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:3.4.24.17 (MMP-3)
3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Procollagenase M(r) 85,000 (SDS-PAGE) was purified from buffy coat to homogeneity and represents a stable single polypeptide chain forming the entire proenzyme. The procollagenase can be activated by various proteinases, e.g. trypsin, chymotrypsin, cathepsin G, kallikrein and stromelysin and by different mercurial compounds. Proteolytic conversion of the latent enzyme to the active form by chymotrypsin is accompanied by a molecular weight reduction to an apparent M(r) 64,000. This active enzyme lacks the first 79 N-terminal residues. Activation by trypsin leads to a latent intermediate of apparent M(r) 70,000, lacking 48 N-terminal residues. The active enzyme is therefore generated upon prolonged incubation with trypsin by further cleavage of 22 N-terminal residues. Another latent intermediate form with apparent M(r) 69,000 is generated from the proenzyme upon incubation with leukocyte elastase by N-terminal cleavage of 53 or 64 residues, respectively. However, latent collagenase cannot be activated by plasmin. Activation by different mercurial compounds finally results in the formation of active collagenase with apparent M(r) 64,000. In contrast to the proenzyme, active collagenase can autolyse to give active M(r) 57,000 and 45,000 intermediates and two M(r) 28,000 fragments. Purification of latent leukocyte gelatinase yields three final products with apparent M(r) 98,000, 125,000 and 220,000 (SDS-PAGE; non reduced). Upon reduction, only the M(r) 98,000 form can be detected. The latent gelatinase can be activated in a similar manner as collagenase. Proteolytic activation by trypsin leads after N-terminal cleavage to an active gelatinase with sequence homology to leukocyte collagenase.
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PMID:Latent collagenase and gelatinase from human neutrophils and their activation. 148 34

The tissue inhibitor of metalloproteinases (TIMP, M(r) 30,000) is secreted by many cell and tissue types and has been shown to inhibit most secreted mammalian metalloproteinases. In matrix and tissue invasion assays, the inactivation or removal of TIMP enhances invasiveness. However, many of the cells that secrete TIMP also secrete other metalloproteinase inhibitors. By analysis of medium conditioned by various endothelial, mesenchymal, and neural cells on SDS-.substrate-polyacrylamide-inhibitor gels (reverse zymograms), we have detected at least three other distinct inhibitors of metalloproteinases (IMPs). Some or all of these IMPs have been detected in secretions of mouse, rabbit, sheep, and human cells and are all smaller in apparent molecular size than TIMP (IMP-1, M(r) 26,000; IMP-2, M(r) 21,000; IMP-3, M(r) 18,000). These IMPs are not proteolytic degradation products of TIMP nor do they represent nonglycosylated TIMP. The IMPs do not cross-react in the native or denatured state with any of several anti-TIMP antibodies. The IMPs appear to be regulated independently of each other and of TIMP. In vitro, the complex consisting of one of the IMPs, or TIMP, and a metalloproteinase can be dissociated into functional inhibitor and metalloproteinase. Whether this characteristic is significant in vivo is not known. IMP-2 has been purified from several sources and shares sequence homology with TIMP, suggesting that the IMPs and TIMP may constitute a gene family. The most significant characteristic of IMP-2 is that it appears to preferentially inhibit, on a mole:mole basis, the M(r) 68,000 gelatinase rather than collagenase or stromelysin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Secreted inhibitors of metalloproteinases (IMPs) that are distinct from TIMP. 148 40

Extracellular matrix (ECM) remodeling accompanies cell migration, cell-cell interactions, embryo expansion, uterine implantation and tissue invasion during mammalian embryogenesis. We have found that mouse embryos express mRNA transcripts for collagenase, stromelysin and the tissue inhibitor of metalloproteinases (TIMP) and secrete functional ECM-degrading metalloproteinases, including collagenase and stromelysin. These metalloproteinases are inhibitable by TIMP and are regulated during peri-implantation development and endoderm differentiation. The involvement of a controlled proteolytic reaction, dependent on metalloproteinases, during the implantation of mouse embryos is suggested by the secretion of proteinases by trophoblast during its invasive phase and by the reciprocal expression of TIMP in the maternal deciduum. Exogenous TIMP affects the migration of parietal endoderm cells during blastocyst outgrowth in vitro. Taken together, these data suggest that metalloproteinases function in cell-ECM interactions during mammalian development.
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PMID:Expression and function of matrix metalloproteinases in development. 148 58

