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:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antibacterial activity of a myeloperoxidase (MPO)-glucose oxidase system was found to be greatly increased by granulocyte elastase, present in azurophil granules of human neutrophils. The MPO-H2O3-mediated killing of both Escherichia coli and Staphylococcus aureus was potentiated by granuocyte elastase at an acid pH, whereas at pH 7.4 only killing of E. coli was potentiated. The potentiating effect of elastase was not dependent on the enzymatic properties of the protein since it was not abolished by heating, which destroys the enzymatic activity. A peptide chloromethyl ketone elastase inhibitor abolished both elastolytic activity and the pctentiating effects on MPO-H2-O2-mediated bacterial killing. The antibacterial activity of chymotrypsin-like cationic protein of human neutrophils was also potentiated by elastase. Other degradative enzymes isolated from human granulocytes, e.g., collagenase and lysozyme, did not potentiate MPO-H2O2-mediated or cationic protein-dependent bacterial killing. The present study indicates that a neutrophil constitutent, elastase, which is not microbicidal by itself, can initiate sublethal changes that render some microorganisms more susceptible to the action of microbicidal agents like MPO and chymotrypsin-like cationic protein.
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PMID:Microbicidal mechanisms of human granulocytes: synergistic effects of granulocyte elastase and myeloperoxidase or chymotrypsin-like cationic protein. 1 11

Complex formation in vitro between human alpha2-macroglobulin and the human proteases cationic trypsin, chymotrypsin, plasmin and granulocyte elastase and collagenase was clearly visualized by the use of thin-layer electrofocusing in polyacrylamide gel followed by electrophoresis in agarose gel containing antibodies against human alpha2-macroglobulin. The technique permits semi-quantitative determination of the amount of complex and can demonstrate the formation of complexes between alpha2-macroglobulin and protease in vivo in ascitic fluid in peritonitis.
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PMID:Demonstration and semiquantitative determination of complexes between various proteases and human alpha2-macroglobulin. 17 30

The low molecular weight bronchial protease inhibitor isolated from purulent bronchial secretions of man was shown to be a potent inhibitor of the elastase from human granulocytes. At a molar ratio of 1:1, the inhibitor prevented elastase digestion of insoluble elastin and soluble elastin, and blocked the hydrolysis of t-BOC-L-alanine-p-nitrophenyl ester. The collagenolytic activity of granulocyte collagenase was not inhibited by the bronchial inhibitor. Antisera were raised in rabbits for the isolation of specific IgG fractions in order to localize and quantitate the inhibitor. 125I-labelled inhibitor was used to study enzyme interactions further by gel filtration. These studies demonstrated that the bronchial inhibitor formed firm complexes with granulocyte elastase but did not form complexes with granulocyte collagenase.
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PMID:Inhibition of elastase from granulocytes by the low molecular weight bronchial protease inhibitor. 18 83

Matrix metalloproteinase 9 (MMP-9) has been purified as an inactive zymogen of M(r) 92,000 (proMMP-9) from the culture medium of HT 1080 human fibrosarcoma cells. The NH2-terminal sequence of proMMP-9 is Ala-Pro-Arg-Gln-Arg-Gln-Ser-Thr-Leu-Val-Leu-Phe-Pro, which is identical to that of the 92-kDa type IV collagenase/gelatinase. The zymogen can be activated by 4-aminophenylmercuric acetate, yielding an intermediate form of M(r) 83,000 and an active species of M(r) 67,000, the second of which has a new NH2 terminus of Met-Arg-Thr-Pro-Arg-(Cys)-Gly-Val-Pro-Asp-Leu-Gly-Arg-Phe-Gln-Thr- Phe-Glu. Immunoblot analyses demonstrate that this activation process is achieved by sequential processing of both NH2- and COOH-terminal peptides. TIMP-1 complexed with proMMP-9 inhibits the conversion of the intermediate form to the active species of M(r) 67,000. The proenzyme is fully activated by cathepsin G, trypsin, alpha-chymotrypsin, and MMP-3 (stromelysin 1) but not by plasmin, leukocyte elastase, plasma kallikrein, thrombin, or MMP-1 (tissue collagenase). During the activation by MMP-3, proMMP-9 is converted to an active species of M(r) 64,000 that lacks both NH2- and COOH-terminal peptides. In addition, HOCl partially activates the zymogen by reacting with an intermediate species of M(r) 83,000. The enzyme degrades type I gelatin rapidly and also cleaves native collagens including alpha 2 chain of type I collagen, collagen types III, IV, and V at undenaturing temperatures. These results indicate that MMP-9 has different activation mechanisms and substrate specificity from those of MMP-2 (72-kDa gelatinase/type IV collagenase).
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PMID:Matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase) from HT 1080 human fibrosarcoma cells. Purification and activation of the precursor and enzymic properties. 140 Apr 81

