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)

Human neutrophils use the H2O2-myeloperoxidase-chloride system to generate chlorinated oxidants capable of activating metalloproteinase zymogens that hydrolyze not only native and denatured collagens, but also the serine proteinase inhibitor (serpin) alpha 1-proteinase inhibitor (alpha 1 PI). To identify the metalloenzyme that hydrolyzes and inactivates alpha 1 PI, neutrophil releasates were chromatographed over gelatin-Sepharose and divided into fractions containing either progelatinase or procollagenase. The gelatinase-containing fraction cleaved alpha 1 PI in a manner inhibitable by native type V, but not type I, collagen. Conversely, while the collagenase-containing fraction also cleaved alpha 1 PI, this activity was inhibited by type I, but not type V, collagen. Because type I and V collagens are competitive substrates for collagenase and gelatinase, respectively, each of the metalloproteinase zymogens were purified to apparent homogeneity and examined for alpha 1 PI-hydrolytic activities. Both purified gelatinase and collagenase inactivated alpha 1PI by hydrolyzing the serpin within its active-site loop at the Phe352-Leu353 and Pro357-Met358 bonds, albeit with distinct kinetic properties. Furthermore, purified collagenase, but not gelatinase, cleaved a second serpin, alpha 1-antichymotrypsin, by hydrolyzing the Ala362-Leu363 bond within its active-site loop. These data demonstrate that human neutrophils use chlorinated oxidants to activate collagenolytic metalloproteinases whose substrate specificities can be extended to members of the serpin superfamily.
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PMID:Proteolytic inactivation of alpha 1-proteinase inhibitor and alpha 1-antichymotrypsin by oxidatively activated human neutrophil metalloproteinases. 131 27

The events leading to neutrophil collagenase activation in vivo were analyzed using phorbol myristate acetate (PMA) stimulated neutrophil supernatant. Under the conditions when this supernatant was incubated with the serine proteinase inhibitor, phenylmethylsulfonyl fluoride (PMSF), and then treated with the oxidant, hypochlorous acid (HOCl), collagenase was activated. When cathepsin G, a known activator of neutrophil collagenase, was also present, less HOCl was required to activate the latent collagenase. These experiments support the conclusion that activation of neutrophil collagenase occurs in vivo by both an oxidant and an enzymatic mechanism where the effectiveness of oxidants is enhanced by cathepsin G.
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PMID:Neutrophil collagenase activation: the role of oxidants and cathepsin G. 166 4

The mechanism of proteoglycan (GAG) loss from rat femoral articular cartilage (FHC) induced by recombinant human interleukin-1 beta (rhIL-1 beta) in vitro has been investigated. The metalloproteinase inhibitor 1,10-phenanthroline, the serine proteinase inhibitor N alpha-p-tosyl-l-lysine chloromethyl ketone (TLCK), the activator of latent metalloproteinase p-aminophenylmercuric acid (APMA), and an inhibitory metalloproteinase substrate analogue U27391 were tested for their ability to modulate rhIL-1 beta-induced GAG loss and GAG synthesis ([35S]O4 uptake) inhibition. As expected 1,10-phenanthroline inhibited GAG loss, however [35S]O4 incorporation was significantly reduced. TLCK was without effect, and APMA inhibited both parameters. U27391 reversed both the inhibition of [35S]O4 incorporation and GAG loss. It is concluded that the adverse effects on proteoglycan metabolism explain the inhibitory actions of 1,10-phenanthroline and APMA, whilst the action of TLCK may indicate that serine proteinases are not involved in the activation of latent metalloproteinase. U27391 exhibited chondroprotective activity and confirmed the induction of either metalloproteinases such as stromelysin or collagenase by rhIL-1 beta.
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PMID:Investigation of the role of metalloproteinases in recombinant human interleukin-1 beta-induced degradation of rat femoral head cartilage. 179 2

Fibronectin contains two latent gelatinolytic enzymes, FN-gelatinase and FN-laminase that can be activated in the presence of Ca2+ from the purified cathepsin D-produced 190-kDa fibronectin fragment. The results of this work show that Achromobacter collagenase cleaves fibronectin and generates an active FN-gelatinase. In contrast to the cathepsin D digest, the collagenase digest directly exhibits gelatinolytic activity without additional activation. The gelatinolytic activity of the total collagenase digest can be inhibited by phenylmethanesulfonyl fluoride, a serine proteinase inhibitor and by pepstatin A, an aspartic-acid proteinase inhibitor. FN-laminase activity, when assayed with its synthetic substrate GPAGPR and also with laminin was revealed after separation of the collagenase digest of fibronectin on heparin Ultrogel. FN-gelatinase and FN-laminase activities were found in heparin unretained and heparin strongly retained fractions. These results have demonstrated that in contrast to cathepsin D, Achromobacter collagenase activates two matrix-degrading proteinases from fibronectin, FN-Gelatinase und FN-Laminase.
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PMID:Collagenase activation of latent matrix-degrading proteinases from human plasma fibronectin. 215 10

