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:3.4.21.4 (trypsin)
42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the hypothesis that mast cell and neutrophil proteases stimulate airway gland secretion, we studied the effects of two mast cell proteases (tryptase and chymase) and two neutrophil enzymes (human neutrophil elastase and cathepsin G) on secretion of 35S-labeled macro-molecules from cultured bovine airway gland serous cells. Tryptase had no effect, but the other three enzymes stimulated secretion. Threshold concentrations of the enzymes (greater than or equal to 10(-10) M) were lower by two orders of magnitude than other agonists (e.g., histamine, prostaglandins, beta-adrenergic agonists). Only proteases induced maximal secretory response (greater than or equal to 80% depletion of 35S-labeled macromolecules), and these responses were greater than 10-fold larger than those of other agonists. The active catalytic sites of the enzymes are required for their secretory activities. These findings suggest a role for these enzymes in the pathogenesis of inflammatory airway diseases associated with hypersecretion, and they suggest that the use of selective site-directed inhibitors of these enzymes may provide a novel strategy for intervention in inflammatory diseases of the airways associated with hypersecretion (e.g., cystic fibrosis, chronic bronchitis).
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PMID:Role of mast cell and neutrophil proteases in airway secretion. 189 27

The role of human neutrophil cathepsin G (Cat G) on Eimeria tenella sporozoites was studied in vitro. Sporozoites were incubated for 2 hr at 37 C in PO4 buffer, 0.9% NaCl (PBS), pH 7.6 in the presence of Cat G (50 micrograms/ml), diisopropyl fluorophosphate-inhibited Cat G (DFP-Cat G) (50 micrograms/ml) or PBS alone, prior to being inoculated into embryonated eggs. As judged by oocyst production on day 7 postinoculation, embryo mortality and the hemorrhage scores, both Cat G and DFP-Cat G demonstrated anticoccidial activity; greater activity was obtained with the DFP-Cat G. Sporozoites were exposed also to increasing concentrations of native and trypsin-digested DFP-Cat G (0-100 micrograms/ml) under the same conditions. Significant protection (37% and 49% for native and digested DFP-Cat G, respectively) was obtained with a low concentration (5 mu/ml), and higher concentrations resulted in 70% and 84% protection, respectively. The primary bactericidal domain of Cat G, the HPQYNQR peptide, at 3 concentrations (25, 50, and 100 micrograms/ml), reduced the oocyst production by 46%, 16%, and 15%, respectively. The anticoccidial activity of Cat G may involve a peptide fragment different from the antimicrobial domain of the enzyme.
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PMID:In vitro activity of the human neutrophil cathepsin G on Eimeria tenella sporozoites. 191 28

We examined the roles of enzymes from mast cells and from neutrophils in stimulating airway submucosal gland secretion. To avoid effects on surface epithelial cells and goblet cells, we studied a line of cultured bovine tracheal gland serous cells. We discovered that mast cell chymase and neutrophil elastase are the most potent secretagogues of airway submucosal glands described. Mast cell chymase markedly stimulated serous cell secretion in a concentration-dependent fashion with a threshold of 10(-10) M, whereas tryptase had no effect. The response to 10(-8) M chymase (1,530 +/- 80% over baseline; mean +/- SEM) was approximately 10-fold higher than that evoked by other agonists such as histamine and isoproterenol. Both neutrophil proteases also stimulated secretion in a concentration-dependent fashion with a threshold of greater than 10(-10) M. Elastase was more potent than cathepsin G, causing a maximal secretory response of 1,810 +/- 60% over baseline at 10(-8) M. Secretion by the 3 proteases was noncytotoxic and required catalytically active enzymes. These findings suggest a potential role for neutrophil and mast cell proteases in the pathogenesis of increased and abnormal submucosal gland secretions in diseases associated with inflammation of the airways.
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PMID:Role of enzymes from inflammatory cells on airway submucosal gland secretion. 192 74

Human mucus proteinase inhibitor is a two-domain protein which inactivates bovine trypsin and chymotrypsin, leukocyte elastase and cathepsin G. In order to localize the site(s) responsible for these inhibitory activities, the two domains were isolated after specific cleavage of the Asp49-Pro50 bond following mild acid treatment of the bronchial inhibitor. The carboxy-terminal domain was active against leukocyte elastase, trypsin and chymotrypsin whereas the amino-terminal domain, which contained a putative antitryptic active site, was devoid of activity. This implicates that, in the whole molecule, the inhibitory activity region is localized only in the carboxy-terminal domain.
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PMID:Separation of the two domains of human mucus proteinase inhibitor: inhibitory activity is only located in the carboxy-terminal domain. 193 Jan 99

To study the mechanisms of activation of human neutrophil gelatinase, the enzyme has been purified using a combination of chromatography on a DEAE-Sephacel and a gelatin-peptide-Sepharose column. On reducing SDS-polyacrylamide-gel electrophoresis the purified gelatinase ran as a single band of about 94,000 Da, and had a specific activity of 5624.4 units/mg of enzyme protein. When latent gelatinase was treated with trypsin, cathepsin G, neutrophil elastase, HgCl2 or urea, its activity was enhanced and the enzyme was processed and converted into species of the lower molecular mass. Upon activation, the protein band of 94,000 Da of reduced latent gelatinase underwent a decrease of about 6,000-12,000 Da. Formation of the species of lower molecular mass during urea activation could be blocked by the addition of EDTA.
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PMID:The activation of human neutrophil gelatinase. 196 83

