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)

A new type of enzyme hydrolyzing the elastase substrate succinyl-L-alanyl-L-alanine-4-nitroanilide has been found in cell-free rheuma todi synovial fluid. Normal plasma and osteoarthritic synovial fluid contained relatively little enzyme. The pH optimum was 8.0. Unexpectedly, the enzyme activity was not due to leukocyte elastase or any proteinase bound to alpha2-macroglobulin. The enzyme activity was metal-dependent being inhibited by chelating agents but not by di-isopropylfluorophos phate or thiol-blocking reagents. Gel chromatography showed the enzyme activity was associated with material of high molecular weight. On Sepharose 4B chromatography two-thirds of the activity eluted in the void volume and one-third in a position of about 106 mol wt. Utracentrifugation showed that both components were associated with lipid. The buoyant density of the higher molecular weight material was 1.15-1.22 g/ml., and that of lower molecular weight material was 1.2-1.33 g/ml. No latency of the enzyme was revealed by freezing and thawing or treatment with detergents. The nature of the enzyme is discussed. It is likely to be a proteinase possibly bound to some kind of membrane fragment.
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PMID:Hydrolysis of the elastase substrate succinyltrialanine nitroanilide by a metal-dependent enzyme in rheumatoid synovial fluid. 1 38

At pH 5.5, sodium trifluoroacetate is a potent competitive inhibitor of porcine elastase (Ki = 2.6 mM) and human leukocyte elastase (Ki = 9.3 mM). For both enzymes the Ki increases strongly with pH. Sodium fluoride is inactive on pancreatic elastase and sodium acetate is a weak inhibitor of this enzyme. Trifluoroethanol inhibits both enzymes but is less active than trifluoroacetate in acidic pH conditions. Bovine trypsin and alpha-chymotrypsin are resistant to the action of sodium trifluoroacetate and trifluoroethanol. The interaction between sodium trifluoroacetate and pancreatic elastase is also demonstrated by 19F NMR spectroscopy. Trifluoroacetyltrialanine is able to displace trifluoroacetate from its complex with pancreatic elastase. In addition, a method using turkey ovomucoid for the active site titration of leukocyte and pancreatic elastase is described.
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PMID:NMR and enzymatic investigation of the interaction between elastase and sodium trifluoroacetate. 2 76

Radioiodinated leukocyte elastase was found to bind rapidly and specifically to alveolar macrophages in vitro. In contrast to the binding of pancreatic and bacterial proteases, leukocyte elastase binding did not require the presence of alpha 2 macroglobulin. The binding was inhibited by an excess of unlabeled enzyme and was saturable by increasing elastase concentrations. Leukocyte elastase binding thus met criteria for receptor-mediated binding, with and estimated association constant of 4.97 x 10(5) M-1 and an estimated total of 640 x 10(6) binding sites/cell. It differed from the previously described binding of lysosomal glycosidases to macrophages in that it was insensitive to trypsin pretreatment, did not require calcium ions, and was not inhibited by yeast mannan. High-resolution autoradiography indicated that the cell-associated radiolabeled leukocyte elastase was rapidly incorporated into phagolysosomes. Macrophage binding may have a role in clearance of leukocyte elastase from tissue sites where alpha 2 macroglobulin is absent or present in low concentration. Thus, enzyme uptake by alveolar macrophages may be an important factor in the amelioration of lung tissue injury by extracellular leukocyte elastase.
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PMID:Receptor-mediated binding and internalization of leukocyte elastase by alveolar macrophages in vitro. 8 20

Methods are described for the covalent attachment of succinoyl-Ala-Ala-Pro-ValCH2Cl, an active site-directed inhibitor of human leukocyte elastase (EC 3.4.21.11), to microspheres of human albumin. The insertion of side arms of various lengths revealed that maximum inhibition of this enzyme was obtained when the spacer arm was at least 24.3 A in length. Approximately 30 molecules of the inhibitor could be attached to each molecule of albumin. Such derivatized microspheres were capable of inhibiting approximately one mole of elastase per mole of albumin, which is comparable to the inhibitory activity of alpha 1-antitrypsin. Experiments in vivo in which rats were injected intravenously with radiolabeled microspheres to which the inhibitor had been attached showed a rapid and exclusive uptake by the lungs. About 40--50% of the injected microspheres subsequently remained in the lungs with a half-life of approximately 17 days. These derivatized microspheres thus appear to offer promise as a therapeutic agent for emphysema.
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PMID:Albumin microspheres as carrier of an inhibitor of leukocyte elastase: potential therapeutic agent for emphysema. 28 51

To study the possible role of suppression of antiproteases by cigarette smoke in the pathogenesis of pulmonary emphysema in smokers, the following experiments were carried out. Elastin-agarose gels were impregnated with cigarette smoke condensate dissolved in dimethyl sulfoxide or with the solvent alone. This procedure affected neither local pH of the gel nor subsequent physical behavior (diffusion) of antiprotease. Elastases from various sources were then allowed to diffuse through the impregnated gels toward a counter-diffusing sample of antiprotease. The effectiveness of the antiprotease in blocking the enzyme was determined from the extent of elastolysis. The elastin substrates used included beef ligament elastin and dog lung elastin. The enzymes used were porcine pancreatic elastase and pure human leukocyte elastase. The antiproteases tested included human serum, pure human a1-antitrypsin, human bronchopulmonary lavage fluid, and a synthetic chloromethyl ketone inactivator of elastase. The results showed that whole, unfractionated cigarette smoke condensate suppressed all of the antiproteases tested, except for the chloromethyl ketone. These observations are discussed in terms of the protease-pathogenesis model of pulmonary emphysema.
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PMID:Possible mechanisms of emphysema in smokers: cigarette smoke condensate suppresses protease inhibition in vitro. 30 25