Procollagenase M(r) 85,000 (SDS-PAGE) was purified from buffy coat to homogeneity and represents a stable single polypeptide chain forming the entire proenzyme. The procollagenase can be activated by various proteinases, e.g. trypsin, chymotrypsin, cathepsin G, kallikrein and stromelysin and by different mercurial compounds. Proteolytic conversion of the latent enzyme to the active form by chymotrypsin is accompanied by a molecular weight reduction to an apparent M(r) 64,000. This active enzyme lacks the first 79 N-terminal residues. Activation by trypsin leads to a latent intermediate of apparent M(r) 70,000, lacking 48 N-terminal residues. The active enzyme is therefore generated upon prolonged incubation with trypsin by further cleavage of 22 N-terminal residues. Another latent intermediate form with apparent M(r) 69,000 is generated from the proenzyme upon incubation with leukocyte elastase by N-terminal cleavage of 53 or 64 residues, respectively. However, latent collagenase cannot be activated by plasmin. Activation by different mercurial compounds finally results in the formation of active collagenase with apparent M(r) 64,000. In contrast to the proenzyme, active collagenase can autolyse to give active M(r) 57,000 and 45,000 intermediates and two M(r) 28,000 fragments. Purification of latent leukocyte gelatinase yields three final products with apparent M(r) 98,000, 125,000 and 220,000 (SDS-PAGE; non reduced). Upon reduction, only the M(r) 98,000 form can be detected. The latent gelatinase can be activated in a similar manner as collagenase. Proteolytic activation by trypsin leads after N-terminal cleavage to an active gelatinase with sequence homology to leukocyte collagenase.
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PMID:Latent collagenase and gelatinase from human neutrophils and their activation. 148 34

Recruitment of inflammatory cells to the lung capillaries has been proposed as an important step in the sequence of events that lead to acute lung injury. Frequently, in the clinical setting, bacteremia and sepsis syndrome precede the acute lung failure and endotoxin priming may represent a comparable paradigm, useful for experimental pursuit. Following addition of the chemotactic tripeptide FMLP (10(-9) to 10(-6) M) to the cell-free, salt solution perfusate of isolated rat lungs, only a small degree of vasoconstriction was observed. However, in lungs isolated from rats that received 2 mg/kg intraperitoneal Salmonella enteritidis endotoxin 2 h before lung perfusion, FMLP dose dependently caused a large, transient pulmonary pressor response, edema formation, and release of large amounts of thromboxane and leukotriene B4. Since in vitro priming with endotoxin, direct vascular injury by neutrophil elastase, nor direct stimulation with FMLP of pulmonary artery rings from endotoxin-pretreated rats, mimicked the effects of in vivo endotoxin priming, we conclude that the presence of inflammatory cells in the lung capillaries accounted for the large amount of eicosanoids produced by the lungs after FMLP stimulation. In fact, by retrograde lavage of the lung circulation with a collagenase solution, previously adherent cell clumps were mobilized and identified. These cell clumps, composed of red blood cells, neutrophils, and platelets, were not seen in the vascular lavage sediment obtained from unprimed control lungs. Indomethacin, a thromboxane antagonist, AA861, a 5-lipoxygenase inhibitor, and WEB 2086, a platelet-activating factor (PAF) antagonist, reduced the thromboxane synthesis and release after FMLP (10(-7) M) in in vivo endotoxin-primed lungs. None of the inhibitors employed exclusively inhibited only one particular eicosanoid mediator but rather affected the release of several mediators, suggesting a close link between the different synthetic arachidonic acid pathways. An inhibitor of phospholipase C (2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate), NCDC, but not an inhibitor of phospholipase D (Wortmannin) or of protein kinase C (staurosporine) inhibited the FMLP-stimulated pulmonary pressure rise and eicosanoid release in endotoxin-primed lungs in vivo. Our data suggest that eicosanoids (in particular thromboxane) released from cells trapped in the lung circulation, but not from constitutive lung cells, contribute to vasoconstriction and edema formation caused by the chemoattractant FMLP in endotoxin-primed lungs.
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PMID:FMLP causes eicosanoid-dependent vasoconstriction and edema in lungs from endotoxin-primed rats. 154 53

