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)

Tissue inhibitors of metalloproteinases (TIMPs) constitute a family of secreted glycoproteins involved in regulating extracellular matrix degradation in both normal and malignant tissues. We have expressed a cDNA clone of mouse TIMP-1 as a 22-kDa protein with 12 cysteine residues in E. coli and purified protein that shows inhibitory activity against collagenase following renaturation by chemical means. The low specific activity and circular dichroism measurements suggest, however, that the renaturation of the mouse recombinant (non-glycosylated) protein is not efficient under the conditions we have used, indicative of either thermodynamic instability or the transition to kinetic intermediates which have very low in vitro refolding rates.
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PMID:Expression and purification of mouse TIMP-1 from E. coli. 132 39

1. The midgut extracts of 13 Australian spider species produced cellular disruption in mouse skin in tissue culture conditions. 2. Microbial collagenase and the venoms of some of these species had similar effects. 3. Five venoms also caused severe dermonecrosis in living mice. 4. Pre-mixing the venoms with L-cysteine caused complete in vivo and partial in vitro inhibition of their effects. 5. It was concluded that collagenase is a major factor in the aetiology of necrotic arachnidism.
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PMID:The involvement of collagenase in the necrosis induced by the bites of some spiders. 135 16

The proenzyme form of human fibroblast collagenase has been expressed in E. coli from its cDNA clone and has been shown to be functionally identical to the human enzyme. Mutants at one of three cysteine residues were constructed by site-directed mutagenesis of the cDNA and their relative activities compared to the wild type enzyme. A cysteine contained in the propeptide domain of procollagenase and other matrix metalloproteinases was shown to be essential for maintaining the proenzyme in an inactive state. A model to explain the importance of this highly conserved cysteine to the maintenance of latency is discussed.
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PMID:The latency of the human fibroblast collagenase precursor depends on an internal cysteine residue. 148 32

Both lysosomal cysteine-proteinases and collagenase appear to be necessary for the resorption of actively growing, immature woven bone, but their relative roles are not yet clearly elucidated. The present evidence indicates that, during bone resorption, the osteoclast first solubilizes the mineral by a secretion of acid and then removes the exposed demineralized collagen by the action of secreted lysosomal collagenolytic cysteine-proteinases. Collagenase in bone seems to be mainly a product of osteoblasts and related cells, not osteoclasts. Its role could be limited in the removal of any non-mineralized collagen layers which could be covering mineralized bone surfaces and which seem to prevent the activation of osteoclasts and thus their action; such a "shield" of unmineralized osteoid is well-established at the surface of actively growing woven bone, although not on the resorbing surfaces of mature lamellar bone. Moreover, some osteoblast-derived procollagenase is stored in the mineralized bone matrix from which it can be released by demineralization. It is therefore possible that it may also contribute to the degradation of demineralized bone collagen once it has been released and activated by lysosomal cysteine-proteinases under the osteoclast.
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PMID:Relative roles of collagenase and lysosomal cysteine-proteinases in bone resorption. 148 65

Recent studies suggest that proteolytic enzymes located within the glomerulus are involved in the degradation of extracellular matrix components. In the present investigation glomerular proteinase activities were followed in a variety of non-immune-mediated renal diseases as well as during different dietary manipulations. Azocaseinolysis was significantly reduced in the obese Zucker rat compared with lean littermates (pH 5.4:8.9 +/- 0.4 vs 11.4 +/- 0.7; pH 7.4:5.8 +/- 0.7 vs 9.3 +/- 0.6 arb. U/mg protein). When the glomerular proteolytic capacity was measured in old rats, again a significant decline in proteolysis was observed (pH 5.4:9.8 +/- 0.8 vs 17.7 +/- 0.8; pH 7.4:6.4 +/- 0.7 vs 11.7 +/- 0.5 arb. U/mg protein). In Goldblatt hypertensive rats the unclipped kidney, which is exposed to high blood pressure, revealed lower glomerular azocaseinolytic activity compared with the contralateral clipped kidney (pH 5.4:8.1 +/- 0.4 vs 12.9 +/- 0.5 arb. U/mg protein). In parallel, the cathepsin B content was also diminished in glomeruli from kidneys exposed to hypertension. When proteinases were followed in glomeruli from intact kidneys of rats fed protein-modified diets (fraction of casein 0.05, 0.20 or 0.60) a significant fall in the activities of cysteine proteinases, e.g. cathepsin B (casein 0.05:1,498 +/- 110 vs casein 0.60:914 +/- 84 microU/micrograms DNA), as well as metalloproteinases, e.g. collagenase (casein 0.05:233 +/- 14 vs casein 0.60:137 +/- 11 microU/micrograms DNA), occurred. These data indicate that in both early and late stages of glomerulosclerosis, proteolytic activities within the glomerulus tend to be reduced, which could allow extracellular matrix accumulation. Moreover, changes in dietary protein intake resulted in profound alterations of glomerular proteinases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of glomerular proteinases in the evolution of glomerulosclerosis. 149 56