Human neutrophils, when stimulated with phorbol myristate acetate or fMet-Leu-Phe in the presence or absence of cytochalasin B, released metalloproteinases that catalytically inactivated the plasma serine proteinase inhibitor, alpha 1-antitrypsin. Inactivation, measured as loss of elastase inhibitory capacity, was accompanied by cleavage of a Mr 4,000 peptide from the COOH-terminus. Cleavage of alpha 1-antitrypsin by cell supernatants was inhibited by EDTA, o-phenanthroline, and DTT, but not by inhibitors of serine or thiol proteinases. Gelatinase and collagenase were separated from the medium of stimulated neutrophils. Both preparations cleaved and inactivated alpha 1-antitrypsin, with cleavage occurring close to the reactive center, at the Phe-Leu bond between positions P7 and P6. Cleavage by purified gelatinase was very slow and could account for only a minor fraction of the activity of neutrophil supernatants. The collagenase preparation was more active. However, the unusual cleavage site, and the ability of fMet-Leu-Phe-stimulated neutrophils to cleave alpha 1-antitrypsin without releasing collagenase, suggests that collagenase is not responsible for cleavage by the cells, which, by implication, is due to an as yet uncharacterized metalloenzyme. Our results demonstrate that by releasing metalloproteinases, neutrophils could proteolytically inactivate alpha 1-antitrypsin at sites of inflammation. This provides an alternative to the previously documented mechanism of inactivation by neutrophil-derived oxidants.
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PMID:Cleavage and inactivation of alpha 1-antitrypsin by metalloproteinases released from neutrophils. 284 59

From the present investigation it can be summarized that breaking strength of an incisional wound, measured with the sutures in situ, decreased markedly early after the operation in all tissues investigated if the sutures were inserted 1.5 mm from the incision; that the decrease was also found if new sutures, placed between and substituting the old, were inserted before measuring breaking strength, indicating that the decrease in strength occurs all along the wound; that breaking strength did not decrease if the sutures were inserted 3 mm from the incision; that breaking strength decreased markedly in the wounds sutured under stretching, even if the sutures were inserted 4 mm from the incision; that collagen content and solubility, and the histological appearance of the submucosal collagen layer, were only insignificantly changed in the early period after the operation; that the decrease in breaking strength was eliminated in animals made neutropenic by anti-neutrophil serum; that the decrease in breaking strength was reduced, but not eliminated, by oxygen free radical scavengers; that the decrease in breaking strength was eliminated by a group-specific serine proteinase inhibitor and was reduced, but not eliminated, by proposed collagenase inhibitors; that the serine proteinase inhibitor and the oxygen free radical scavengers did not reduce the increase in myeoloperoxidase activity in the anastomotic segment and did not, at histological examination, reduce the accumulation of neutrophils there, and that the serine proteinase inhibitor did not impair the subsequent gain in breaking strength, measured after removal of the sutures, during the fibroplasia period. From these findings it can be concluded that there is a narrow zone of decrease in tissue strength adjacent to an incisional wound; that measurement of collagen content and solubility, and histology, are methods too crude to reveal the collagen changes that should be responsible for the decrease; that the neutrophils seem to be responsible for the decrease; that the mechanisms are probably a combined effect of neutral proteinases and oxygen free radicals, and that drug therapy modifying neutrophil function may be of value as prophylaxis against intestinal anastomotic dehiscence and burst abdomen.
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PMID:Mechanisms and prevention of decrease in wound margin strength in intestinal anastomoses and laparotomy wounds. 347 29

Hypodermin A, a serine proteinase from the larva Hypoderma lineatum, with a molecular weight of 27 000 was obtained in pure form by ion-exchange chromatography. It is inhibited by diisopropyl phosphofluorate, a serine proteinase inhibitor, but not by metallo or cysteine enzyme inhibitors such as EDTA or thiol reagents. In the same way, it is fully inactivated by trypsin inhibitors, but not by specific chymotrypsin inhibitors. Its specificity, limited to carboxyl side of arginine residue in B-chain of insulin, is more complicated on other polypeptide substrates. Sequence analysis suggests structural homology with H. lineatum collagenase as well as with other members of the trypsin family.
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PMID:Hypodermin A, a trypsin-like neutral proteinase from the insect Hypoderma lineatum. 701 79

