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)

1. Proteoglycan was obtained from bovine nasal cartilage by a procedure involving sequential extraction with a low-ionic-strength KCl solution, then a high-ionic-strength CaCl2 solution. Purification was by CsCl-density-gradient centrifugation. 2. The CaCl2- extracted proteoglycan was subjected to proteolytic degradation by papain, trypsin, cathepsin D, cathepsin B, lysosomal elastase or cathepsin G. Degradation was allowed to proceed until no further decrease in viscosity was detectable. 3. The size and chemical composition of the final degradation products varied with the different proteinases. Cathepsin D and cathepsin G produced glycosaminoglycan-peptides of largest average size, and papain produced the smallest product. 4. The KCl-extracted proteoglycan was intermediate in molecular size and composition between the CaCl2-extracted proteoglycan and the largest final degradation products, and may have been formed by limited proteolysis during the extraction procedure. 5. It is postulated that the glycosaminoglycan chains are arranged in groups along the proteoglycan core protein. Proteolytic cleavage between the groups may be common to the majority of proteinases, whereas clevage within the groups is dependent on the specificity of each individual proteinase.
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PMID:The degradation of cartilage proteoglycans by tissue proteinases. Proteoglycan structure and its susceptibility to proteolysis. 60 25

The cell-free haemolymph of the mollusc Octopus vulgaris inhibited the proteolytic activity of the thermolysin against the high-molecular-mass substrate hide powder azure. The purified inhibitor was a glycoprotein composed of two identical 180 kDa disulphide-linked subunits. In addition to the inhibition of the metalloproteinase thermolysin, the protein inhibited the serine proteinases human neutrophil elastase, pig pancreatic elastase, bovine chymotrypsin, bovine trypsin and the cysteine proteinase papain. A fraction of the proteinase-inhibitor complex resisted dissociation after denaturation indicating that some of the proteinase molecules became covalently bound. The nucleophile beta-aminopropionitrile decreased the covalent binding of proteinases to the Octopus vulgaris protein, suggesting that this interaction is mediated by an internal thiol ester; the reactivity and the amino acid sequence flanking the reactive residues of the putative thiol ester were consistent with this hypothesis. Bound trypsin remained active against the low-molecular-mass chromatogenic substrate H-D-Pro-Phe-Arg p-nitroanilide and was protected from inhibition by active-site-directed protein inhibitors of trypsin; however, the bound trypsin was readily inhibited by small synthetic inhibitors. This indicates that the inhibition of proteinases is accomplished by steric hindrance. The proteinase-inhibitory activity of this protein is characteristic of inhibition by mammalian alpha-macroglobulins and the presence of a putative thiol ester suggests that the Octopus vulgaris proteinase inhibitor is a homologue of human alpha 2-macroglobulin.
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PMID:Purification and characterization of an alpha-macroglobulin proteinase inhibitor from the mollusc Octopus vulgaris. 137 44

IgG1 is cleaved in vitro by granulocyte elastase into Fc, Fab and Fabc fragments. The cleaved products have been isolated by a series of chromatographic procedures and characterized with regard to molecular mass and isoelectric point. The Fc fragment has been previously shown to express at its N-terminal site a neoantigen which is specific for elastase (Kolb, G., Eckle, I., Heidtmann, H.-H., Neurath, F. & Havemann, K. (1988) Scand. J. Rheumatol. S75, 179-189). The production of superoxide radical anions in prestimulated neutrophils is inhibited dose-dependently by the elastase-generated Fc and Fabc fragments. Native IgG1 and Fab fragments show no inhibitory effect, nor do papain-generated Fc fragments. The degree of inhibition depends on the stimulus applied: half-maximal inhibition is obtained by 6 microM Fc after stimulation with 4 beta-phorbol and 2.4 microM after stimulation with fMet-Leu-Phe; neutrophils stimulated with serum-activated zymosan are not inhibited by IgG fragments. The effect of Fc is purely cellular; no inhibition of O2 generation can be produced by applying Fc to the xanthine oxidase/xanthine system. The fragments have no effect on the activation or activity of crude NADPH oxidase, which is the O2-forming enzyme system of neutrophils. Possible mechanisms are discussed by which Fc acts on stimulated neutrophils.
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PMID:Inhibition of neutrophil oxidative burst by elastase-generated IgG fragments. 215 63

