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)

1. L-trans-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) at a concentration of 0.5 mM had no effect on the serine proteinases plasma kallikrein and leucocyte elastase or the metalloproteinases thermolysin and clostridial collagenase. In contrast, 10 muM-E-64 rapidly inactivated the cysteine proteinases cathepsins B, H and L and papain (t0.5 = 0.1-17.3s). The streptococcal cysteine proteinase reacted much more slowly, and there was no irreversible inactivation of clostripain. The cysteine-dependent exopeptidase dipeptidyl peptidase I was very slowly inactivated by E-64. 2. the active-site-directed nature of the interaction of cathepsin B and papain with E-64 was established by protection of the enzyme in the presence of the reversible competitive inhibitor leupeptin and by the stereospecificity for inhibition by the L as opposed to the D compound. 3. It was shown that the rapid stoichiometric reaction of the cysteine proteinases related to papain can be used to determine the operational molarity of solutions of the enzymes and thus to calibrate rate assays. 4. The apparent second-order rate constants for the inactivation of human cathepsins B and H and rat cathepsin L by a series of structural analogues of E-64 are reported, and compared with those for some other active-site-directed inhibitors of cysteine proteinases. 5. L-trans-Epoxysuccinyl-leucylamido(3-methyl)butane (Ep-475) was found to inhibit cathepsins B and L more rapidly than E-64. 6. Fumaryl-leucylamido(3-methyl)butane (Dc-11) was 100-fold less reactive than the corresponding epoxide, but was nevertheless about as effective as iodoacetate.
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PMID:L-trans-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) and its analogues as inhibitors of cysteine proteinases including cathepsins B, H and L. 704 72

The mononuclear cell fraction of rat hind-limb muscle was obtained by digestion with clostridial collagenase in the presence of calcium ions, filtration through nylon screens and washing to remove the enzyme. Final traces of contaminant myofibrillar debris were separated by isopycnic centrifugation in a Percoll density gradient. Whole muscle, washed cells and Percoll-fractionated cells were extracted in the presence of non-ionic detergent and the supernatants assayed for the lysosomal enzymes cathepsins B + L, N-acetyl-beta-glucosaminidase, beta-glucuronidase and protein. The enzyme levels were highest in the muscle from young rats, but the percentage of recovered activity in the mononuclear cell fraction was little altered by the age of the animal. The values obtained were: cathepsin B + L, 2.4-4.0%; N-acetyl-beta-glucuronidase, 4.3-7.6%; and beta-glucuronidase, 6.3-10.3%. Because of unavoidable losses in preparation these are minimal values and the actual levels of activity from the mononuclear cell fraction in muscle would be higher. The specific activity values of the cell lysates were raised after isopycnic centrifugation and were nearly constant over the age range 65-180 days. Substantially higher specific activity values were obtained for the cells from rats of 38 days. When grown in culture the mononuclear cell fractions were seen to contain mainly fibroblasts and myoblasts with only few leucocytes. The cultures reached confluence by the second week, at which time numerous myotubes had formed. In addition there were groups of large, circular cells with a prominent centrosphere. The origin of these latter cells is uncertain. It was concluded that although total lysosomal enzyme activity was higher in young rats there was little effect of age on the distribution of activity between muscle fibres and mononuclear cells in the muscle.
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PMID:The mononuclear cell population in rat leg muscle: its contribution to the lysosomal enzyme activities of whole muscle extracts. 718 82

