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:3.4.21.1 (chymotrypsin)
10,938 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SR 26831 ([[5-(2-chloro-benzyl-2-(terbutyloxycarbonyl)]-4,5,6,7- tetrahydrothieno(3,2-c)pyridine]N-oxide) is the first member of a new class of human leukocyte elastase inhibitors. SR 26831 inhibited in a dose-dependent manner elastases from human leukocytes or pancreas with IC50 values of 80 +/- 2.6 nM and 4.8 +/- 0.12 microM, respectively. Steady-state studies revealed that SR 26831 behaved like a noncompetitive, irreversible inhibitor of both types of enzymes. SR 26831 inhibited in a dose-dependent manner degradation of [3H]elastin and [3H]collagens (types I and IV) by human leukocyte elastase (IC50 values were between 1.2 and 1.8 microM). In this respect, SR 26831 was 3- to 20-fold more active than alpha-1-antitrypsin. SR 26831 was also highly selective for elastases inasmuch as it did not inhibit pepsin, collagenase, trypsin, alpha-chymotrypsin, factor Xa, plasmin, kallikrein, cathepsins B, C, D and G and thrombin. In the rabbit, SR 26831 was cleared rapidly from blood after i.v. injection, but affected intracellular leukocyte elastase activity shortly after either i.v. or p.o. administration. In the rat, i.v. or p.o. administration of SR 26831 prevented in a dose-dependent manner acute lung injury induced by intratracheal instillation of human leukocyte elastase. SR 26831 (1 mg/kg) was still efficient when it was administered 90 min before elastase instillation and was also able to limit further hemorrhage development in response to elastase, after it had begun. SR 26831 may therefore be of therapeutic value in the treatment of diseases such as rheumatoid arthritis or pulmonary emphysema thought to be due to the destructive action of leukocyte elastase.
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PMID:Biochemical and pharmacological activities of SR 26831, a potent and selective elastase inhibitor. 173 26

Bovine, pig and horse leukocyte elastase inhibitors represent the first example of functionally active intracellular serpin. Sequence analysis yields data indicating that the reactive site encompasses P1-P'1 Ala-Met sequence. Oxidation of swine (as well as equine) inhibitor reduced its association rate constants kon with the tested enzymes (by at least 1 order of magnitude). However in case of bovine inhibitor, only a slight reduction has been observed for human neutrophil elastase but not for chymotrypsin or pancreatic elastase.
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PMID:Elastase inhibitor from mammalian neutrophil cytosol. 180 44

A protein which inhibits the prophenoloxidase----phenoloxidase (EC 1.14.18.1) proteolytic activation in hemocyte extracts of Locusta migratoria was isolated from the plasma of the same insect and partially characterized. It shows a molecular weight of 14,000, an inhibiting activity toward the cascade system in the insect hemocytes, which resulted in a lower production of phenoloxidase, a key enzyme for the defence mechanism in arthropods. To identify the specificity of the Locusta inhibitor and consequently the specificity of its target enzyme, inhibitory tests were performed against a number of known serine-proteases. A strong in vitro inhibiting activity toward chymotrypsin and, to a lesser extent, toward human leukocyte elastase was present, while trypsin, Carlsberg subtilisin, human thrombin and pancreatic elastase failed to react. The lack of trypsin inhibition by the isolated inhibitor suggested that the trypsin-catalysed activation of the system in the hemocyte extract takes place under different controls or at an earlier stage of the cascade. The N-terminal sequence of the inhibitor reveals that this molecule is different from the protease inhibitors isolated from other arthropods.
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PMID:Purification of a protease inhibitor which controls prophenoloxidase activation in hemolymph of Locusta migratoria (insecta). 191 Mar 40

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

Pro-Val pseudo dipeptides incorporating protio and halo enol lactones were tested for inhibitory activity against the serine proteases human leukocyte elastase (HLE), porcine pancreatic elastase, alpha-chymotrypsin, trypsin, thrombin, and urokinase. The protio enol lactones 1a-c were found to be HLE substrates but were poor alternate substrate inhibitors. The bromo enol lactone trans isomer 2a was found to be a very effective inhibitor of HLE and chymotrypsin, as shown by the binding constants (KI), acylation rates (ka), inactivation rates, and partition ratios determined for each enzyme. This inhibitor shows better specificity toward its target enzyme HLE than monosubstituted halo enol lactones; we attribute this to a pseudo dipeptide acyl enzyme whose structure is similar to that adopted by good peptide substrates of HLE. Inactivation of chymotrypsin by the bromo enol lactone 2a is permanent, but inactivation of HLE is partially recoverable upon treatment with the nucleophile hydrazine, indicating that lactone 2a produces two species of inactivated HLE. The more stable of these species could be the result of alkylation of His-57 by the electrophilic bromomethyl ketone revealed in the acyl enzyme, and the less stable, hydrazine-reactivatable species could be the result of alkylation of Asp-102 or the hydrolysis of the bromomethyl ketone group in the initially formed acyl enzyme to form a new, more stable acyl enzyme.
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PMID:Proline-valine pseudo peptide enol lactones. Effective and selective inhibitors of chymotrypsin and human leukocyte elastase. 198 87

