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:3.4.21.37 (neutrophil elastase)
4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinase 7 (MMP-7) has been purified as an inactive zymogen of M(r) 28,000 (proMMP-7) from the culture medium of CaR-1 human rectal carcinoma cells. The NH2-terminal sequence of proMMP-7 is Lys-Pro-Lys-Pro-Gln-Glu, which is identical to that of matrilysin. The zymogen is activated by 4-aminophenylmercuric acetate (APMA), yielding an intermediate form of M(r) 21,000 and an active species of M(r) 19,000 which shows the new NH2-terminal sequence of Tyr78-Ser-Leu-Phe-Pro-Asn-Ser. Although trypsin fully activates the zymogen, the activation rate by plasmin or leukocyte elastase is confined to approximately 50%. ProMMP-7 can be activated by MMP-3 (stromelysin 1) to its full activity in a single-step mechanism and generates the same NH2 terminus obtained by APMA activation, whereas MMP-1 (tissue collagenase), MMP-2 (gelatinase A), and MMP-9 (gelatinase B) do not have such an effect. On the other hand, proMMP-1 is activated by MMP-7 to an activity similar to that obtained by APMA and the activation by MMP-7 is enhanced up to approximately 6.5 fold in the presence of APMA. This enhanced activity is donated by specific cleavage at the Gln80-Phe81 bond of proMMP-1. MMP-7 can also activate proMMP-9 up to approximately 50% of the full activity with a new NH2 terminus of Leu16-Arg-Thr-(Asn)-Leu. Incubation of proMMP-2 or proMMP-3 with MMP-7 results in no activation of these proMMPs. MMP-7 degrades type IV collagen, laminin-1, fibronectin, proteoglycan, type I gelatin, and insoluble elastin. These results suggest that in vivo MMP-7 may play a role in degradation of extracellular matrix macromolecules in concert with MMP-1, -3, and -9 under pathological conditions.
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PMID:Matrix metalloproteinase 7 (matrilysin) from human rectal carcinoma cells. Activation of the precursor, interaction with other matrix metalloproteinases and enzymic properties. 789 11

An apparatus and test method were developed to determine the elastic stiffness and damping coefficient of human cartilage in compression. An underdamped, counterbalanced beam applied a sudden compressive force to a full-thickness cylindrical specimen of articular cartilage. The initial oscillatory response decayed to steady state creep after approximately 10 cycles of oscillation. The results were consistent with a Voigt phenomenological model with linear stiffness and damping terms. Standard dynamics analysis of the transient oscillatory response enabled the elastic stiffness to be determined from the frequency and the damping coefficient to be derived from the logarithmic decrement of the decay of the oscillations. The relationship between the mechanical properties and structure of cartilage was determined by treating specimens with two specific proteolytic enzymes. Digestion and removal of proteoglycans alone with cathepsin D caused the damping coefficient to decrease with no change in elastic stiffness. The action of leukocyte elastase on collagen caused a decrease in both damping coefficient and elastic stiffness. It was concluded that the collagen fibrils in cartilage largely control the elastic response while the viscous response is controlled largely by the hydrated proteoglycans. The effects of cartilage thickness was also examined and found to be inversely proportional to the elastic stiffness. It is suggested that this method could be used to uncouple elastic and viscous properties of other viscoelastic materials.
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PMID:The short-term compressive properties of adult human articular cartilage. 795 Aug 72

Matrix metalloproteinases (MMPs) and neutrophil elastase (NE) may each contribute to fibrillar collagen degradation in various disease states. Little, however, is known about the activation and localization of MMP in the heart. Accordingly, we extracted MMP and examined mechanisms of proMMP activation in whole tissue extracts of the adult rat myocardium. Incubation of extracts with serine proteases (i.e., trypsin or neutrophil elastase) at 37 degrees C resulted in a time-dependent activation of proMMPs. Based on immunoblot and measurements of MMP activity by zymography, the molecular weight of active MMP was deduced to be 52 kDa. The second-order rate constant for activation of proMMP by serine protease was 5.5 +/- 0.2 x 10(5) M-1min-1 and for oxidized glutathione (GSSG) 1.5 +/- 0.1 M-1min-1. Incubation of the extract with both serine protease and GSSG increased the rate of activation 30-fold. Based on reverse zymographic analysis of collagenase inhibition, tissue inhibitors of metalloproteinases were identified. Indirect immunofluorescence localized proMMPs/MMPs to the endothelium and subendothelial space of the endocardium and throughout the interstitial space found between groups of muscle fibers. These results suggest that the mechanism of activation of MMPs by either a serine protease and by oxidizing, thiol-modifying reagents are mechanistically different and the presence of either a serine protease or GSSG synergistically increase the rate of activation of proMMPs. Our results also suggest that MMPs may be regulated by its own endogenous inhibitors. The contribution of this proteolytic enzyme to tissue remodeling and wound healing responses that occur in various diseases states remains to be established.
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PMID:Myocardial matrix metalloproteinase(s): localization and activation. 810 89