Primitive biliary cells are known to migrate from the ductal plate into the mesenchyme during human intrahepatic bile duct development, and this migration process is essential for normal development of intrahepatic bile ducts. However, its molecular mechanism is unknown. Matrix proteinases play an important role in cell migration during cancer invasion and organ development. In this study, we therefore investigated in situ expression of matrix metalloproteinases (MMP) and tissue inhibitors of MMP (TIMP) during human intrahepatic bile duct development, using 32 human fetal livers. We also examined in situ expression of trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B, which are matrix proteinases and activators of MMP. MMP-1 expression was noted in the ductal plate and migrating primitive biliary cells. MMP-2, MMP-3, and MMP-9 were expressed in the ductal plate. TIMP-1 and TIMP-2 were expressed in the ductal plate and migrating primitive biliary cells. Trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B were also expressed in primitive biliary cells. These data suggest that MMP, trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B play a critical role in biliary cell migration during human intrahepatic bile duct development by degrading extracellular matrix proteins. The data also suggest that MMP inhibitors (TIMP-1 and TIMP-2) and MMP activators (trypsin, chymotrypsin, and cathepsin B) play an important role in biliary cell migration. The coordinated expression of MMP, MMP inhibitors, and MMP activators may be necessary for the normal development of human intrahepatic bile ducts.
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PMID:Expression of matrix proteinases during human intrahepatic bile duct development. A possible role in biliary cell migration. 748 84

We have developed a monoclonal antibody AF-28 that specifically recognizes a neo-epitope on polypeptides with N-terminal FFGVG ... sequences. This sequence is found at the N-terminus of aggrecan fragments that have been digested with matrix metalloproteinases (MMPs). By immunoblotting, monoclonal antibody AF-28 specifically detected G2 fragments derived from an aggrecan G1-G2 substrate digested with stromelysin, collagenase, gelatinase and matrilysin, but failed to detect G2 fragments obtained from elastase, trypsin or cathepsin B digests. Undigested G1-G2 was not detected. In addition, AF-28 antibody detected fragments derived from whole aggrecan and this detection did not require prior treatment with chondroitinase or keratanase. Competition experiments confirmed that peptides containing internal ... FFGVG ... sequences were not detected by the antibody, while native MMP-digested aggrecan fragments and a synthetic 32-mer peptide with FFGVG ... N-termini were equally competitive on a molar basis. An FFGVG 5-mer, and an FGVGGEEDI9-mer which lacked the N-terminal phenylalanine residue, were 50 times and 230 times respectively less competitive than the FFGVG ... 32-mer. Two fragments from the interglobular domain, F342-F373 and F342-D441, that are predicted products of G1-G2 digestion by neutrophil collagenase but have not previously been detected, could be detected with AF-28. The epitope recognized by AF-28 was also detected in human synovial fluids by Western blot analysis. A broad band of 100-200 kDa was detected in some patients and a dominant band of 40-60 kDa was found in two patients. The size of this small fragment corresponds with that seen for the porcine F342-E373 product and may represent the natural physiological product of aggrecan cleaved in vivo at both the MMP site (... DIPEN341 decreases F342FGVG ...) and the aggrecanase site (... ITEGE373 decreases A374RGSVI ...).
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PMID:Development of a cleavage-site-specific monoclonal antibody for detecting metalloproteinase-derived aggrecan fragments: detection of fragments in human synovial fluids. 754 17

The volatile sulphur compound methyl mercaptan (CH3SH) is a by-product of protein metabolism and a principal component of oral malodour. This investigation examines the effect of CH3SH on the enzymatic activities of cathepsins B and G and elastase, and on the production by human gingival fibroblasts of two key factors, prostaglandin E (PGE) and cAMP, of the PGE2-cAMP-dependent pathway, which may contribute to the increased production of collagenase and tissue destruction in human periodontal disease. The results demonstrate that CH3SH alone, or in combination with interleukin-1 (IL-1) or lipopolysaccharide, can significantly enhance the secretion of PGE2, cAMP and procollagenase by human gingival fibroblasts. CH3SH also stimulated mononuclear cells to produce IL-1, which can increase cAMP production, and act in synergism with the direct effect of CH3SH on cAMP. CH3SH also significantly enhanced the activity of cathepsin B, moderately suppressed that of cathepsin G, but did not significantly affect elastase. These results provide evidence that CH3SH could be a contributing factor in the enzymatic and immunological cascade of events leading to tissue degradation in periodontal diseases.
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PMID:Stimulation of enzyme and cytokine production by methyl mercaptan in human gingival fibroblast and monocyte cell cultures. 760 61

