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 effects of various reactive oxygen species on latent human neutrophil and fibroblast-type interstitial collagenases were studied. Latent human neutrophil collagenases (proMMP-8) was efficiently activated by hypochlorous acid and hydrogen peroxide and less efficiently by the serine proteinases trypsin and chymotrypsin. Human plasmin and plasma kallikrein did not activate latent human neutrophil collagenase. The activation of latent human neutrophil collagenase by hypochlorous acid and hydrogen peroxide corresponded to the activation obtained with the other known non-proteolytic activators phenylmercuric chloride and gold thioglucose. The activation by hydrogen peroxide was inhibited by mannitol and desferoxamine, suggesting a localized Fenton-type reaction to be responsible for the generation of hydroxyl radical and/or hydroxyl radical-like reactive oxygen pathway of neutrophil procollagenase does not involve plasmin and plasma kallikrein, which are efficient proteolytic activators of latent fibroblast-type procollagenase (proMMP-1). Fibroblast procollagenase was also slightly activated by hypochlorous acid and gold thioglucose. Thus neutrophil procollagenase seems to prefer non-proteolytic means of activation and reactive oxygen species can be regarded as potent activators in vivo. Synovial-fluid neutrophils from rheumatoid arthritis patients were found to release collagenase in 30% active form when compared to same patients' peripheral blood neutrophils, which released collagenase in completely latent form. This may indicate that the triggering of neutrophil at the site of inflammation in vivo involves initial oxidative activation of collagenase upon the degranulation process.
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PMID:Reactive oxygen species as regulators of human neutrophil and fibroblast interstitial collagenases. 144 75

Mature (average patient age = 29.5 yr, closed apical foramen) and immature (average patient age = 17.5 yr, open apical foramen) root shards were placed in dialysis tubing and demineralized to completion using either 10% disodium EDTA plus protease inhibitors or 0.6 N HCl. The demineralized shards were re-extracted (five times) with 0.05 M tris-HCl, 1.0 M NaCl and then collagenase digested. No major differences were observed in chromatograms of extracts, re-extracts or collagenase digests from root shards demineralized in either way. In contrast, chromatograms of immature and mature roots showed qualitative differences. Chromatograms of mature roots demineralized in either way showed broader protein peaks and less organic phosphorus than those from immature tooth roots. A distinct band amid degraded phosphoprotein (150 K) was found in SDS-PAGE gels (7.5%) from EDTA-extracted immature tooth roots but not from mature tooth roots. Electroelution of this band revealed a typical phosphoprotein amino-acid profile containing increased aspartic acid and serine residues. Comparison of the total phosphoprotein and amino acid composition of extracts, re-extracts and collagenase digests revealed that phosphoprotein, serine and to a lesser extent aspartic acid were recovered in greater quantities from immature roots than mature tooth roots. These data suggest that the degree of maturation is crucial to the isolation of an intact phosphoprotein and provides additional evidence that human dentine phosphoprotein undergoes amino acid compositional changes during maturation.
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PMID:Comparison of phosphoprotein isolated from mature and immature human tooth roots. 147 54

Stromelysin/Transin is a member of the matrix metalloprotease gene family. This metalloprotease is synthesized as a preproenzyme with a predicted size of 53,977 Da including a 17 amino acid signal peptide. Prostromelysin is secreted from normal and transformed cells in two forms with apparent molecular masses on NaDodSO4 gels of 60 and 58-kDa. The minor 60-kDa species contains N-linked oligosaccharide(s). Stromelysin consists of three domains the amino terminal propeptide(s) domain contains the tribasic amino acid sequence RRK which is important in the proteolytic activation of this zymogen by trypsin-like serine proteases. The second domain consists of the catalytic domain which contains the zinc binding site. The carboxyl-terminal hemopexin domain has no known function and can be removed without a loss of enzymatic activity. Stromelysin has a broad range of substrate specificity including proteoglycans, casein, fibronectin, laminin, native type IV and IX collagen and gelatin but not type I collagen. In the presence of trypsin or plasmin, catalytic amounts of this enzyme can also fully activate interstitial fibroblast collagenase. We have developed a panel of monoclonal antibodies against stromelysin which will be useful for the tissue localization of the various species of this enzyme in tissues. In addition, we have demonstrated that either human rIL-1 (alpha) or rTNF (alpha) can stimulate the expression of this enzyme in cultured bovine articular cartilage at least 10-fold. Based on western blot analysis, the zymogen form of the enzyme was the major enzyme species detected in either the media or cartilage matrix compartments of cytokine treated cultures.
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PMID:Primary structure and function of stromelysin/transin in cartilage matrix turnover. 148 63