Neutral proteolytic activity, having a pH optimum of about 7, was present in the high molecular weight fraction of bovine interphotoreceptor matrix (IPM) separated by gel filtration on Sephacryl S-500. The enzyme(s) was active toward a number of exogenous substrates, including albumin, Azocoll, and gelatin. However, it was inactive toward a synthetic substrate for bacterial collagenase. Proteolytic activity was proportional to protein; however, the time course of the reaction was nonlinear, suggesting that "activation" of a precursor form might be necessary. Of a number of specific inhibitors tested, those directed toward metalloproteinases (1,10-phenanthroline greater than EDTA greater than EGTA) proved most effective. While activity was also inhibited by sulfhydryl reagents and dithiothreitol, inhibitors specific for cysteine proteinases were ineffective. Higher specific activity was present in IPM obtained from retinal pigment epithelium (RPE) than from retina. An endogenous proteinase inhibitor(s) was also found in IPM from both RPE and retina. It was effective against the endogenous metalloproteolytic activity of IPM and also against thermolysin, but not against trypsin or papain. Fractionation of IPM on Sephacryl S-500 revealed a broad peak of inhibitory activity at molecular weights of less than 10(5) daltons. This is the first report of the presence of neutral proteolytic activity and metalloproteinase inhibitor(s) in bovine IPM. These materials may function in concert to maintain the proper level of various components within this matrix.
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PMID:The presence of neutral metalloproteolytic activity and metalloproteinase inhibitors in the interphotoreceptor matrix. 155 92

The effects of potential anti-osteoarthritic compounds both on the direct inhibition of collagenase and neutral protease activities and on IL-1 induced release of neutral proteases from rabbit articular chondrocytes were investigated. WY-46,135 ((+)-N-[[[(5-chloro-2-benzothiazolyl)thio]phenyl]acetyl]-L- cysteine) directly inhibited collagenase activity (IC50 = 15.4 microM). This inhibition was reversible upon dialysis. WY-46,135 also directly inhibited neutral protease activity (IC50 = 16.8 microM) but did not significantly block bacterial collagenase activity at a concentration of 80 microM. In contrast, WY-48,989 (4-[[2-(7-chloro-2-phenyl-2H-pyrazolo[4,3-c]quinolin-4- yl)ethyl]amino]benzonitrile) did not directly inhibit either collagenase (10 microM) or neutral protease (100 microM) activity. Both WY-48,989 and WY-46,135 inhibited IL-1 stimulated release of neutral proteases (IC50 = 3 microM). The activities of these compounds represents two potential approaches for the treatment of osteoarthritis. WY-46,135 combines direct metalloprotease inhibitory activity with the inhibition of IL-1 stimulated neutral protease release from articular chondrocytes while WY-48,989 selectively inhibits the IL-1 induced release of metalloproteases.
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PMID:Inhibition of interleukin-1 (IL-1) induced neutral proteases from rabbit articular chondrocytes by WY-46,135 and WY-48,989. 166 95