The interaction of serum alpha 1-antitrypsin with leukocyte elastolytic activity was examined in 71 patients with chronic obstructive pulmonary disease and 46 normal subjects. Residual elastolytic activity was present despite adequate amounts of alpha1-antitrypsin in 33 of the 71 patients compared to 6 of the 46 normal control subjects (P less than 0.001). This elastolytic activity was completely abolished by a specific human leukocyte elastase inhibitor. A crossover study designed to detect the source of this abnormal activity revealed that the plasma fraction containing alpha 1-antitrypsin was responsible for inadequate inhibition in 30 of the 39 cases. The residual elastolytic activity from a given patient did not correlate with the serum alpha 1-antitrypsin concentration, alpha 1-antitrypsin phenotype, or history of smoking. Our data suggest that the abnormal interaction of alhpa 1-antitrypsin with leukocyte elastolytic activity is an important additional variable in the gensis of chronic obstructive pulmonary disease.
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PMID:Abnormal interaction of alpha 1-antitrypsin and leukocyte elastolytic activity in patients with chronic obstructive pulmonary disease. 31 51

Leukocyte elastase and alpha 1-antitrypsin have been implicated in the pathogenesis of pulmonary emphysema. The relationship between these proteins has been studied in sputum both qualitatively and quantitatively in bronchitic patients with and without chest infections. Leukocyte elastase was found in 75% of the noninfected samples but was enzymatically inactive, suggesting complete inhibition. During infection, leukocyte elastase and alpha 1-antitrypsin concentrations increased, although the enzyme was only partially inactivated. The proportion of alpha 1-antitrypsin present as "complex" was smaller in the presence of infection, suggesting damage of the protein by excess enzyme.
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PMID:Alpha,-antitrypsin and leukocyte elastase in infected and noninfected sputum. 31 41

The effect of surface-bound immune complexes on the secretion of neutral proteases by human peripheral monocytes was examined. Monocytes cultured on 125I-fibrin secreted plasminogen activator in a continuous fashion. Monocytes incubated on 125I-fibrin with surface-bound immune complexes displayed a burst of plasminogen-independent fibrinolytic activity, whereas no release of plasminogen activator was observed through 21 h. The plasminogen-independent fibrinolytic enzymes were derived from monocytes and not from lymphocytes or contaminating polymorphonuclear neutrophils. The effects of various protease inhibitors on the secretion of plasminogen-dependent and independent enzymes were determined. Chymostatin selectively inhibited the monocyte-derived plasminogen activators. Similar effects of chymostatin were observed on human urokinase in the absence of cells. The predominant protease producing plasminogen-independent fibrinolysis exhibited responses to inhibitors characteristic of leukocyte elastase. When monocytes were cultured on 125I-fibrin with adherent immune complexes approximately equal to 40% of the solubilized radioactivity represented deiodination and not proteolysis. It was concluded that culture of human monocytes on surface-bound immune complexes stimulates the secretion of plasminogen-independent fibrinolytic proteases, primarily elastase, and of deiodinating enzymes. Under these conditions, plasminogen activator secretion is inhibited. Neutral proteases secreted from newly recruited monocytes may contribute to tissue injury in human diseases characterized by the presence of adherent immune complexes.
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PMID:Neutral protease secretion by human monocytes. Effect of surface-bound immune complexes. 42 65

The action of human leukocyte elastase on a series of acetyl and trifluoroacetyl tri-, tetra-, and pentapeptide chloromethyl ketones has been investigated. Leukocyte and pancreatic elastases react quite differently with these irreversible inhibitors. For instance, leukocyte elastase has a much lower affinity for the compounds than pancreatic elastase. On the other hand, the inhibition rate constants of the two enzymes are not influenced in the same way by peptide chain elongation. The two elastases, however, share a common property: trifluoroacetyl tri- and tetraalanine chloromethyl ketones are more tightly bound but are less reactive than the corresponding acetylated inhibitors. This behavior is probably due to the formation of nonproductive complexes between the enzymes and the trifluoroacetylated inhibitors.
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PMID:Inhibition of human leukocyte elastase by acetyl and trifluoroacetyl oligopeptide chloromethyl ketones. 44 43

Trifluoroacetylated peptides are much more potent inhibitors of human leukocyte elastase than the corresponding unblocked, acylated or benzyloxycarbonylated peptides. The most active compound was trifluoroacetyl-Val-Tyr-Val (Ki = 1.3 micron). A number of free and NH2-terminal-substituted peptides exhibited similar affinities for porcine pancreatic and human leukocyte elastase, indicating that these two enzymes must have similar specificity sites.
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PMID:Trifluoroacetyl tripeptides as potent inhibitors of human leukocyte elastase. 56 Oct 67


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