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)

Formation of the covalently stabilized alpha 1-antitrypsin (alpha 1-AT)-neutrophil elastase complex, the archetype of serpin-enzyme complexes, results in a structurally rearranged alpha 1-AT molecule that possesses chemo-attractant activities, mediates an increase in synthesis of alpha 1-AT by mononuclear phagocytes and hepatocytes, and is more rapidly cleared from the circulation than is the native alpha 1-AT molecule. We have recently identified an abundant, high affinity cell surface receptor on human hepatoma HepG2 cells and human monocytes that binds alpha 1-AT-elastase complexes, mediates endocytosis and lysosomal degradation of alpha 1-AT-elastase complexes, and induces an increase in synthesis of alpha 1-AT. We have referred to this receptor as the serpin-enzyme complex, or SEC, receptor because it also recognizes complexes of serpins antithrombin III, alpha 1-antichymotrypsin, and C1 inhibitor with their cognate enzymes. In the current study, we show that a pentapeptide domain in the carboxyl terminal fragment of alpha 1-AT (amino acids 370-374, FVFLM) is sufficient for binding to the SEC receptor. A synthetic analog of this pentapeptide (peptide 105C, FVYLI) blocks binding and internalization of alpha 1-AT-125I-trypsin complexes by HepG2 cells. 125I-Peptide 105C binds specifically and saturably to HepG2 cells, and its binding is blocked by alpha 1-AT-trypsin or alpha 1-AT-elastase complexes. Alterations of this sequence introduced into synthetic peptides (mutations, deletions, or scrambling) demonstrate that binding of the pentapeptide domain is sequence-specific. Comparisons with the sequences of other serpins in the corresponding region indicate that this pentapeptide neodomain is highly conserved.
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PMID:The SEC receptor recognizes a pentapeptide neodomain of alpha 1-antitrypsin-protease complexes. 164 29

Immunohistochemical investigations were performed on decalcified, paraffin-embedded iliac crest trephine biopsy specimens from 30 cases of acute myeloid leukemia (AML, as defined by the FAB classification) with antibodies against B cells (L26, 4KB5, MB1, Ki-B3), T cells (UCHL1, MT1), myeloid/histiocytic cells (anti-neutrophil elastase, MAC387, anti-S-100 protein, anti-alpha 1-antichymotrypsin, DAKO-M1), natural killer/killer cells (anti-Leu-7), and megakaryocytes (anti-factor VIII-related antigen). (1) The blast cells of all the cases reacted with from at least two to at most eight different antibodies. Each antibody reacted with blast cells in a minimum of two (maximum 30) cases. (2) MT1, Ki-B3, anti-alpha 1-antichymotrypsin anti-neutrophil elastase, anti-S-100 protein, and MAC387 stained blast cells in more than 50% of the cases; MB1, L26, UCHL1, 4KB5, and DAKO-M1 in 20% to 50% of the cases; and anti-Leu-7 and anti-factor VIII-related antigen in less than 20% of the cases. (3) In the majority of cases many T lymphocytes, a small-to-moderate number of B lymphocytes, and a few Leu-7-positive lymphoid cells were intermingled with the blast cells. In some cases, especially where only a minor proportion of the blast cells was immunostained, it was nearly impossible to distinguish the lymphocytes of the tumor's stromal reaction from small blast cells. Thus, AML exhibits a heterogeneous immunophenotype in trephine biopsy specimens. Immunohistologic diagnosis of this disease in such specimens may be extremely difficult. Since staining of the blast cells with one or more of the antibodies generally used to define B cells, T cells, or their neoplastic derivatives is not uncommon, misinterpretation as non-Hodgkin's lymphoma of high-grade malignancy could easily occur. These findings also suggest that mixed-type (hybrid) acute leukemias with coexpression of myeloid and lymphoid cell markers could be more common than generally realized.
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PMID:Acute myeloid leukemia: immunohistologic findings in paraffin-embedded bone marrow biopsy specimens. 169 93

