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)

Lipoprotein (a) [Lp(a)] is a plasma component whose concentration is related to the development of atherosclerosis, although the underlying mechanisms are not known. Lp(a) contains a unique structure, apolipoprotein (a), that shares partial homology with plasminogen. We now report that plasmin catalyzes the binding of Lp(a) to both immobilized fibrinogen and fibrin in a manner analogous to our previously reported studies with plasminogen. Plasmin treatment of immobilized fibrinogen induces a 3.7-fold increase in Lp(a) binding. Low density lipoprotein, molecules similar to Lp(a) but lacking apolipoprotein (a), bind poorly to immobilized fibrinogen and binding is not increased by plasmin. Trypsin but not neutrophil elastase also increases the binding of Lp(a) to fibrinogen. Lp(a) also complexes to plasmin-fibrinogen digests, and binding increases in proportion to the time of plasmin-induced fibrinogen degradation. Lp(a) binding is lysine-binding site dependent as it is inhibited by epsilon-aminocaproic acid. Lp(a) inhibits the binding of plasminogen to plasmin-modified immobilized fibrinogen, indicating that both molecules compete for similar lysine-binding sites. These findings demonstrate an affinity between Lp(a) and protease-modified fibrinogen or fibrin and thereby provide a potential mechanism to explain the association between thrombosis, coronary atherosclerosis, and increased blood concentrations of Lp(a).
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PMID:Plasmin catalyzes binding of lipoprotein (a) to immobilized fibrinogen and fibrin. 252 34

Proteolytic enzymes exist in ultrafiltrated plasma, concentrated dialysates and urine fractions of patients with posttraumatic renal failure. Differences in digestion pattern of phosphorylase kinase suggest the existence of different proteases in patients with hypercatabolic renal failure. Trypsin binding capacity is reduced in RDT patients and markedly lower in patients with posttraumatic ARF. Protein catabolism is inhibited in vitro by alpha 2-macroglobulin. From our in vitro studies we favour the application of fresh frozen plasma instead of the available plasma protein solutions to hypercatabolic patients. Hemodialysis may enhance proteinase inhibitory capacity of the plasma. Hemodialysis therapy induces the increase of plasma E-X1 PI. The continuous release of granulocyte elastase during hemodialysis therapy may enhance the risk for the development of destructive lung disease.
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PMID:Proteolytic activity in patients with hypercatabolic renal failure. 636 14

The N-acylsaccharins and N-acylbenzoisothiazolinones form a new class of acylating inhibitors of the serine proteases with a broad spectrum of activity. However, they are unique in that they are able to differentiate between various serine proteases because of the differential stability of the presumptive acyl-enzyme formed. Furoyl saccharin was the best studied among this class of inhibitors. We report evidence that the amide bond in the heterocyclic ring of this compound is cleaved by porcine pancreatic and human leukocyte elastases and chymotrypsin, forming acyl-enzymes. Radioisotope studies indicate that the saccharin portion of furoyl saccharin is attached to these enzymes in approximately a 1:1 molar ratio with enzyme, blocking the active site serine. The acylelastases thus prepared are unusually stable to hydrolysis, with kdeacyl values at neutral pH of 2.3 x 10(-6) s-1 for porcine pancreatic elastase and 1.4 x 10(-6) s-1 for human leukocyte elastase. Trypsin appears to be inhibited by a different mechanism. These data suggest a new approach to the design of specific synthetic protease inhibitors.
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PMID:Inhibition of elastase and other serine proteases by heterocyclic acylating agents. 677 4

Dog serum treated with the oxidant chloramine-T is rapidly and selectively depleted of its ability to inhibit porcine pancreatic elastase or dog neutrophil elastase. Trypsin inhibitory capacity of serum is not affected. Purified dog alpha-1-proteinase inhibitor (alpha-1-PI) is similarly oxidized with an apparent rate constant of 1.1 x 10(3) M-1 sec-1. Reversal of the oxidative inactivation using dithiothreitol was demonstrated. Cigarette smoke also directly affects the inhibitory capacity of both serum and pure alpha-1-PI. These studies form a basis for developing a model of functionally deficient alpha-1-PI by taking advantage of oxidative inactivation of normal proteinase inhibitor levels.
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PMID:The effect of the oxidizing agents chloramine-T and cigarette smoke on dog serum proteinase inhibitor(s). 701 94