Preterm deliveries (PTDs) are a leading cause of neonatal morbidity and mortality in the world. Efforts to prevent PTD have been hampered by a poor understanding of the underlying pathophysiology, inadequate diagnostic tools, and generally ineffective therapies. There is increasing clinical and laboratory evidence that many PTDs result from premature activation of cells in the cervix, decidua, and fetal membranes in response to local mediators of maternal or fetal stress, ascending genital tract infection, and/or decidual hemorrhage. Putative mediators include peptide hormones (e.g. corticotropin releasing hormone (CRH)) and/or inflammatory-cytokines (e.g. interleukin-1, -6, and -8 (IL-1, -6 and -8)) which promote the production of oxytotic factors (e.g. prostanoids and endothelin) capable of eliciting uterine contractions and enhancing expression of proteases capable of initiating cervical change and/or membrane rupture. The identification of cervical, decidual, and/or chorionic extracellular matrix (ECM) proteins (e.g. collagen fragments and fetal fibronectin) and ECM-degrading proteases (e.g. collagenases and granulocyte elastase) in maternal serum and cervicovaginal secretions may provide new approaches to the detection of patients at high risk for PTD. In addition, our growing understanding of the pathogenic processes preceding PTD have led to new therapeutic approaches including antibiotic, anticytokine, and antiprotease treatments.
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PMID:Recent advances in elucidating the pathogenesis of preterm delivery, the detection of patients at risk, and preventative therapies. 818 Mar 54

alpha 1-Proteinase inhibitor (alpha 1-PI) is the major endogenous inhibitor of human leukocyte elastase (HLE). We have employed two different methods to quantitate the binding of alpha 1-PI to extracellular matrix (ECM), composed of 51% glycoproteins and proteoglycans, 37% types I and III collagen, and 12% elastin, derived from rat heart smooth muscle cells. alpha 1-PI is tightly bound to ECM via a saturable adsorption process; the bound protein fails to dissociate from the matrix after repeated washing. Binding of alpha 1-PI is unaffected by the prior removal of ECM glycoproteins with trypsin. Binding to ECM is not decreased in the presence of high salt but is decreased at low pH. A 40-fold excess of unlabeled alpha 1-PI displaces only 50% of [125I]alpha 1-PI prebound to ECM. A 30% decrease in the levels of alpha 1-PI bound to ECM is observed after DTT washes of ECM preincubated with alpha 1-PI or when alpha 1-PI is modified with iodoacetamide prior to incubation with ECM, implying that a fraction of bound alpha 1-PI is covalently linked to ECM via disulfide bond formation. Moreover, high molecular weight complexes between [125I]alpha 1-PI and ECM components can be visualized by SDS-PAGE under nonreducing conditions but disappear upon reduction. Approximately 50% of the total alpha 1-PI bound covalently or noncovalently to ECM retains the ability to inhibit HLE-mediated ECM proteolysis. alpha 1-PI-HLE complexes bound to ECM can be visualized by SDS-PAGE following the addition of HLE to ECM that was pretreated with [125I]alpha 1-PI. alpha 1-PI from normal plasma or serum also binds to ECM with retention of immunoreactivity and partial retention of inhibitory activity. However, ECM pretreated with alpha 1-PI-deficient serum retains no HLE-inhibitory activity.
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PMID:Human alpha 1-proteinase inhibitor binds to extracellular matrix in vitro. 825 98

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

Elastolytic strains of Prevotella intermedia were isolated from pus samples of adult periodontal lesions. Elastase was found to associate with envelope, and it could be solubilized with guanidine-HCl. The enzyme was purified to homogeneity by sequential procedures including ion-exchange chromatography, gel filtration, and hydrophobic interaction chromatography. This elastase was a serine protease, and its mass was 31 kDa. It hydrolyzed elastin powder, but collagen and azodye-conjugated proteins were not degraded by this enzyme. Both synthetic substrates for human pancreatic (glutaryl-L-alanyl-L-alanyl-L-prolyl-L-leucine p-nitroanilide) and leukocyte elastase (methoxy succinyl-L-alanyl-alanyl-L-prolyl-L-valine p-nitroanilide) were hydrolyzed.
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PMID:Purification and partial characterization of an elastolytic serine protease of Prevotella intermedia. 835 46