Formation of the covalently stabilized complex of alpha 1-antitrypsin (alpha 1-AT) with neutrophil elastase, the archetype of serine proteinase inhibitor serpin-enzyme complexes, is associated with structural rearrangement of the alpha 1-AT molecule and hydrolysis of a reactive-site peptide bond. An approximately 4-kDa carboxyl-terminal cleavage fragment is generated. alpha 1-AT-elastase complexes are biologically active, possessing chemotactic activity and mediating increases in expression of the alpha 1-AT gene in human monocytes and macrophages. This suggested that structural rearrangement of the alpha 1-AT molecule, during formation of a complex with elastase, exposes a domain that is recognized by a specific cell surface receptor or receptors. To test this hypothesis, the known three-dimensional structure of alpha 1-AT and comparisons of the primary structures of the serpins were used to select a potentially exteriorly exposed and highly conserved region in the complexed form of alpha 1-AT as a candidate ligand (carboxyl-terminal fragment, amino acids 359-374). We show here that synthetic peptides based on the sequence of this region bind specifically and saturably to human hepatoma cells and human monocytes (Kd = 4.0 X 10(-8) M, 4.5 X 10(5) plasma membrane receptors per cell) and mediate increases in synthesis of alpha 1-AT. Binding of peptide 105Y (Ser-Ile-Pro-Pro-Glu-Val-Lys-Phe-Asn-Lys-Pro-Phe-Val-Tyr-Leu-Ile) is blocked by alpha 1-AT-elastase complexes, antithrombin III (AT III)-thrombin complexes, alpha 1-antichymotrypsin (alpha 1-ACT)-cathepsin G complexes, and, to a lesser extent, complement component C1 inhibitor-C1s complexes, but not by the corresponding native proteins. Binding of peptide 105Y is also blocked by peptides with sequence corresponding to carboxy-terminal fragments of the serpins AT III and alpha 1-ACT, but not by peptides having the sequence of the extreme amino terminus of alpha 1-AT. The results also show that peptide 105Y inhibits binding of 125I-labeled alpha 1-AT-elastase complexes. Thus, these studies demonstrate an abundant, relatively high-affinity cell surface receptor which recognizes serpin-enzyme complexes (SEC receptor). This receptor is capable of modulating the production of at least one of the serpins, alpha 1-AT. Since the ligand specificity is similar to that previously described for in vivo clearance of serpin-enzyme complexes, the SEC receptor may also be involved in the clearance of certain serpin-enzyme complexes.
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PMID:Identification of a serpin-enzyme complex receptor on human hepatoma cells and human monocytes. 216 76

Monitoring of plasma proteinases, proteinase inhibitors and other selective plasma proteins was evaluated in patients undergoing Y-graft aortofemoral bypass operation. Fast-reacting acute-phase proteins (C-reactive protein, antichymotrypsin, alpha 1-acid glycoprotein) and slow-reacting proteins (haptoglobin, alpha 1-antitrypsin) increased significantly 48-120 h after operation. By contrast, no significant increase was found between plasma ceruloplasmin levels before clamping and after declamping. Activity and concentration of alpha 2-macroglobulin decreased postoperatively and remained significantly lowered throughout the observation period. Plasma levels of granulocyte elastase were elevated significantly 1 h after declamping, whereas trypsin-binding capacity decreased immediately after the release of the clamp. Aprotinin pretreatment caused higher trypsin-binding capacity of the plasma, significantly lower 'unspecific' proteolytic (azocasein-hydrolyzing) activity and significantly lower non-TCA precipitable low molecular weight plasma protein concentration. Our results confirm the data of several authors that monitoring of plasma proteinases, proteinase inhibitors and other selective plasma proteins may be helpful in evaluating surgical patients postoperatively.
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PMID:Plasma proteinases, proteinase inhibitors and other selective plasma proteins following aortofemoral bypass operation. 242 35