Alpha-1 proteinase inhibitor (A1-Pi) is the main serine proteinase inhibitor found in human plasma and is a potent elastase inhibitor in various tissues, including lung. A1-Pi is expressed and induced in liver during inflammatory responses but can also be produced by epithelial cells. Since hepatocyte A1-Pi production is stimulated by interleukin-6 (IL-6) and other gp130-cytokines, such as leukemia inhibitory factor (LIF) and oncostatin M (OM), we investigated the role of these cytokines in regulating A1-Pi in lung epithelial cells. We show that OM, a monocyte and T cell product, can specifically and potently induce A1-Pi production in lung-derived A549 alveolar (epithelial) cells, as well as in liver-derived HepG2 cells. Both A1-Pi protein (as detected by ELISA and Western blots) and mRNA levels were enhanced 20-fold to 30-fold in A549 cells. OM was also able to stimulate the expression of tissue inhibitor of metalloproteinase-1 in these cells. Interestingly, other members of the IL-6 family (IL-6 and LIF) had little or no effect on A549 cells, and proinflammatory cytokines, such as IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) also had no stimulatory effect on A1-Pi synthesis in A549 cells. Costimulation with IL-1 beta resulted in a decrease in A1-Pi production from OM-stimulated A549 cells. However, IL-6 production was synergistically enhanced. OM was also able to stimulate A1-Pi production from a bronchial epithelial primary cell line, whereas an intestinal epithelial cell line HT29 responded to IL-6 but not OM. These results suggest that lung levels A1-Pi could be derived not only from liver and inflammatory cells but also from epithelial cells, which can be upregulated on stimulation by OM. This may have implications for regulation of local activity of human neutrophil elastase (HNE) in such diseases as emphysema and cystic fibrosis.
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PMID:Oncostatin M, but not interleukin-6 or leukemia inhibitory factor, stimulates expression of alpha1-proteinase inhibitor in A549 human alveolar epithelial cells. 919 1

Glomerular accumulation of extracellular matrix (ECM) is the common pathologic feature following glomerular injury, and the alteration in the synthesis and degradation of ECM may be involved in the glomerular accumulation of ECM. Glomerular fibrin formation occurs in various forms of human and experimental glomerulonephritis, and it may play an important role in progressive glomerular injury. Thrombin, a multifunctional serine proteinase that is generated at the site of vascular injury, has central functions in hemostasis and it also shows various biologic effects. In this study, it is hypothesized that thrombin may alter the production and the degradation of type IV collagen, which is an important component of ECM in the glomeruli. Human mesangial cells (HMC) were cultured, and the levels of type IV collagen, tissue inhibitor of metalloproteinase-1 (TIMP-1), and matrix metalloproteinase-2 (MMP-2) in the culture supernatants were measured by enzyme immunoassay using specific antibodies. MMP-2 activity was also evaluated by zymography using polyacrylamide/ sodium dodecyl sulfate gel-containing gelatin. Thrombin increased the production of type IV collagen and TIMP-1 in a dose-and time-dependent manner, but it did not increase MMP-2. Thrombin also stimulated the gene expressions of the type IV collagen and TIMP-1 in HMC in a dose- and time-dependent manner. Thrombin treated with diisopropylfluorophosphate, a serine proteinase inhibitor, did not show any of these effects. Hirudin, a natural thrombin inhibitor, and anti-transforming growth factor-beta-neutralizing antibody inhibited the stimulating effect of thrombin. These findings suggest that thrombin may contribute to the excessive accumulation of ECM and progression of glomerulosclerosis through an increase of type IV collagen production and a decreased matrix degradation presumably via a transforming growth factor-beta-dependent mechanism.
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PMID:Thrombin stimulates synthesis of type IV collagen and tissue inhibitor of metalloproteinases-1 by cultured human mesangial cells. 1040 7

Degradation of ECM, particularly interstitial collagen, promotes plaque instability, rendering atheroma prone to rupture. Previous studies implicated matrix metalloproteinases (MMPs) in these processes, suggesting that dysregulated MMP activity, probably due to imbalance with endogenous inhibitors, promotes complications of atherosclerosis. We report here that the serine proteinase inhibitor tissue factor pathway inhibitor-2 (TFPI-2) can function as an MMP inhibitor. TFPI-2 diminished the ability of the interstitial collagenases MMP-1 and MMP-13 to degrade triple-helical collagen, the primary load-bearing molecule of the ECM within human atheroma. In addition, TFPI-2 also reduced the activity of the gelatinases MMP-2 and MMP-9. In contrast to the "classical" tissue inhibitors of MMPs (TIMPs), TFPI-2 expression in situ correlated inversely with MMP levels in human atheroma. TFPI-2 colocalized primarily with smooth muscle cells in the normal media as well as the plaque's fibrous cap. Conversely, the macrophage-enriched shoulder region, the prototypical site of matrix degradation and plaque rupture, stained only weakly for TFPI-2 but intensely for gelatinases and interstitial collagenases. Evidently, human mononuclear phagocytes, an abundant source of MMPs within human atheroma, lost their ability to express this inhibitor during differentiation in vitro. These findings establish a new, anti-inflammatory function of TFPI-2 of potential pathophysiological significance for human diseases, including atherosclerosis.
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PMID:Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis. 1134 75


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