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)

The rates of interaction of a number of serine proteinases with a mutant form of alpha 1-proteinase inhibitor (referred to as alpha 1-proteinase inhibitor (Pittsburgh)), in which a methionine-358 to arginine-358 mutation has occurred, have been determined. An approximately 6,000-fold increase in the second order association rate constant with human thrombin was observed (48 M-1 X s-1 for the normal protein to 3.1 X 10(5) M-1 X s-1 for the arginine mutant), confirming previously observed data using bovine thrombin (Owen, M.C., Brennan, S.O., Lewis, J.H. & Carrell, R.W. (1983) New England J. Med. 309, 694-698). However, substantial increases in the rates of association with other trypsin-like enzymes were also noted, indicating that the replacement of methionine by a basic residue affects all serine proteinases with this kind of specificity. There was a marked decrease in the rates of interaction of the Pittsburgh mutant with both human neutrophil elastase and porcine pancreatic elastase, the inhibitor being converted into lower molecular mass fragments after interaction with either enzyme. Butanedione caused a substantial loss in the inhibitory activity of the arginine mutant, while having no effect on the normal protein. These data, when compared to those previously reported for differences in reaction rates between normal and oxidized alpha 1-proteinase inhibitor (Beatty, K., Bieth, J. & Travis, J. (1980) J. Biol. Chem. 255, 3931-3934), are consistent with the interpretation that the amino acid in the P1-position at the reactive site of this protein has a marked effect on determining its primary specificity.
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PMID:Kinetic studies on the interaction of alpha 1-proteinase inhibitor (Pittsburgh) with trypsin-like serine proteinases. 353 43

We report the isolation of the human gene encoding an inhibitor of neutrophil elastase and cathepsin G. We have sequenced the gene and a cDNA clone isolated from human parotid tissue. The protein encoded by this gene appears to contain two functional domains, one having a trypsin inhibitory site and the other an elastase inhibitory site. The two-domain structure of the protein is reflected in the organization of the gene, with each domain represented by a separate exon. We have also noted that the intervening sequence separating the trypsin-inhibitor-exon and the elastase-inhibitor-exon is flanked by eleven base-pair direct repeats, suggesting that this intron may have been generated by a transposition-type event.
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PMID:Isolation and sequence of a human gene encoding a potent inhibitor of leukocyte proteases. 364 Mar 38

A neutrophil elastase-inhibitor isolated from lysed pneumococcal cells, as well as trypsin-digest peptides derived from this factor, were tested for their ability to suppress acute lung injury in mice treated with human neutrophil granule extracts. Injury was assessed by measuring pulmonary sequestration of circulating 125I-labeled albumin, lung water, and lung hemoglobin. Both the native inhibitor and the tryptic-peptides gave good protection when preincubated with granule extract for brief periods before intrapulmonary instillation. Lesser, but still significant, protection was observed in the absence of preincubation. Protection was not simply due to addition of exogenous proteins to the granule extract because substitution of goat immunoglobulin for pneumococcal fraction was ineffective. These results suggest that pneumococcal elastase-inhibitors, recently described by us, may play a role in minimizing lung injury during pneumococcal pneumonia.
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PMID:A new elastase inhibitor from Streptococcus pneumoniae protects against acute lung injury induced by neutrophil granules. 384 26

Human inter-alpha-trypsin inhibitor has been found to inactivate human trypsin, chymotrypsin, neutrophil elastase and cathepsin G. The protein was cleaved into two major fragments without loss of activity by incubation with Serratia marcescens metalloproteinase, and these were separated by ion-exchange chromatography. Inhibitory activity was found in only one of the fragments, the amino-terminal sequence of which was found to be identical with that of the native protein, as well as with that reported earlier for the urinary trypsin inhibitor. It may thus be concluded that the reactive site of the inter-alpha-trypsin inhibitor is located in the amino-terminal region.
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PMID:The reactive site of human inter-alpha-trypsin inhibitor is in the amino-terminal half of the protein. 389 Aug 90

The authors wished to determine whether secretory cell metaplasia (SCM) induced in the bronchi of hamsters by human neutrophil elastase (HNE) was enzymatically mediated. We also wished to determine whether SCM could be induced by a proteolytic enzyme devoid of elastolytic activity. Accordingly, groups of weight-matched hamsters were given a single intratracheal instillation of 0.5 ml of saline solution containing one of the following: 300 micrograms of HNE purified from blood neutrophils, n = 14; 300 micrograms of HNE inactivated with Suc-Ala-Ala-Pro-Val chloromethyl ketone (CMK), n = 10; 500 micrograms of porcine pancreatic trypsin treated with CMK to eliminate residual active elastase, n = 10; 500 micrograms of trypsin inactivated by tosyl lysine chloromethyl ketone, n = 10; 2 micrograms CMK, n = 10; and saline alone, n = 10. Seven untreated animals served as additional controls. Twenty-one days post treatment, 5-6 micron paraffin-embedded sections, from the left lung hilar region, stained by Alcian blue and periodic acid-Schiff reaction were graded on a five-point scale for determination of the secretory cell index, which reflects SCM. Both elastase and trypsin produced severe SCM: mean +/- SEM secretory cell indices were 2.96 +/- 0.11 and 2.72 +/- 0.19, respectively, compared with values of 0.90 +/- 0.35 for the untreated group and 0.93 +/- 0.46 for the saline group (p less than .05). The secretory cell indices of the groups treated with inactivated elastase or trypsin were comparable to those of the saline-treated and untreated groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Proteolytic activity of human neutrophil elastase and porcine pancreatic trypsin causes bronchial secretory cell metaplasia in hamsters. 390 65