Latent collagenase has been isolated in pure form from the rheumatoid synovial fluid. The final preparation, activated by trypsin, yielded a collagenase of specific activity 2,227 units/mg. Electrophoresis in sodium dodecyl sulfate polyacrylamide gels revealed a protein doublet of 54 and 50 kDa. Trypsin or HgCl2 activation resulted in disappearance of the doublet and emergence of a new doublet of 47 and 43 kDa. The latent collagenase could also be activated by leucocyte cathepsin G or plasmin. Neither the latent nor the active collagenase from synovial fluid showed any cross-reactivity with the antibodies against leucocyte collagenase. The trypsin activated collagenase degraded collagen type I, II, III giving typical cleavage products but did not degrade type IV and V collagen.
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PMID:Some properties of latent collagenase from human synovial fluid. 196 84

Interstitial collagenases (matrix metalloproteinase-1, EC 3.4.24.7), isolated from extracts of inflamed human gingiva, gingival crevicular fluid and saliva were characterized for their molecular weight, proteolytic and non-proteolytic activation and substrate specificity against soluble collagen types I, II and III. All three collagenases had Mr of 70 K. The enzymes existed predominantly in a latent form that could be activated by aminophenylmercuric acetate, gold thioglucose and hypochlorous acid. Among serine proteases tested, trypsin, chymotrypsin, neutrophil cathepsin G and a combination of trypsin and human gingival fibroblast prostromelysin activated gingival and salivary interstitial collagenases. Plasmin and plasma kallikrein, however, were relatively ineffective activators. The collagenases degraded soluble type I and II collagens at apparently equal rates but considerably faster than they did type III collagen. These findings suggest that the characteristics of interstitial collagenases found in inflamed human gingiva, gingival crevicular fluid and saliva are consistent with those of human neutrophil interstitial collagenase rather than the fibroblast-type interstitial collagenase. Thus, neutrophils are suggested to be the main source of such enzymes in inflamed human gingiva, crevicular fluid and saliva during adult periodontitis.
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PMID:The role of gingival crevicular fluid and salivary interstitial collagenases in human periodontal diseases. 196 17

An inhibitor of the serine proteinases human leucocyte elastase (EC 3.4.21.37), of cathepsin G (EC 3.4.21.20) and of trypsin (EC 3.4.21.4) has been purified from human articular cartilage. The apparent Mr of the cationic (pI greater than 10) protein was determined to 15,000 by SDS/PAGE. It was shown to cross-react in Western blot with a specific antibody to a recombinant-derived serine-proteinase inhibitor of human mucous secretions. Identity of both inhibitors is indicated by the determination of the N-terminal amino acid sequence of the cartilage-derived serine-proteinase inhibitor. In all 24 residues the cartilage inhibitor was shown to be identical with the human secretory leucocyte proteinase inhibitor ('SLPI'). The inhibitor molecule may play a crucial role in the protection of cartilage matrix proteins against proteolytic attack.
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PMID:Purification of a serine-proteinase inhibitor from human articular cartilage. Identity with the acid-stable proteinase inhibitor of mucous secretions. 200 Dec 42

Recent studies have led to a rapid expansion of knowledge concerning the structure and biology of the two major mast cell proteinases, tryptase and chymase. Tryptase is an abundant, trypsin-like enzyme found in the secretory granules of all human lung mast cells. The subunits of the heparin-associated tryptase tetramer appear to be the products of a multigene family whose intron-exon organization is unique and is not closely related to that of other mast cell or leukocyte serine proteinases. In vitro studies suggest that tryptases may participate in lung and airway responses by regulating airway neuropeptide activity, bronchomotor tone, and fibroblast mitogenesis. Mast cell chymases are chymotrypsin-like proteinases related closely to neutrophil cathepsin G and lymphocyte granzymes. The cDNA-derived structures of tryptase and chymase suggest that the two enzymes may differ in modes of activation from proenzyme forms, although the mature enzymes are packaged and released together. Chymase expression appears to be limited to a subset of human lung mast cells most prevalent in the airway submucosa. Possible roles for chymase include inactivation of sensory neuropeptides, regulation of submucosal gland secretion, and potentiation of histamine-induced vascular permeability.
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PMID:The structure and airway biology of mast cell proteinases. 202 78

Neutrophil-activating peptide 2 (NAP-2) is generated by cleavage of two inactive precursors, connective-tissue-activating peptide III (CTAP-III) and platelet basic protein (PBP), which are stored in the alpha-granules of blood platelets. Using highly purified CTAP-III as the substrate we studied the generation of NAP-2 by several neutral tissue proteinases. CTAP-III was rapidly cleaved by chymotrypsin, cathepsin G and trypsin, yielding products with neutrophil-stimulating activity. This activity remained unchanged for 24 h in the presence of chymotrypsin, decreased only slowly in the presence of cathepsin G, but was rapidly destroyed by trypsin. CTAP-III was also degraded by human neutrophil elastase and porcine pancreatic elastase, but no active fragments were obtained. By contrast, no degradation of CTAP-III was observed with thrombin, plasmin or 'granzymes' from cytolytic T-lymphocyte granules. Two active fragments of CTAP-III, generated by chymotrypsin or cathepsin G, were purified and partially sequenced, and were found to have the same N-terminal sequence as NAP-2. These results indicate that both proteinases cleave preferentially the bond between amino acids 15 (Tyr) and 16 (Ala) of CTAP-III. We conclude that chymotrypsin-like proteolytic activity in the vicinity of activated platelets may generate NAP-2 intravascularly. Due to its presence in the primary granules of neutrophils and monocytes cathepsin G is likely to be involved in this process.
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PMID:Formation of neutrophil-activating peptide 2 from platelet-derived connective-tissue-activating peptide III by different tissue proteinases. 203 37


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