Three fluorescein- and one Texas Red-labeled derivatives of [1-(N-dipeptidylamino)alkyl]phosphonate diphenyl esters were synthesized and evaluated as inhibitors of serine proteases. The two fluorophores, FITC and TXR, were attached to the peptide phosphonates via an epsilon-aminocaproyl unit that acts as a spacer group and facilitates the binding of the phosphonate inhibitor to the targeted enzymes. These derivatives are potent and specific inhibitors of chymotrypsin, porcine pancreatic elastase (PPE), and human leukocyte elastase (HLE). FTC-Aca-Phe-Leu-PheP(OPh)2 (3) inhibited chymotrypsin very potently (k(obsd)/[I] = 9500 M-1 s-1) and 600-fold better than it did PPE (k(obsd)/[I] = 16 M-1 s-1). FTC-Aca-Ala-Ala-MetP(OPh)2 (1) was a more effective inhibitor of chymotrypsin (k(obsd)/[I] = 190 M-1 s-1) than PPE and HLE (k(obsd)/[I] = 13 and 22 M-1 s-1, respectively). Only HLE and PPE were inhibited by FTC-Aca-Ala-Ala-AlaP(OPh)2 (2) (k(obsd)/[I] = 41 and 22 M-1 s-1, respectively). The specificity of these inhibitors toward the targeted serine proteases depends on the sequence of the tripeptide portion and was not affected by the presence of the fluorescent label. Trypsin, for instance, was not inhibited by any of these compounds. In some cases, the inhibitory potency was increased by the fluorescent label. For example, chymotrypsin was inhibited by the fluorescent compounds, FTC-Aca-Ala-Ala-MetP(OPh)2 (1) and FTC-Aca-Phe-Leu-PheP(OPh)2 (3), more potently than by the nonfluorescent compounds, Boc-Ala-Ala-MetP(OPh)2 (5) and Z-Phe-Leu-PheP(OPh)2 (7).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fluorescent derivatives of diphenyl [1-(N-peptidylamino)alkyl]phosphonate esters: synthesis and use in the inhibition and cellular localization of serine proteases. 784 68

Rat liver cells (the C-9 cell line) are stimulated to metabolize arachidonic acid by alpha-thrombin, its receptor polypeptide, gamma-thrombin, and trypsin. Prostaglandin (PG) I2 synthesis stimulated by alpha-thrombin is inhibited by dansylarginine N-(3-ethyl-1,5-pentanediyl) amide (DAPA), by hirudin, by the synthetic tyrosine-sulfated dodecapeptide corresponding to residues 53-64 of hirudin (hirugen), by the Tyr(SO3H)63-hirudin fragment 54-65 and by rabbit lung thrombomodulin. Stimulation of arachidonic acid metabolism by the receptor octapeptide, SFLLRNPN, is not affected by DAPA or hirudin. gamma-Thrombin stimulates arachidonic acid metabolism but at 300 to 400-fold higher concentrations. Trypsin stimulates arachidonic acid metabolism. Trypsin's proteolytic activity is required--its ability to stimulate is abolished if it is incubated with Na-p-tosyl-L-lysine chloromethyl ketone (TLCK) or bovine pancreatic trypsin inhibitor. Prior treatment of the rat liver cells with alpha-thrombin blocks subsequent stimulation by alpha-thrombin, but not by trypsin, whereas prior treatment with trypsin blocks subsequent stimulation by trypsin, but not the activity stimulated by alpha-thrombin. Prior treatment of the cells with the serine-proteases, chymotrypsin, pancreatic or neutrophil elastase and thrombocytin from Bothrups atrox venom, block alpha-thrombin's activation of PGI2 production, but not the activity stimulated by trypsin. These findings indicate that alpha-thrombin and trypsin stimulate PGI2 production via different receptors.
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PMID:Alpha-thrombin and trypsin use different receptors to stimulate arachidonic acid metabolism. 793 15

The role of matrix metalloproteinase-9 (MMP-9, 92 kDa gelatinase/type IV collagenase) in invasion of mononuclear phagocytes was studied with U937 monoblastoid cells. 12-o-tetradecanoyl 13-phorbol acetate (TPA) differentiated them to macrophage-like cells with induction of MMP-9, and tumor necrosis factor alpha (TNF alpha) and interleukin-1 alpha (IL-1 alpha) stimulated the production of MMP-9 by TPA-treated cells. TNF alpha also induced the production of MMP-9 by TPA-untreated U937 cells without morphological differentiation. Other agents including dimethyl sulfoxide (DMSO), all-trans-retinoic acid (all-trans-RA), platelet-derived growth factor and 3';5'-cyclic monophosphate had no effects on MMP-9 production by TPA-treated or -untreated cells, but all-trans-RA and DMSO did have a morphological effect on the differentiation of the cells. These data suggest that MMP-9 production by U937 cells is regulated by a mechanism independent of the differentiation to macrophage-like cells. MMP-9 was purified to homogeneity as an inactive zymogen with M(r) 92,000 (proMMP-9) from TPA-differentiated U937 cells treated with TNF alpha. ProMMP-9 was activated by p-aminophenylmercuric acetate (APMA) generating an active species of M(r) 67,000. Trypsin and cathepsin G also attained activation of the zymogen to its full activity obtained by APMA activation, but plasmin, leukocyte elastase, thrombin and plasma kallikrein had no ability to activate it. APMA-activated MMP-9 degraded type I gelatin readily and cleaved native collagen types III, IV and V. Invasion assays using reconstituted basement membrane coupled with a type IV collagenolysis assay showed good correlations between invasiveness, type IV collagenolysis and proMMP-9 production. Invasion was significantly inhibited by EDTA, alpha 2-macroglobulin and tissue inhibitor of metalloproteinases-1, but not by inhibitors of cathepsin G and leukocyte elastase. These data suggest that MMP-9 plays an important role in the invasion of mononuclear phagocytes through basement membranes.
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PMID:Matrix metalloproteinase-9 (92 kDa gelatinase/type IV collagenase) from U937 monoblastoid cells: correlation with cellular invasion. 831 9