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

Two metallo-proteinases of human neutrophil leucocytes, collagenase and gelatinase, were studied. Collagenase specifically cleaved native collagen into the TCA and TCB fragments, whereas gelatinase degraded denatured collagen, i.e. gelatin, and the TCA fragments produced by collagenase. On subcellular fractionation by zonal sedimentation, collagenase was found to be localized in the specific granules, separate from gelatinase, which was recovered in smaller subcellular organelles known as C-particles. Neither enzyme was present in the azurophil granules, which contain the two major serine proteinases of neutrophils, elastase and cathepsin G. Collagenase and gelatinase were separated by gel filtration from extracts of partially purified granules. Both enzymes were found to occur in latent forms and were activated either by trypsin or by 4-aminophenylmercuric acetate. Gelatinase was also activated by cathepsin G, which, however, destroyed collagenase. Both enzymes were destroyed by neutrophil elastase. Activation resulted in a decrease by 25 000 in the apparent mol. wt. of both latent metallo-proteinases.
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PMID:The latent collagenase and gelatinase of human polymorphonuclear neutrophil leucocytes. 626 56

Human alveolar macrophages from lungs of cigarette smokers were retrieved by lavage of surgical specimens. The macrophage secretions were harvested after 18 h of incubation. The medium contained at least 2 acid-stable factors that could release enzymes from cytochalasin-B-treated human neutrophils. Our study focused on the largest of these factors, which had an apparent mass ratio of 5,400 by gel filtration chromatography in 10% acetic acid. The high molecular weight (HMW) factor was partially degraded by trypsin. Chymotrypsin completely destroyed the factor, but human neutrophil elastase did not affect it. The factor is partially extractable into chloroform indicating that it is very hydrophobic and may contain a lipid. High concentrations of the HMW factor inhibited the release of lysozyme and myeloperoxidase. Because elastases can cause emphysema when introduced into alveoli of animals, the most important observation may be that the HMW factor was able to release elastase from human neutrophils attached to Millipore membranes in the absence of cytochalasin B. The enzyme-releasing factors may be identical to neutrophil chemotactic factors recently described by others. The contribution of the released elastase to the protease load in the lung may be augmented by the simultaneous release from neutrophils of myeloperoxidase, which can inactivate alpha 1-antitrypsin. This interaction between alveolar macrophages and neutrophils may have importance in the pathogenesis of emphysema.
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PMID:The release of elastase, myeloperoxidase, and lysozyme from human alveolar macrophages. 628 85

Retained maxillary sinus secretions from 10 consecutive patients suffering from maxillary sinusitis were studied with regard to proteolytic activity and its possible sources. All secretions were proteolytically active. In 3 purulent secretions the proteolytic activity was of the same magnitude as that of a standard with an excess of pancreatic trypsin. The enzymes responsible for the proteolytical activity were found to be mainly of granulocyte origin, neutrophil elastase, unspecific collagenase and chymotrypsin-like cationic protein (CCP).
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PMID:Granulocyte proteases in human maxillary sinus secretions. 630 29

The effects of neutrophil elastase on endothelial prostacyclin (PGI2) production, nucleotide release, and responsiveness to vasoactive agents were compared with the effects of cathepsin G (the other major neutral protease of neutrophils), pancreatic elastase, trypsin, chymotrypsin, and thrombin. PGI2 production by pig aortic endothelial cells cultured on microcarrier beads and perfused in columns was stimulated in a dose-dependent manner by trypsin, chymotrypsin, and cathepsin G (1-100 micrograms/ml for 3 min). Thrombin, while active at low concentrations (0.1-10 National Institutes of Health U/ml), induced smaller responses. Neutrophil and pancreatic elastase had little or no effect on PGI2 production. Dose-dependent, selective release of adenine nucleotides was induced by neutrophil elastase (3-30 micrograms/ml). The other proteases were much less active; for example, trypsin (100 micrograms/ml) induced a response only approximately 5% as great as did 30 micrograms/ml neutrophil elastase. After exposure to 30 micrograms/ml neutrophil elastase, cells did not exhibit the characteristic burst of PGI2 production in response to extracellular ATP; responsiveness gradually returned after 40-120 min. This effect was not seen with the other proteases. Elastase partly inhibited responses to bradykinin and had no effect on PGI2 production that was stimulated by ionophore A23187. There was no evidence of cytotoxicity, as measured by release of lactate dehydrogenase. Neutrophil degranulation can generate concentrations of elastase and cathepsin G comparable with those tested in the present study, and the effects of these enzymes on endothelial function lead us to suggest that they may play a role in vasoregulation and vascular pathology.
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PMID:Effects of neutrophil elastase and other proteases on porcine aortic endothelial prostaglandin I2 production, adenine nucleotide release, and responses to vasoactive agents. 643 44


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