Expression of neoantigens during denaturation of IgG by oxygen radicals or proteolysis was assumed to be a possible mechanism for stimulation of rheumatoid factor (RF) formation and/or granulocyte dependent inflammative joint destruction. The so-called human leukocyte elastase (HLE) regularly released by stimulated neutrophils f.e. into the RA synovial fluid is known to split IgG in vitro into papain like fragments and low molecular weight peptides. The n-terminal site of the HLE related Fc is bearing a neoantigenic group which is located near the hinge region but not expressed by the native IgG. The neoantigen itself is represented by the low molecular weight peptides produced by prolonged HLE-IgG proteolysis. Detection of HLE generated Fc in synovial fluids was performed by radioimmunoassay specific for the neoantigen. Patients were divided into the three groups; I RA (n = 23), II inflammative joint effusions except RA (n = 23), III osteoarthritis and trauma (n = 19). The biological effect of the neoantigen on to granulocyte oxidative metabolism was tested by Cytochrome C reduction and chemiluminescence. Neoantigen bearing Fc could be detected in 15 of 23 cases of group I, in group II in 11 of 23 cases and only in 7 of 19 cases in group III. The median concentrations were 0.62 micrograms in group I and zero in II and III. The HLE derived Fc were able to inhibit the oxidative metabolism of activated granulocytes in vitro. The O2- production of stimulated granulocytes was depressed dose dependent by the neoantigen. The neoantigenic group itself does not react with RF as proved by nephelometric titration of HLE derived Fc, neoantigenic peptide and native IgG against a RF standard.
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PMID:Neoantigenic group on Fc fragments in rheumatoid arthritis synovial fluids. 246 51

Human polymorphonuclear leukocyte elastase (PMN elastase) is inhibited by L-659,286 (7 alpha-methoxy-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4- triaz-in-3-yl)thio]methyl]-5-thia-1-aza-6R-bicyclo[4.2.O]oct-2-ene -2- pyrrolidine carboxamide-5,-dioxide) with a Ki of 0.4 microM. This inhibition is time-dependent, rapid, and only slowly reversible, with a t1/2 of greater than 3 days at 25 degrees C. L-659,286 is also highly selective for PMN elastase, as it does not inhibit thrombin, trypsin, papain, plasmin, chymotrypsin, or cathepsin G. L-659,286 administered intratracheally inhibits lung damage caused by administration via the same route of human PMN elastase into hamsters. In marmosets, L-659,286 is cleared from blood very rapidly after an intravenous injection but is recovered in bronchoalveolar lavage fluid for several hours after intratracheal administration.
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PMID:Pharmacological profile of the substituted beta-lactam L-659,286: a member of a new class of human PMN elastase inhibitors. 249 9

Limited proteolysis of T-kininogen by heterologous and homologous endopeptidases (bovine trypsin, human leukocyte elastase, rat submaxillary gland endopeptidase k, and rat mast cell chymase) produced similar fragmentation. Amino-terminal sequence analysis of whole T-kininogen lysates and purified proteolytic fragments identified four susceptible regions which contained all the preferential cleavage sites for these proteinases. Two of these susceptible regions were close to the junction between heavy chain cystatin-like domains, the third was in the kinin-containing region, and the fourth was close to the carboxyl terminus of the T-kininogen light chain. There was only one primary site for each proteinase in the kinin-containing region, which explains why catalytic amounts of these proteinases did not release immunoreactive kinin from this kininogen. However, preferential cleavage of T-kininogen close to the junction between cystatin-like domains released fragments which, provided they included cystatin-like domains 2 and/or 3, strongly inhibited papain and cathepsin L. The fragments were inhibitory even when parts of the amino-terminal ends of the domains were lacking. The highly conserved glycyl residue, thought to be involved in the inhibitory reactive site of cystatin-like inhibitors, was not required in purified domain 3 for inhibition of cathepsin L.
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PMID:Limited proteolysis of T-kininogen (thiostatin). Release of comparable fragments by different endopeptidases. 264 33