The concentration of doxycycline required to inhibit 50% (50% inhibitory concentration for serpinase activity) of alpha-1-antitrypsin degradation by purified neutrophil collagenase was found to be approximately 20 microM, a value similar to the 50% inhibitory concentration of doxycycline required to inhibit collagen degradation by neutrophil collagenase. Doxycycline also efficiently inhibited phorbol myristate acetate-triggered neutrophil-mediated degradation of alpha-1-antitrypsin. This suggests that doxycycline can protect alpha-1-antitrypsin from collagenase and gelatinase in the presence of other proteases and biologically active molecules that are released by triggered neutrophils. The protection of a body's alpha-1-antitrypsin shield from serpinolytic activity of collagenase and matrix metallproteinases can result in inhibition of serine proteases such as neutrophil elastase. Tetracyclines may thus protect matrix constituents from a wider spectrum of neutral proteases than previously recognized, not just from the matrix metalloproteinases collagenase and gelatinase.
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PMID:Doxycycline in the protection of serum alpha-1-antitrypsin from human neutrophil collagenase and gelatinase. 838 19

Elastinolytic activity of medullasin was investigated precisely and compared with that of human leukocyte elastase, because the structure of medullasin is quite similar to that of human neutrophil elastase, which was reported to have elastinolytic activity. When elastinolytic activity of medullasin and human leukocyte elastase was determined by employing unstained elastin fibers and measuring the increase in 280-nm absorbance of the supernatant, elastinolytic activity amounting to several percent of that of porcine pancreas elastase was apparently observed. However, the susceptibility of elastin preparations to these proteases was proportional to their hydroxyproline content. Both medullasin and human leukocyte elastase digested collagen fibers obtained from bovine Achilles tendon to the same extent as collagenase from Clostridium histolyticum. When elastinolytic activity was determined by employing elastin fibers stained with orcein, both proteases showed negligible elastinolytic activity. The activity remained negligible even when the pH or ionic strength of the reaction mixture was altered. These results indicate that medullasin and human leukocyte elastase are essentially devoid of elastinolytic activity, and that apparent elastinolytic activity observed when unstained elastin fibers were employed as the substrate is due to the digestion of collagen fibers mingled with elastin preparations.
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PMID:Both medullasin and human leukocyte elastase are essentially devoid of elastinolytic activity. 840 64

Interstitial collagenases, members of the matrix metalloproteinase family, are key initiators of collagen destruction during various disorders such as rheumatoid arthritis. Recently interstitial collagenases were found to efficiently degrade an additional non-collagenous substrate, the serum alpha-1-antitrypsin (AAT also called alpha-1-proteinase inhibitor or serpin). Serpins are major endogenous inhibitors of serine proteinases, particularly neutrophil elastase. Of relevance to neutrophil-mediated collagen degradation, the tetracycline family of antibiotics are now known to inhibit inhibit mammalian collagenases by a mechanism unrelated to their antimicrobial activity. This study identifies an additional mechanism by which tetracyclines may retard tissue breakdown during inflammatory diseases. Doxycycline, added to the reaction mixture as in concentrations as low as 10 microM, which correspond to levels of the drug readily achieved in vivo, produced detectable inhibition of serpinase activity of neutrophil collagenase, although levels of 50-100 microM or greater were required to reduce AAT degradation more than 75%. The concentration of doxycycline to inhibit 50% (IC50 of serpinase activity) of AAT degradation by neutrophil collagenase was found to approximate 20 microM, a value similar to the IC50 for doxycycline required to inhibit collagen degradation by neutrophil collagenase. Doxycycline was also found to inhibit at cell level neutrophil-mediated degradation of AAT. The protection of bodies' AAT-shield from serpinolytic activity of collagenase would result in inhibition of serine proteinases such as neutrophil elastase. Tetracyclines may thus protect matrix constituents from a wider spectrum of neutral proteases than previously recognized, not just from the matrix metalloproteinases collagenase and gelatinase.
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PMID:Doxycycline protects serum alpha-1-antitrypsin from human neutrophil collagenase. 845 33


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