The human protease inhibitor genes alpha 1 antitrypsin (alpha 1-PI) and alpha 1-antichymotrypsin (alpha 1-ACT) are acute-phase proteins which are induced in response to inflammation. These inhibitors function to limit the activity of serine proteases in vivo. alpha 1-PI acts as an inhibitor of neutrophil elastase to protect the elastin fibers of the lung. Genetic deficiencies of alpha 1-PI result in development of chronic pulmonary emphysema. The physiologic role of alpha 1-ACT has not been clearly defined, but it also appears to function in the maintenance of protease-protease inhibitor equilibrium in the lung. Nucleic acid and protein sequence homologies detected between alpha 1-PI and alpha 1-ACT suggested an evolutionary relationship. Gene mapping experiments were performed to determine if these protease inhibitor genes reside at the same chromosomal locus in man. In situ hybridization data demonstrate that both alpha 1-PI and alpha 1-ACT map to the same region, q31-q32.3, on chromosome 14.
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PMID:Regional location of alpha 1-antichymotrypsin and alpha 1-antitrypsin genes on human chromosome 14. 348 24

The effects of ozone on human alpha 1-proteinase inhibitor (A-1-PI), alpha 1-antichymotrypsin (A-1-Achy), bronchial leukocyte proteinase inhibitor (BLPI), and Eglin C were studied using in vitro exposures in phosphate-buffered solutions. Following ozone exposure, inhibitory activities against human neutrophil elastase (HNE) and/or cathepsin G (Cat G) were measured. Exposure of A-1-PI to 50 mol O3/mol protein resulted in a complete loss of HNE inhibitory activity, whereas A-1-Achy lost only 50% of its Cat G inhibitory activity and remained half active even after exposure to 250 mol of O3. At 40 mol O3/mol protein, BLPI lost 79% of its activity against HNE and 87% of its Cat G inhibitory activity. Eglin C, a leech-derived inhibitor, lost 81% of its HNE inhibitory activity and 92% of its ability to inhibit Cat G when exposed to 40 mol O3/mol. Amino acid analyses of ozone-exposed inhibitors showed destruction of Trp, Met, Tyr, and His with as little as 10 mol O3/mol protein, and higher levels of O3 resulted in more extensive oxidation of susceptible residues. The variable ozone susceptibility of the different amino acid residues in the four proteins indicated that oxidation was a function of protein structure, as well as the inherent susceptibility of particular amino acids. Exposure of A-1-PI and BLPI in the presence of the antioxidants, Trolox C (water soluble vitamin E) and ascorbic acid (vitamin C), showed that antioxidant vitamins may protect proteins from oxidative inactivation by ozone. Methionine-specific modification of BLPI reduced its HNE and Cat G inhibitory activities. Two moles of N-chlorosuccinimide per mole of BLPI methionine caused an 80% reduction in activity against Cat G, but only a 40% reduction in HNE inhibitory activity.
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PMID:Ozone effects on inhibitors of human neutrophil proteinases. 349 63

A comparative study was made of granulocyte proteases and protease inhibitors in middle ear effusions (MEE) from patients with acute otitis media (OMA) and serous otitis media (SOM). The mean concentrations of the granulocyte proteases, neutral protease and elastase were three- to fourfold higher in OMA as compared to SOM effusions. The mean concentration of granulocyte elastase in SOM effusions was approximately 1 400, and in OMA effusions 5 500 times higher than the corresponding plasma concentrations. In OMA patients the individual MEE/plasma ratios of the main plasma protease inhibitors, alpha 1-antitrypsin, antichymotrypsin and alpha 2-macroglobulin, showed a positive uniform correlation with corresponding albumin MEE/plasma ratios. In SOM effusions, the concentration of alpha 2-macroglobulin was low, indicating a restricted membrane passage in SOM. In SOM effusions both alpha 1-antitrypsin and the locally produced antileukoprotease showed a residual inhibitory capacity. In OMA effusions the inhibitory capacity of anti-leukoprotease was saturated, whereas there was a residual inhibitory capacity of alpha 1-antitrypsin. However, in those OMA effusions, where large amounts of alpha 1-antitrypsin complexes with granulocyte proteases were found, most of the remaining free alpha 1-antitrypsin was inactive.
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PMID:Granulocyte protease inhibition in acute and chronic middle ear effusion. 618 18