During experiments studying dietary effects on phosphorylation/dephosphorylation of MAP-2 we found that incubation of microtubules with alkaline phosphatase resulted in extensive proteolysis of MAP-2 but not of tubulin or Tau proteins. In the absence of tubulin, when microtubule-associated proteins (MAPs) were incubated with alkaline phosphatase, MAP-2 was not proteolyzed. This suggests that binding to tubulin induces a conformational change in MAP-2 which makes it more susceptible to proteolysis. The proteolysis of MAP-2 by alkaline phosphatase was prevented by inhibitors of serine proteases, suggesting that the commercial preparation of the enzyme is contaminated by a serine protease and/or that the enzyme also has a weaker proteolytic activity. In addition, selective proteolysis of MAP-2 can be obtained with the metalloprotease collagenase. Brain homogenates are shown to contain a Ca(2+)-dependent protease which selectively degrades MAP-2 bound to tubulin. These results suggest that selective proteolysis of tubulin-bound MAP-2 could play a role in the regulation of microtubule dynamics in response to extracellular signals.
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PMID:The susceptibility of MAP-2 to proteolytic degradation increases when bound to tubulin. 150 6

Our investigations indicate that a variety of neutral serine proteases exist in highly purified, IL-2-activated rat NK (A-NK) cells. These enzymatic activities are not restricted to only cytolysin-containing granules and are not defined by only the assay of N-alpha-benzyloxycarbonyl-L-lysine thiobenzylesterase activity. These activities, which we term A-NKP 1, A-NKP 2, A-NKP 3, and A-NKP 4, cleave, respectively, the following fluorogenic peptide substrates: Boc-Phe-Ser-Arg-7-amino-4-methylcoumarin (AMC, trypsin-like); Suc-Ala-Ala-Phe AMC (chymotrypsin-like); Suc-Gly-Pro-Leu-Gly-Pro AMC (collagenase-like), and Z-Phe-Arg AMC (another trypsin-like enzyme). The proteases A-NKP 1, A-NKP 2, and A-NKP 3 are not cell surface-associated and appear to be cytosolic as defined by isopycnic sucrose density gradient centrifugation. In contrast, A-NKP 4 appears to be located in lysosomes. Treatment of rat A-NK cells with protease inhibitors that inhibit A-NKP 2 and A-NKP 3 also substantially inhibit A-NK cell-mediated cytotoxicity against both NK-sensitive and -resistant targets (YAC-1 and P815, respectively). These results indicate that A-NKP2 and A-NKP 3 may play a role in IL-2-activated NK cell-mediated cytotoxicity. A variety of proteolytic enzymes, in addition to granzymes, therefore exist in A-NK cells. Our studies indicate that a prerequisite to a thorough understanding of the role of proteases in killer cell function is the investigation of several classes of enzymes in addition to granzymes contained in lytic granules.
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PMID:Nongranular proteolytic enzymes of rat IL-2-activated natural killer cells. I. Subcellular localization and functional role. 151 70