Barley serpin BSZx is a potent inhibitor of trypsin and chymotrypsin at overlapping reactive sites (Dahl, S.W., Rasmussen, S.K. and Hejgaard, J. (1996) J. Biol. Chem., in press). We have now investigated the interactions of BSZx with a range of serine proteinases from human plasma, pancreas and leukocytes, a fungal trypsin and three subtilisins. Thrombin, plasma kallikrein, factor VIIa/tissue factor and factor Xa were inhibited by BSZx at heparin independent association rates (k(ass)) of 4.5 X 10(3)-1.3 x 10(5) M(-1) s(-1) at 22 degrees C. Only factor Xa turned a significant fraction of BSZx over as substrate. Complexes of these proteinase with BSZx resisted boiling in SDS, and amino acid sequencing showed that cleavage in the reactive center loop only occurred after P1 Arg. Activated protein C and leukocyte elastase were slowly inhibited by BSZx (k(ass)=1-2 x 10(2) M(-1) s(-1)) whereas factor XIIa, urokinase and tissue type plasminogen activator, plasmin and pancreas kallikrein and elastase were not or only weakly affected. The inhibition pattern with mammalian proteinases reveal a specificity of BSZx similar to that of antithrombin III. Trypsin from Fusarium was not inhibited while interaction with subtilisin Carlsberg and Novo was rapid but most BSZx was cleaved as a substrate. Identification of a monoclonal antibody specific for native BSZx indicate that complex formation and loop cleavage result in similar conformational changes.
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PMID:Inhibition of coagulation factors by recombinant barley serpin BSZx. 884 56

Pyridyl esters of 6-substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid were designed as mechanism-based inhibitors of human leukocyte elastase. Compounds of series 4 specifically inhibited this enzyme. Several of the tested compounds (series 2 and 3) acted as powerful time-dependent inhibitors of both human leukocyte elastase and alpha-chymotrypsin; some compounds of these series inhibited thrombin. Trypsin was not inhibited. A transient inactivation was observed for human leukocyte elastase (k(i)/K(I) = 107 000 M(-1). s(-1) for 4c) and thrombin (k(i)/K(I) = 7 200 M(-1).s(-1) for 3b) as demonstrated by spontaneous or hydroxylamine-accelerated reactivation, irrespective of the nature of the substituent at the 6-position. Conversely, alpha-chymotrypsin was irreversibly inhibited by 6-chloromethyl derivatives (k(i)/K(I) = 107 400 M(-1). s(-1) for 3b). The presence of a latent alkylating function at the 6-position (chloromethyl group) was required for leading to this inactivation. In the absence of such an alkylating function (series 4), human leukocyte elastase was specifically inhibited suggesting that this new series of human leukocyte elastase inhibitors may be of potential therapeutic interest in degradative and degenerative processes involving this enzyme.
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PMID:6-Substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid as a core structure for specific inhibitors of human leukocyte elastase. 1051 86

Intestinal inflammatory disease or infection often results in the loss of the epithelial layer as a result mainly of the action of proteases, including the leucocyte serine proteinases (neutrophil elastase), lysosomal cathepsins and the matrix metalloproteinases from recruited inflammatory cells. Previous studies have shown that bronchial or intestinal epithelial cells (IEC) can respond to proteolytic attack by producing cytokines. In this study, we have determined the effect of protease treatment on interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) production by IEC lines. Both neutrophil elastase and trypsin treatment induced elevated levels of mRNA for IL-6 in rat IEC-6 cells. Non-proteolytic detachment of the IEC-6 cells also induced elevated levels of IL-6 mRNA, suggesting that the effect was not caused by a specific protease or degradation product, but probably by an effect on cell shape or cell detachment. Similar results were seen with the IEC-18 cell line. Trypsin treatment of the IEC-6 cells also enhanced unstimulated and IL-1 beta costimulated IL-6 secretion, but not MCP-1 secretion or mRNA levels. Finally, nuclear levels of the CCAAT/enhancer binding protein-beta (C/EBP-beta) were rapidly enhanced after proteolytic detachment of the IEC-6 cells, suggesting a mechanism for the enhancement of IL-6 mRNA responses. These data indicate that epithelial cells can respond to proteolytic attack or cell detachment by producing IL-6, a cytokine with several anti-inflammatory and antiprotease effects, which may be important in moderating the loss of the epithelial layer by its effects on nearby epithelial or inflammatory cells.
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PMID:Epithelial cells respond to proteolytic and non-proteolytic detachment by enhancing interleukin-6 responses. 1184 20


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