Association rates have been determined for the interaction of human alpha 2-macroglobulin with human neutrophil elastase, cathepsin G, and human plasma kallikrein. Both of the neutrophil enzymes are rapidly inactivated by this inhibitor; however, the inactivation of plasma kallikrein is much slower. Comparison of the rates of inactivation with those already established for other inhibitors clearly indicate that alpha 1-proteinase inhibitor is the controlling inhibitor for neutrophil elastase and alpha 1-antichymotrypsin for cathepsin G, alpha 2-macroglobulin acting only as a secondary inhibitor. The control of plasma kallikrein would appear to be rather poor since neither alpha 2-macroglobulin nor C1-inhibitor appears to react very rapidly with this proteinase. Thus, a primary role for alpha 2-macroglobulin in directly inactivating proteinases in blood, under normal physiological conditions, remains to be established.
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PMID:Kinetics of association of human proteinases with human alpha 2-macroglobulin. 620 76

The elastase inhibitory capacity per mg of alpha 1-proteinase inhibitor (alpha 1 PI) was measured in the bronchoalveolar lavage (BAL) fluid from 26 healthy smokers and 24 nonsmokers. Activity was decreased by 40% in smokers' BAL fluid compared to nonsmokers. This effect was demonstrable by using human neutrophil elastase as well as porcine pancreatic elastase as test enzyme (elastase, EC 3.4.21.11) and was reproducible when selected individuals in each group underwent lavage on repeated occasions. In contrast, the functional activity of alpha 1-antichymotrypsin was not decreased in smokers' BAL fluid. Crossed antigen-antibody electrophoresis confirmed that inactivation of alpha 1 PI was responsible for the decrease in the elastase inhibitory capacity of smokers' BAL fluid. alpha 1 PI purified from smokers' BAL fluids contained methionine sulfoxide (4 mol/mol of inactive alpha 1 PI), whereas alpha 1 PI from nonsmokers' BAL fluid did not. Smokers' alpha 1 PI was indistinguishable from nonsmokers' alpha 1 PI on the basis of electrophoretic mobility, molecular weight, and immunoreactivity. Thus, oxidation of methionine residues in lung alpha 1 PI is associated with cigarette smoking. Because chemical oxidation of alpha 1 PI in vitro causes loss of its elastase inhibitory activity, the present observations suggest that methionine oxidation may also be the cause of decreased functional activity of lung alpha 1 PI in smokers. Oxidative inactivation of alpha 1 PI in the lungs of cigarette smokers may play a role in the development of pulmonary emphysema in this group.
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PMID:Potential mechanism of emphysema: alpha 1-proteinase inhibitor recovered from lungs of cigarette smokers contains oxidized methionine and has decreased elastase inhibitory capacity. 697 49

Polymorphonuclear neutrophils (PMN) play an important role in myocardial ischemia/reperfusion (MI/R) injury; however, the role of neutrophilic proteases is less understood. The effects of a novel serine protease inhibitor (serpin), LEX032, were investigated in a murine model of MI (20 min) and R (24 hr) injury in vivo. LEX032 is a recombinant human alpha 1-antichymotrypsin in which six amino acid residues were replaced around the active center with those of alpha-1 protease inhibitor. LEX032 has the ability to inhibit both neutrophil elastase and cathepsin G, two major neutral serine proteases in neutrophils, as well as superoxide generation. LEX032 (25 or 50 mg/kg) administered i.v. 1 min before reperfusion significantly attenuated myocardial necrotic injury evaluated by cardiac creatine kinase loss compared to MI/R rats receiving only vehicle (P < .001). Moreover, cardiac myeloperoxidase activity, an index of PMN accumulation, in the ischemic myocardium was significantly attenuated by LEX032 as compared with rats receiving vehicle (P < .001). LEX032 also moderately attenuated leukotriene B4-stimulated PMN adherence to rat superior mesenteric artery endothelium and markedly diminished superoxide radical release from LTB4-stimulated PMN in vitro. In a glycogen-induced rat peritonitis model, LEX032 (50 mg/kg) significantly attenuated PMN transmigration into the peritoneal cavity in vivo. In conclusion, the recombinant serine protease inhibitor, LEX032, appears to be an effective agent for attenuating MI/R injury by inhibiting neutrophil-accumulation into the ischemic-reperfused myocardium and by inactivating cytotoxic metabolites (proteases and superoxide radical) released from neutrophils.
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PMID:Cardioprotection by a novel recombinant serine protease inhibitor in myocardial ischemia and reperfusion injury. 756 95


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