In vitro granulocyte elastase is known to cleave a large number of substrates e.g. complement components, fibrinogen, collagen and IgG. In vivo the enzyme is rapidly complexed by the plasma inhibitors a1proteinase inhibitor (a1PI) and a2macroglobulin. Therefore in biological fluids elastase is measured as the inactive a1PI-complex. We present a radioimmunoassay for elastase specific IgG split products as marker for the elastase activity in vivo. Elastase splits human IgG1 in Fab and Fc fragments and low molecular weight peptides. We produced specific antibodies against the elastase induced Fc fragment by immunization with an elastase generated peptide. After purification of the antibodies there is no crossreactivity with native IgG nor with similar Fc fragments produced by plasmin or papain. The elastase specific IgG split products are detected in synovial fluid samples of patients with rheumatoid arthritis. The measured concentrations are higher in the RA group than in control groups of patients with other inflammatory joint diseases.
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PMID:Detection of granulocyte elastase specific IgG split products in rheumatoid synovial fluid. 324 4

alpha 1-Antitrypsin Christchurch was isolated from the plasma of a Cambodian woman who was heterozygous for this variant and for the normal M protein. Tryptic peptide maps revealed that the inhibitory-site peptide, 359-365 Ser-Ile-Pro-Pro-Glu,Val,Lys, was missing and replaced by two new peptides Ser-Ile-Pro-Pro,Lys and Val-Lys, indicating a mutation of 363 Glu----Lys. There was no obvious clinical condition associated with this new antitrypsin. Competition experiments showed that antitrypsin Christchurch reacted at the same rate as normal antitrypsin in the presence of limiting amounts of trypsin, chymotrypsin, thrombin and neutrophil elastase. Both inhibitors were inactivated by catalytic amounts of papain. This inactivation was due to cleavage at the phenylalanine residue at the P7 position, seven residues towards the N-terminal of the inhibitory site. A one-step ethanol extraction procedure is described for isolating the papain cleavage products.
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PMID:alpha 1-Antitrypsin Christchurch, 363 Glu----Lys: mutation at the P'5 position does not affect inhibitory activity. 352 73

Macrophages at sites of inflammation are exposed to proteolytic enzymes derived from neutrophils, platelets, clotting factors, complement, and damaged tissues. To investigate the possible effect of proteases on the plasma membrane-mediated oxidative metabolic response of macrophages in inflammatory sites, cultured human monocyte-derived macrophages were treated in vitro with proteolytic enzymes and were then assayed for their ability to release superoxide anion (O2-) and hydrogen peroxide (H2O2) in response to stimuli. Macrophages pretreated for 1 to 20 min with trypsin, chymotrypsin, pronase, or papain, 0.1 to 200 micrograms/ml, released up to 3.5-times more O2- and H2O2 than did control (untreated) cells. This enhanced production of oxygen metabolites was observed by using either phorbol myristate acetate or opsonized zymosan as the stimulus. Macrophages were also "primed" for enhanced O2- release (2.3-fold) by pretreatment with a subfraction of granules extracted from human neutrophils. This subfraction contained primarily elastase and cathepsin G. Similar enhancement was observed with 60 ng/ml or purified human neutrophil cathepsin G (2.2-fold) and with 20 micrograms/ml of purified neutrophil elastase (3.3-fold). Priming by these neutrophil proteases could be blocked by specific inhibitors of their proteolytic activity. These results suggest that macrophages involved in an inflammatory response might be rapidly primed by proteases released from degranulating neutrophils. Primed macrophages could mount a more effective oxidative metabolic response to microorganisms or tumor cells, but might also cause greater tissue damage.
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PMID:Enhanced release of oxygen metabolites by monocyte-derived macrophages exposed to proteolytic enzymes: activity of neutrophil elastase and cathepsin G. 608 32

Mouse macrophage elastase, a metalloproteinase secreted by inflammatory macrophages, catalyzed the limited proteolysis of selected subclasses of mouse immunoglobulins, including monomeric IgG2a, IgG3, and some forms of IgG2b. Mouse IgG1 was resistant to elastase degradation; however, human IgG1 was degraded. IgG3 in immune complexes was cleaved in a manner similar to that of monomeric IgG3. Degradation by macrophage elastase was limited to the heavy chain, resulting in products that did not compete for binding to the macrophage Fc receptor. Macrophage elastase usually produced a pepsin-like rather than a papain-like pattern of proteolysis, resulting in the release of F(ab')2 and Fc' subfragments. This degradation of IgG differed from the papain-like cleavage of IgG by granulocyte elastase. Macrophage elastase degraded papain-generated Fc fragments of IgG2a into multiple fragments. Therefore, macrophage elastase at concentrations found in culture medium has the potential to regulate some aspects of cellular events associated with immunoglobulins.
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PMID:Selective proteolysis of immunoglobulins by mouse macrophage elastase. 622 Jan 7


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