Arthritis was induced by injecting cationic amidated bovine serum albumin (aBSA) (pI approximately 9.2) into the knee joint of immunized guinea pigs and the mechanisms of articular cartilage destruction were studied morphologically and biochemically. Marked synovitis associated with polymorphonuclear leukocyte (PML) infiltration occurred within 1 day of the challenge. Articular cartilage infiltrated by PMLs was almost completely destroyed after 2 weeks. During the initial destructive process, proteoglycans were depleted from the cartilage and later collagen fibers disappeared. Granulation tissue growing in the inflamed synovium and bone marrow replaced the destroyed cartilage and joint cavity and formed fibrous scar tissue (fibrous ankylosis) by 8 weeks. Subsequently, the knee joints developed cartilagenous ankylosis by 12 weeks and finally bony ankylosis at 28 weeks. Autoradiography using 125I-aBSA and immunofluorescence studies for immunoglobulin (IgG) and complement (C3) demonstrated that the antigen is trapped in all zones of the articular cartilage and serves as a trigger for immune complex formation. Significantly increased neutral proteinase activities against substrates of proteoglycan subunits, [3H]carboxymethylated transferrin and L-pyroglutamyl-L-prolyl-L-valine-paranitroanilide were detected in homogenates of the synovium and cartilage from arthritic knee joints 1 and 2 weeks after induction. Inhibitor studies and pH curves suggested that the proteinase is leukocyte elastase. Measurable amounts of gelatinolytic activity, detected by activation with 4-aminophenylmercuric acetate and inhibited with EDTA, were also present in the same samples, but there was no detectable collagenase activity. The data on SDS-gelatin substrate gel showed that the proteinase is gelatinase derived from PMLs. These results suggest that in aBSA-induced arthritis, elastase and gelatinase from PMLs invading articular cartilage may play important roles in cartilage destruction.
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PMID:Arthritis induced immunologically with cationic amidated bovine serum albumin in the guinea pig. A morphological and biochemical study on the destruction of articular cartilage. 167 78

Positive affinity chromatography on heparin-Sepharose has proved a most crucial step in the purification of pregnancy-associated plasma protein A (PAPP-A). In this chromatographic procedure, PAPP-A was purified almost 500-fold from term pregnancy serum. Further purification was achieved by gel filtration and negative immunoaffinity chromatography. Both PAPP-A and free heparin inhibited granulocyte elastase (HGE) activity. Whereas free heparin inhibited only in hypotonic buffers, PAPP-A inhibited HGE in hypertonic buffers also. However, PAPP-A did not inhibit other proteases (trypsin, chymotrypsin, plasmin, fibroblast collagenase) or proteolytic cascades (complement activation). Since heparin was not detected in the purified PAPP-A, the inhibition of HGE was not due to desorbed or leeched heparin ligand.
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PMID:Pregnancy-associated plasma protein A interaction with heparin: a critical appraisal. 172 Oct 35

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

Human rheumatoid synovial cells in culture secrete at least three related metalloproteinases that digest extracellular matrix macromolecules. One of them, termed matrix metalloproteinase 2 (MMP-2), has been purified as an inactive zymogen (proMMP-2). The final product is homogeneous on SDS/PAGE with Mr = 72,000 under reducing conditions. The NH2-terminal sequence of proMMP-2 is Ala-Pro-Ser-Pro-Ile-Ile-Lys-Phe-Pro-Gly-Asp-Val-Ala-Pro-Lys-Thr, which is identical to that of the so-called '72-kDa type IV collagenase/gelatinase'. The zymogen can be rapidly activated by 4-aminophenylmercuric acetate to an active form of MMP-2 with Mr = 67,000, and the new NH2-terminal generated is Tyr-Asn-Phe-Phe-Pro-Arg-Lys-Pro-Lys-Trp-Asp-Lys-Asn-Gln-Ile. However, following 4-aminophenylmercuric acetate activation, MMP-2 is gradually inactivated by autolysis. Nine endopeptidases (trypsin, chymotrypsin, plasmin, plasma kallikrein, thrombin, neutrophil elastase, cathepsin G, matrix metalloproteinase 3, and thermolysin) were tested for their abilities to activate proMMP-2, but none had this ability. This contrasts with the proteolytic activation of proMMP-1 (procollagenase) and proMMP-3 (prostromelysin). The optimal activity of MMP-2 against azocoll is around pH 8.5, but about 50% of activity is retained at pH 6.5. Enzymic activity is inhibited by EDTA, 1,10-phenanthroline or tissue inhibitor of metalloproteinases, but not by inhibitors of serine, cysteine or aspartic proteinases. MMP-2 digests gelatin, fibronectin, laminin, and collagen type V, and to a lesser extent type IV collagen, cartilage proteoglycan and elastin. Comparative studies on digestion of collagen types IV and V by MMP-2 and MMP-3 (stromelysin) indicate that MMP-3 degrades type IV collagen more readily than MMP-2, while MMP-2 digests type V collagen effectively. Biosynthetic studies of MMPs using cultured human rheumatoid synovial fibroblasts indicated that the production of both proMMP-1 and proMMP-3 is negligible but it is greatly enhanced by the treatment with rabbit-macrophage-conditioned medium, whereas the synthesis of proMMP-2 is constitutively expressed by these cells and is not significantly affected by the treatment. This suggests that the physiological and/or pathological role of MMP-2 and its site of action may be different from those of MMP-1 and MMP-3.
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PMID:Matrix metalloproteinase 2 from human rheumatoid synovial fibroblasts. Purification and activation of the precursor and enzymic properties. 226 96


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