations suggest that the expression of the neutrophil elastase gene is likely under very tight control, and is likely different than that for other constituents of the neutrophil granules.
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PMID:Expression of the neutrophil elastase gene during human bone marrow cell differentiation. 253 48

Cathepsin G is a 26,000-Da serine protease that is found in the azurophil granules of neutrophils and monocytes. The cathepsin G gene is expressed at high levels in U937 promonocytic cells, but is down-regulated with phorbol-induced differentiation. To characterize the genomic sequences responsible for the regulated expression of this gene, we screened a human genomic fibroblast library using cathepsin G cDNA, and obtained two lambda clones that contained the cathepsin G locus. The cathepsin G gene spans 2.7 kilobase pairs of genomic DNA and consists of 5 exons and 4 introns. The genomic organization of cathepsin G is similar to that of human neutrophil elastase, rat mast cell protease II, murine adipsin, and murine cytotoxic T-cell serine proteases, with protease catalytic residues located near the borders of exons 2, 3, and 5. Using in situ hybridization techniques, we localized cathepsin G to chromosome 14q11.2, a site that is near the alpha/delta T-cell receptor complex. Cathepsin G transcription is abolished in U937 nuclei with 2 micrograms/ml alpha-amanitin, indicating that this gene is probably transcribed by RNA polymerase II. The 5' end of the cathepsin G gene was defined by primer extension and S1 nuclease protection assays. A TATA box is found at position -29, and a CAAT box is found at -69 with respect to the transcription initiation site. Having defined the genomic structure and chromosomal location of cathepsin G, we are now attempting to identify the DNA elements in or near this gene that mediate its tissue and development-specific pattern of expression.
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PMID:Genomic organization and chromosomal localization of the human cathepsin G gene. 256 62

alpha 1-antitrypsin, a 52 kDa antiprotease, provides the major defense to the lower respiratory tract against the ravages of neutrophil elastase, a powerful serine protease. A variety of mutations in the coding exons of the alpha 1-antitrypsin gene result in 'alpha 1-antitrypsin deficiency', leading to emphysema at an early age. A subset of mutations cause liver disease and a rare mutation is associated with a bleeding diathesis. Preventive treatment for the emphysema associated with alpha 1-antitrypsin deficiency is available in the form of intermittent infusions with alpha 1-antitrypsin, and strategies have been developed to reverse the deficiency state with gene therapy.
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PMID:The alpha 1-antitrypsin gene and its deficiency states. 269 85

By stepwise extraction of kidney stones, first with 10% acetic acid then 0.1 M EDTA, three pools of protein material have been obtained. The soluble material from the acid extract showed well defined bands when analyzed by sodium dodecyl sulfate (SDS) gel electrophoresis, and amino acid sequence analysis of peptides identified hemoglobin as a common constituent. From one stone neutrophil elastase has been identified along with another serine protease of unknown origin. The second pool of material which was soluble in EDTA showed a smear on SDS gel electrophoresis while the third pool consisted of the insoluble matrix. The finding of proteolytic enzymes opens up the possibility that limited proteolysis might be involved in the stone forming process.
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PMID:Identification of hemoglobin and two serine proteases in acid extracts of calcium containing kidney stones. 273

Elastase, a serine protease, is capable of inducing severe lung destruction in experimental animal models. We now report that this proteinase exists preformed in neutrophil-free sonicates of purified human lung mast cells (greater than 98% purity) and in circulating peripheral blood basophils (greater than 97% purity). The elastase levels in both cell types (41-174 ng/10(6) cells) represents approximately 3-20% of those found in human neutrophils; both cell types released their elastase following anti-IgE and ionophore A23187 challenge. The apparent molecular size of the mast cell enzyme on Sephadex G-100 gel filtration, as well as its inhibition profile, was identical to that of purified human neutrophil elastase. This mast cell elastase is identical to our previously reported mast cell-derived Hageman factor cleaving activity. Mast cell-, basophil-, and neutrophil-derived elastases cleave Hageman factor into fragments of 52,000 and 28,000 Da; cleavage by all three enzymes is inhibited by preincubation with polyclonal antibodies directed against human neutrophil elastase.
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PMID:Release of elastase from purified human lung mast cells and basophils. Identification as a Hageman factor cleaving enzyme. 278 84


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