Abnormalities in extracellular matrix degradation may play a pathogenetic role in diabetic nephropathy. Cultured renal mesangial cells are known to synthesize increased amounts of matrix proteins when incubated in high glucose media (e.g., 30 mmol/l). However, the effect of glucose loading on degradative enzymes is unknown. Primary cultures of rat mesangial cells were grown until confluent in the presence of fetal calf serum (FCS) and insulin (0.67 U/ml). Cells were then cultured for 7 days in plastic wells in either 10 or 30 mmol/l glucose media containing neither FCS nor insulin. Collagenase activity in media were determined by zymography and quantitative spectrofluorometry. Cathepsin B and D activities in cell extracts were measured by spectrofluorometry (using the fluorescent substrate Z-Arg-Arg-7-amido-4-methylcoumarin) and 125I-labeled hemoglobin digestion, respectively. Gelatin-degrading activity of live mesangial cells was also determined. mRNA levels for collagenase IV, cathepsin B, and cathepsin D were determined by Northern analysis. A major band of collagenase activity with a molecular size of 72 kDa was observed in all mesangial cell media. Exposure of cells to high glucose media resulted in significant reductions in collagenase and cathepsin B activities as well as impairment in gelatin-degrading activity. Collagenase IV and cathepsin B and D mRNA levels were also decreased by glucose loading. To exclude the possibility that glucose loading was injurious to cells, 3H-leucine uptake (as a measure of protein synthesis) and membrane alkaline phosphatase activity (as a biochemical marker of viability) were not affected by the high glucose condition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased degradative enzymes in mesangial cells cultured in high glucose media. 762 99

Several members of the matrix metalloproteinase family have been reported to cleave aggrecan in the interglobular domain between Asn-341 and Phe-342. An antiserum was prepared against a peptide conjugate corresponding to the C-terminal sequence of the matrix metalloproteinase-generated aggrecan G1 fragment (Phe335-Val-Asp-Ile-Pro-Glu-Asn341). A quantitative radioimmunoassay, with a limit of detection of about 80 pM, was developed using this antiserum. This antiserum requires the free carboxyl group of the C-terminal asparagine for optimal recognition. If the C-terminal asparagine is excised from the sequence, replaced with closely related amino acids, or extended across the matrix metalloproteinase cleavage site, there is a 40-10,000-fold loss in detection. Using peptides cleaved from the N-terminus, it was determined that the antiserum requires the entire Phe-Val-Asp-Ile-Pro-Glu-Asn sequence for optimal recognition. The radioimmunoassay detects matrix metalloproteinase-generated G1 fragments with similar sensitivity to the Phe-Val-Asp-Ile-Pro-Glu-Asn peptide, but it does not recognize intact aggrecan. Immunoreactive aggrecan G1 fragments of molecular mass 50 kDa are generated by the matrix metalloproteinases stromelysin and gelatinase A. In contrast, under identical conditions, the closely related metalloproteinases, gelatinase B and collagenase, as well as cathepsin G, cathepsin B and human leucocyte elastase, did not generate a G1 fragment recognized by the antiserum. The anti-Phe-Val-Asp-Ile-Pro-Glu-Asn serum detects stromelysin-generated aggrecan G1 fragments from mouse, guinea pig, rabbit and human, indicating that the detection is not species-specific. This antiserum and radio-immunoassay should be useful for quantifying and characterizing matrix metalloproteinase-generated aggrecan G1 fragments in articular cartilage and synovial fluids from humans and various animal models of articular-cartilage destruction.
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PMID:Quantification of a matrix metalloproteinase-generated aggrecan G1 fragment using monospecific anti-peptide serum. 771 83