Peptidyl derivatives of diphenyl (alpha-aminoalkyl)phosphonates have been synthesized and are effective and specific inhibitors of serine proteases at low concentrations. Z-PheP(OPh)2 irreversibly reacts with chymotrypsin (kobsd/[I] = 1200 M-1 s-1) and does not react with two elastases. The best inhibitor for most chymotrypsin-like enzymes including bovine chymotrypsin, cathepsin G, and rat mast cell protease II is the tripeptide Suc-Val-Pro-PheP(OPh)2 which corresponds to the sequence of an excellent p-nitroanilide substrate for several chymases. The valine derivative Z-ValP(OPh)2 is specific for elastases and reacts with human leukocyte elastase (HLE, 280 M-1 s-1) but not with chymotrypsin. The tripeptide Boc-Val-Pro-ValP(OPh)2, which has a sequence found in a good trifluoromethyl ketone inhibitor of HLE, is the best inhibitor for HLE (kobsd/[I] = 27,000 M-1 s-1) and porcine pancreatic elastase (PPE, kobsd/[I] = 11,000 M-1 s-1). The rates of inactivation of chymotrypsin by MeO-Suc-Ala-Ala-Pro-PheP(OPh)2 and PPE and HLE by MeO-Suc-Ala-Ala-Pro-ValP(OPh)2 were decreased 2-5-fold in the presence of the corresponding substrate, which demonstrates active site involvement. Only one of two diastereomers of Suc-Val-Pro-PheP(OPh)2 reacts with chymotrypsin (146,000 M-1 s-1), and the enzyme-inhibitor complex had one broad signal at 25.98 ppm in the 31P NMR spectrum corresponding to the Ser-195 phosphonate ester. Phosphonylated serine proteases are extremely stable since the half-time for reactivation was greater than 48 h for the inhibited elastases and 7.5-26 h for chymotrypsin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Irreversible inhibition of serine proteases by peptide derivatives of (alpha-aminoalkyl)phosphonate diphenyl esters. 198 40

We have used 125I-labeled fibronectin (FN) as an extracellular substrate for neutrophils (PMN) in order to investigate the mechanism responsible for FN solubilization by PMN and the effects of recombinant cytokines on this process. Pure active alpha 1-antitrypsin (alpha 1AT), when added to PMN before or during, but not after, adherence to FN, inhibited solubilization of the substrate in a dose-dependent manner, but alpha 1AT that had been inactivated by proteolysis or oxidation and alpha 1AT Pittsburgh (alpha 1AT 358Met-Arg) had no significant effect. The solubilization of FN was also inhibited by the PMN elastase inhibitor N-methoxysuccinyl-alanyl-alanyl-prolyl-valine-chloromethylketone but not by the chymotrypsin and cathepsin G inhibitor N-Cbz-glycyl-glycyl-phenylalanine-chloromethylketone, nor by catalase or superoxide dismutase. The products of solubilization of FN by PMN, analyzed by sodium dodecyl sulphate polyacrylamide electrophoresis, were similar to those produced by pure PMN elastase but not cathepsin G. These results suggest that FN solubilization by PMN is caused largely by the pericellular activity of PMN elastase. The solubilization of FN by PMN was increased significantly by adding tumor necrosis factor-alpha, interleukin-1 alpha, or interferon-gamma to the adherent cells but without a significant general release of elastase into the culture supernatants. Granulocyte/macrophage colony-stimulating factor (GM-CSF) had no significant effect. None of the cytokines had any effect when preincubated with the cells in suspension, and non increased FN solubilization by PMN incubated with the optimal (10(-6) mol/liter) or suboptimal dose (10(-8) mol/liter) of the peptide formylmethionylleucylphenylalanine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Extracellular proteolysis of fibronectin by neutrophils: characterization and the effects of recombinant cytokines. 201 99

ONO-5046, N-[2-[4-(2,2-Dimethylpropionyloxy)phenylsulfonylamino] aminoacetic acid, competitively inhibited human neutrophil elastase (IC50 = 0.044 microM, Ki = 0.2 microM). It also inhibited leukocyte elastase obtained from rabbit, rat, hamster and mouse. However, ONO-5046 did not inhibit trypsin, thrombin, plasmin, plasma kallikrein, pancreas kallikrein, chymotrypsin and cathepsin G even at 100 microM. In in vivo studies, ONO-5046 suppressed lung hemorrhage in hamster (ID50 = 82 micrograms/kg) by intratracheal administration and increase of skin capillary permeability in guinea pig (ID50 = 9.6 mg/kg) by intravenous administration, both of which were induced by human neutrophil elastase.
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PMID:ONO-5046, a novel inhibitor of human neutrophil elastase. 204 3

H-Ser-Pro-Val-Thr-Leu-Asp-Leu-Arg-Tyr-OH and H-Thr-Asn-Val-Val-OH, which correspond to the sequences 41-49 and 60-63 of eglin c, respectively, were synthesized by a conventional solution approach using the newly developed 6-chloro-2-pyridyl ester method. The inhibitory activities of the above two peptides against human leukocyte elastase, cathepsin G, porcine pancreatic elastase and alpha-chymotrypsin were examined in comparison with those of the corresponding methyl esters.
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PMID:Amino acids and peptides. XXX. Synthesis of eglin c (41-49) and eglin c (60-63) and examination of their inhibitory activity towards human leukocyte elastase, cathepsin G, porcine pancreatic elastase and alpha-chymotrypsin. 204 2

A heptacontapeptide corresponding to the entire amino acid sequence of eglin c was synthesized by the conventional solution method using a minimal protecting method. The synthetic eglin c exhibited a symmetrical single peak on HPLC at the same retention time as an authentic eglin c, and had the same inhibitory activity against human leukocyte elastase, cathepsin G and alpha-chymotrypsin (Ki = 6.0 x 10(-9) M, 5.5 x 10(-9) M and 2.5 x 10(-9) M, respectively) as N alpha-acetyl-eglin c synthesized genetically (Ki = 5.1 x 10(-9) M, 1.5 x 10(-8) M and 2.2 x 10(-9) M, respectively).
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PMID:Synthesis of a heptacontapeptide corresponding to the entire amino acid sequence of eglin C. 207 81


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