Oversulphated chondroitin sulphate proteoglycan from squid skin was isolated from 4 M guanidine hydrochloride extract by ion-exchange chromatography, gel chromatography and density gradient centrifugation. The proteoglycan had Mr 3.5 x 10(5), contained on average six oversulphated chondroitin sulphate chains (Mr 4 x 10(4)) bound on a polypeptide of Mr 2.8 x 10(4), and oligosaccharides consisting of both hexosamines, glucuronic acid, sulphates and fucose as the only neutral monosaccharide. The major amino acids of the proteoglycan protein core are glycine (corresponding to about one third of the total amino acids), aspartic acid/asparagine and serine, together amounting to 50% of the total. The proteoglycan was resistant to the proteolytic enzymes V8 protease, trypsin (treated with diphenylcarbamoyl chloride), alpha-chymotrypsin and pronase, while it was completely degraded by papain and to a large extent by collagenase. Pretreated proteoglycan with chondroitinase AC was degraded by pronase to a large extent and slightly by V8 protease and trypsin. The proteoglycan did not interact with hyaluronic acid and did not form self-aggregates. Oversulphated chondroitin sulphate chains were composed of unusual sulphated disaccharide units which were isolated and characterized by HPLC. In particular, it contained 2-acetamido-2-deoxy-3-O-(alpha-L-threo-4-enopyranosyluronic acid)-D-galactose 4-sulphate (delta di-4S) and disulphated disaccharides (delta di-diS) [90% 2-acetamido-2-deoxy-3-O-(alpha-L-threo-4-enopyranosyluronic acid 2/3-sulphate)-D-galactose 6-sulphate (delta di-diSD) and 10% 2-acetamido-2-deoxy-3-O-(alpha-L-threo-4-enopyranosyluronic acid 2/3-sulphate)-D-galactose 4-sulphate (delta di-diSK)] as the major disaccharides, significant amounts of trisulphated disaccharides (delta di-triS) and small amounts of 2-acetamido-2-deoxy-3-O-(alpha-L-threo-4-enopyranosyluronic acid)-D-galactose 6-sulphate (delta di-6S) and 2-acetamido-2-deoxy-3-O-(alpha-L-threo-4-enopyranosyluronic acid)-D-galactose (delta di-OS). Trisulphated disaccharides contained sulphate groups at C-4 and C-6 of the galactosamine and at C-2 or C-3 of the glucuronic acid. By HPLC analysis of a pure preparation of oversulphated chondroitin sulphate, it was found that it contains glucose, galactose, mannose and fucose most likely as branches.
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PMID:Isolation, characterization and properties of the oversulphated chondroitin sulphate proteoglycan from squid skin with peculiar glycosaminoglycan sulphation pattern. 154 Dec 70

Human endothelial cells treated with either interleukin-1 beta, tumor necrosis factor-alpha, or phorbol myristate acetate secreted a metalloproteinase that hydrolyzed and inactivated the two major serine proteinase inhibitors (Serpins) found in plasma, alpha 1-proteinase inhibitor and alpha 1-antichymotrypsin. Surprisingly, the responsible metalloproteinase was identified as human interstitial collagenase (matrix metalloproteinase-1), an enzyme whose only known physiologic substrate has heretofore been believed to be the extracellular matrix molecule, collagen. The metalloproteinase inactivated the Serpins by cleaving peptide bonds at sites unrelated to those hydrolyzed in collagenous macromolecules. NH2-terminal sequence analysis localized the cleavage sites in the Serpins to regions near their respective reactive site centers at three distinct peptide bonds on the amino-terminal side of bulky, hydrophobic residues. Together, these data indicate that matrix metalloproteinase-1 displays an expanded substrate repertoire that supports the existence of a new interface between connective tissue turnover and Serpin function.
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PMID:Interstitial collagenase (matrix metalloproteinase-1) expresses serpinase activity. 164 57