We have studied the degradation of type X collagen by metalloproteinases, cathepsin B, and osteoclast-derived lysates. We had previously shown (Welgus, H. G., C. J. Fliszar, J. L. Seltzer, T. M. Schmid, and J. J. Jeffrey. 1990. J. Biol. Chem. 265:13521-13527) that interstitial collagenase rapidly attacks the native 59-kD type X molecule at two sites, rendering a final product of 32 kD. This 32-kD fragment, however, has a Tm of 43 degrees C due to a very high amino acid content, and thus remains helical at physiologic core temperature. We now report that the 32-kD product resists any further attack by several matrix metalloproteinases including interstitial collagenase, 92-kD gelatinase, and matrilysin. However, this collagenase-generated fragment can be readily degraded to completion by cathepsin B at 37 degrees C and pH 4.4. Interestingly, even under acidic conditions, cathepsin B cannot effectively attack the whole 59-kD type X molecule at 37 degrees C, but only the 32-kD collagenase-generated fragment. Most importantly, the 32-kD fragment was also degraded at acid pH by cell lysates isolated from murine osteoclasts. Degradation of the 32-kD type X collagen fragment by osteoclast lysates exhibited the following properties: (a) cleavage occurred only at acidic pH (4.4) and not at neutral pH; (b) the cysteine proteinase inhibitors E64 and leupeptin completely blocked degradation; and (c) specific antibody to cathepsin B was able to inhibit much of the lysate-derived activity. Based upon these data, we postulate that during in vivo endochondral bone formation type X collagen is first degraded at neutral pH by interstitial collagenase secreted by resorbing cartilage-derived cells. The resulting 32-kD fragment is stable at core temperature and further degradation requires osteoclast-derived cathepsin B supplied by invading bone.
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PMID:Complete degradation of type X collagen requires the combined action of interstitial collagenase and osteoclast-derived cathepsin-B. 773 76

To elucidate hepatic collagen metabolism during liver regeneration after partial hepatectomy, we measured collagen content, collagen synthesis, and collagen-degrading enzyme activity in the remnant livers of rats 3, 5, 7, and 14 days after a partial hepatectomy of 68%. Hepatic collagen synthesis was significantly higher 3, 5, and 7 days after partial hepatectomy than it was in sham-operated control rats, but there was no such difference 14 days after surgery, the maximal hepatic collagen synthesis being observed 5 days after surgery. Although the collagen concentration in the remnant liver was similar to that in the control liver, the total collagen content of the remnant liver increased rapidly with liver regeneration until 7 days after partial hepatectomy. Hepatic collagenase activity was similar to the control; however, hepatic cathepsin B and cathepsin L activity and the intracellular degradation of newly synthesized collagen were markedly decreased 3, 5, and 7 days after partial hepatectomy compared with the controls. Hepatic collagen synthesis was significantly and inversely correlated with cathepsin L activity and with the intracellular degradation of newly synthesized collagen. These findings suggest that a combination of increased collagen synthesis and decreased intracellular collagen degradation contributes to the rapid supply of collagen that is observed during the early phase of liver regeneration.
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PMID:Hepatic collagen synthesis and degradation during liver regeneration after partial hepatectomy. 780 50

Fetuses are surrounded by amniotic fluid rich in nutrients and other factors essential to fetal development and possibly to its scarless wound healing. The purpose of this study was to determine whether amniotic fluid contains factors that regulate activities of major proteases involved in the process of wound healing (e.g., collagenase, hyaluronidase, elastase, and cathepsin B). Human amniotic fluid was assayed in vitro for inhibition or stimulation of the activity of these enzymes. Our results showed that amniotic fluid enhanced collagenase activity at a concentration of 66 micrograms protein (p < 0.01), but inhibited activities of hyaluronidase (132 micrograms protein; p < 0.05), elastase (170 micrograms protein; p < 0.05), and cathepsin B (19 micrograms protein; p < 0.01). This finding suggests that amniotic fluid could have an important role in flawless fetal wound healing by regulating these matrix-degrading enzymes.
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PMID:Effects of amniotic fluid on proteases: a possible role of amniotic fluid in fetal wound healing. 797 42


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