The cDNA that encodes the proenzyme form of human fibroblast collagenase has been expressed in Escherichia coli. It has been shown by a number of criteria to be functionally identical with the enzyme isolated from human sources. Mutations of each of three cysteine residues found in procollagenase were constructed by site-directed mutagenesis of the cDNA. The relative activities of these mutants were compared to the wild-type enzyme. All of the mutants retained proteolytic activity, but not necessarily on collagen. Mutations that interfere with the formation of the sulfhydryl bridge in the carboxy-terminal domain in some cases increased and in other cases decreased the rate of casein cleavage. On the basis of extensive autolysis within E. coli of a mutant with a replacement of cysteine-73, the procollagenase molecule produced appeared to be either spontaneously active or perhaps more susceptible to autolytic activation, despite the continued presence of the propeptide. Experiments designed to capture the active forms of the mutant by use of the irreversible inhibitor alpha 2-macroglobulin showed that some degree of latency still persisted in the autolytic mutant. These findings suggest that the cysteine at position 73 is important for maintaining the proenzyme in an inactive state but that the maintenance of latency in MMPs may be a complex process, involving a number of interactions between the propeptide domain and the remainder of the collagenase molecule.
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PMID:An internal cysteine plays a role in the maintenance of the latency of human fibroblast collagenase. 170 20

P. gingivalis adheres to A. viscosus on mineral surfaces mimicking teeth. To study whether P. gingivalis proteases contribute to its binding, mutants of P. gingivalis deficient in proteases were compared with their parent strain and a P. gingivalis-type strain for their adherence to A. viscosus on saliva-coated hydroxyapatite by manipulating a radio-isotope binding assay. Adherence of P. gingivalis 2561 to A. viscosus was studied by tests of the effects of incubation temperature and known inhibitors or promoters of proteases. Controls were handled by the assay run in PBS buffer at 22 degrees C. Two mutants deficient in trypsin-like protease were found to be deficient in adherence (% attachment relative to control: 3.2 +/- 0.1% and 11.2 +/- 0.4%), while a collagenase-deficient mutant had an adherence score (51.6 +/- 8.4) closer to that of the parent strain (75.6 +/- 7.2%). Heating P. gingivalis at 70 degrees C decreased its subsequent adherence at 22 degrees C by 80%. Adherence decreased by 60% when the assay was run at 4 degrees C, but increased by 70% at 37 degrees C. Reducing agents (dithiothreitol, cysteine, and mercaptoethanol) enhanced P. gingivalis adherence by 50 to 60%. Protease inhibitors (BZMD, SBTI, TPCK, TLCK, CMPS, PMSF) decreased adherence by 10 to 50%. Also, Hg2+ and Zn2+ decreased adherence by 30 to 50%, and arginine decreased it by 50%. Most of these effects on P. gingivalis adherence were statistically significant (p less than 0.05). Analysis of these data suggests that P. gingivalis proteases may contribute to the cohesion of P. gingivalis and A. viscosus.
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PMID:Association of proteases of Porphyromonas (Bacteroides) gingivalis with its adhesion to Actinomyces viscosus. 184 87

Matrix metalloproteinases are an important group of zinc enzymes responsible for degradation of the extracellular matrix components such as collagen and proteoglycans in normal embryogenesis and remodeling and in many disease processes such as arthritis, cancer, periodontitis, and osteoporosis. A matrixin family is defined, comprising at least seven members that range in size from Mr 28,000 to 92,000 and are related in gene sequence to collagenase. All family members are secreted as zymogens that lose peptides of about 10,000 daltons upon activation. Latency is due to a conserved cysteine that binds to zinc at the active center. Latency is overcome by physical (chaotropic agents), chemical (HOCl, mercurials), and enzymatic (trypsin, plasmin) treatments that separate the cysteine residue from the zinc. Expression of the metalloproteinases is switched on by a variety of agents acting through regulatory elements of the gene, particularly the AP-1 binding site. A family of protein inhibitors of Mr 28,500 or less binds strongly and stoichiometrically in noncovalent fashion to inhibit members of the family. The serum protein alpha 2-macroglobulin and relatives are also strongly inhibitory.
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PMID:Matrix metalloproteinases and their inhibitors in connective tissue remodeling. 185 Jul 5


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