A metal-dependent peptidase was isolated from the homogenate of human uterus by standard chromatographic techniques and purified to apparent homogeneity. The peptidase hydrolysed the synthetic vertebrate collagenase substrate 2,4-dinitrophenyl-Pro-Gln-Gly-Ile-Ala-Gly-Gln-D-Arg (Dnp-peptide), the synthetic bacterial collagenase substrate 4-phenylazobenzyloxycarbonyl-Pro-Leu-Gly-Pro-D-Arg (PZ-peptide) and gelatinolytic peptides of gelatin, but was inactive against collagen type I, gelatin and casein. The cleavage site for the Dnp-peptide was the Gly-Ile bond. The enzyme was not only inhibited by metal chelators, such as EDTA, 1,10-phenantroline and dithiothreitol but also by thiol reagents, such as mersalylic acid and N-ethylmaleimid. However, E-64, an inhibitor for thiolproteinases, and leupeptin, an inhibitor for thiol- and serine proteases, did not exhibit any inhibitory activity. Pepstatin, an inhibitor for aspartate proteinases, and inhibitors for serine proteinases like phenylmethanesulfonyl fluoride and Trasylol were ineffective as well. The purified peptidase displayed a single band in the SDS-PAGE with an apparent molecular mass of 65 kDa. Employing isoelectric focusing an IP of 5.0 could be determined. The enzyme's properties are discussed in relation to the proteinase EC 3.4.24.11 and to proteinases of the collagenase family as well as the possibility to discriminate these three metalloproteinase classes by employing the Dnp-peptide.
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PMID:Isolation and properties of a metal-dependent endopeptidase from human uterus hydrolysing synthetic collagenase substrates. 165 Feb 34

Serpins encompass a superfamily of proteinase inhibitors that regulate many of the serine proteinases involved in inflammation and hemostasis. In vitro, many serpins are catalytically inactivated by proteinases that they do not inhibit, leading to the concept of proteolytic down-regulation of serpin inhibitory capacity. The extent to which down-regulation of serpin activity occurs in vivo is debated, since little is known of the rates at which the process occurs. To address this debate, we have measured the rates of inactivation of three serpins, alpha 1-proteinase inhibitor (alpha 1PI), alpha 1-antichymotrypsin (alpha 1ACT), and antithrombin III (ATIII), by three human matrix metalloproteinases (MMPs-1, -2, and -3) thought to be involved in tissue destruction and repair. Our object was to establish a working kinetic model which can be used to predict whether serpin inactivation by these proteinases is likely to occur in vivo. We determined the rates of inactivation of these three serpins by each of the MMPs and compared these to rates of inhibition of the MMPs by an endogenous inhibitor, alpha 2-macroglobulin. An equation designed to predict the extent of substrate hydrolyzed by an enzyme in the presence of an enzyme inhibitor gave the following predictions of the inactivation in vivo: (i) ATIII is unlikely to be inactivated by the MMPs. (ii) MMP-2 (72-kDa gelatinase/type IV collagenase) is unlikely to inactivate any of the three serpins. (iii) MMP-1 (tissue collagenase) will inactivate alpha 1PI and alpha 1ACT only when its concentration saturates that of its controlling inhibitors. (iv) MMP-3 (stromelysin) may inactivate small amounts of alpha 1PI and more significant amounts of alpha 1ACT, even in the presence of its controlling inhibitors. Any physiologic or pathologic inactivation of these serpins by these MMPs that occurs in vivo will probably be due to MMP-3, and will likely only take place in tissues and inflammatory loci where the concentration of MMP inhibitors is depressed.
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PMID:Kinetics and physiologic relevance of the inactivation of alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, and antithrombin III by matrix metalloproteinases-1 (tissue collagenase), -2 (72-kDa gelatinase/type IV collagenase), and -3 (stromelysin). 165 20

The effects of several antirheumatic drugs on the activity of degradative enzymes in normal and pathologic knee joint cartilage and on the proliferative activity of synovial tissue cells were studied. Inflammatory arthropathy was induced in rabbits by intraarticular papain administration. Elevated contents of proteoglycanase and collagenase, together with an increase in serine and cysteine proteinase inhibitors, were found in animals with papain-induced arthropathy. Inflammation also accelerated the rate of proliferation of cells present in the synovial tissue. In the treated animals, the reduction in enzyme activity, decrease in inhibitor content and decreased DNA proliferation rate were registered to a different degree. The suppression of protein synthesis by nonsteroidal antiinflammatory drugs may explain our findings. The best therapeutic results were achieved with glycosaminoglycan polysulphate (Arteparon).
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PMID:Effect of selected antirheumatic drugs on the metabolism of cartilage and synovial tissue in experimental arthropathy. 165 45


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