Inflammation of the periodontium leads to connective tissue degradation and eventual tooth loss. The regulation of matrix metalloproteinases (MMPs) has been studied to determine their role in these processes and also during tissue remodelling. Analysis of gingival crevicular fluid has revealed the presence of collagenase and gelatinase that, in the acute stages of periodontal disease, are derived predominantly from polymorphonuclear leukocytes. These MMPs appear to be intimately associated with tissue destruction since the levels of the active forms of these enzymes obtained from either crevicular fluid or mouthrinse samples correlate with tissue destruction and, therefore, provide a sensitive means of demonstrating disease activity. Transforming growth factor-beta, an important regulator of connective tissue remodelling, has been implicated in the rapid remodelling of periodontal tissues. TGF-beta promotes tissue matrix formation by stimulating both the synthesis of matrix proteins (collagen, fibronectin and SPARC) and proteinase inhibitors (TIMP, PAI-1) and by decreasing the synthesis of MMPs, but not the 72 kDa-gelatinase. Nuclear run-on analyses have shown that TGF-beta reduces collagenase and stromelysin synthesis by suppressing gene transcription without altering mRNA stabilities. In contrast, the transcription of the gelatinase and TIMP genes was increased by TGF-beta, which also increased gelatinase mRNA stability. Remodelling of alveolar bone involves interaction between osteoblasts and osteoclasts. Osteoblasts, under the influence of osteotropic hormones (vit D3, PTH and retinoic acid), produce MMPs which appear to function in the removal of soft tissue that precludes access of osteoclasts to the mineralized tissue surface. Rat osteoblastic cells produce MMPs with activity on native collagen, native collagen 3/4-fragments and gelatin and, in addition, two forms of TIMP activity. The 3/4-collagen endopeptidase, purified to apparent homogeneity, also has significant collagenase and gelatinase activities and an amino terminal sequence almost identical to human 72 kDa-gelatinase. The production of this enzyme was stimulated by TGF-beta, which suppresses bone resorption, and by osteotropic hormones which stimulate bone resorption, supporting a bifunctional role for the gelatinase in connective tissue remodelling. Although there is strong evidence for the involvement of MMPs in the resorption of bone and in the inflammation-mediated destruction of periodontal tissues, the role of MMPs in the remodelling of mature soft connective tissues remains equivocal.
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PMID:Matrix metalloproteinases in periodontal tissue remodelling. 148 60

Human mononuclear phagocytes have the capacity to participate directly in extracellular matrix turnover via the secretion of neutral proteinases. These neutral proteinases include the serine proteinases, elastase and cathepsin G and the metalloproteinases, interstitial collagenase, 92 kD type IV collagenase, 72 kD type IV collagenase and stromelysin. Mononuclear phagocytes also produce the counter-regulatory metalloproteinase inhibitor, TIMP (tissue inhibitor of metalloproteinases). We have studied the capacity of normal human mononuclear phagocytes and of the human monocytic tumor line U937 to elaborate proteinases and inhibitors. The serine proteinases, elastase and cathepsin G, are present only at the earliest stages of mononuclear phagocyte differentiation (U937 cells in the basal state, freshly isolated peripheral blood monocytes) and are stored within intracellular granules. As human mononuclear phagocytes differentiate (U937 cells exposed to phorbol esters, human monocytes cultured in vitro), the cellular content of these serine proteinases declines rapidly. Accompanying the acquisition of a more differentiated state, the ability for regulated secretion of the neutral metalloproteinases is attained. This capacity is acquired in a sequential manner, with secretion of the 92 kD type IV collagenase observed at earlier states of differentiation while release of stromelysin requires a fully differentiated and LPS (lipopolysaccharide)-stimulated alveolar macrophage. Interstitial collagenase and 72 kD type IV collagenase are synthesized at intermediate stages of differentiation. In comparison to human fibroblasts, human mononuclear phagocytes produce approximately 10-30% of the interstitial collagenase, 10% of the stromelysin and 1-2% of the 72 kD type IV collagenase on a per cell basis. Synthesis of the 92 kD type IV collagenase is restricted to the inflammatory cell (but also occurs in neutrophils and keratinocytes).
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PMID:Neutral proteinase expression by human mononuclear phagocytes: a prominent role of cellular differentiation. 148 61

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

The anabolic steroid, stanozolol, is used therapeutically to treat a number of pathological conditions and its clinical effects suggest that it can modulate connective tissue breakdown. The ability of this compound to stimulate prostaglandin E2 (PGE2), collagenase, gelatinase and stromelysin production by human synovial and skin fibroblasts in vitro was examined. The results showed that stanozolol significantly stimulated, in a dose dependent manner, PGE2, collagenase and stromelysin production by skin fibroblasts. However, no stimulation was seen in the synovial cell lines. In contrast, no effect on gelatinase production was seen in either cell type, following exposure to stanozolol. The synovial and skin lines both exhibited a significant stimulation of PGE2 and all three metalloproteinases in response to interleukin-1 beta (IL-1 beta). The anabolic steroids nortestosterone and oxymetholone demonstrated no ability to stimulate PGE2 or collagenase production in either skin or synovial fibroblasts. These results suggest that stanozolol exerts differential effects on skin and synovial fibroblasts in vitro which may enable the elucidation of the mechanism of action of the compound in vivo.
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PMID:The differential responses of human skin and synovial fibroblasts to stanozolol in vitro: production of prostaglandin E2 and matrix metalloproteinases. 152 98

(7-methoxycoumarin-4-yl)Acetyl-Pro-Leu-Gly-Leu-(3-[2,4-dinitrophenyl]-L- 2,3-diaminopropionyl)-Ala-Arg-NH2 (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2) has been synthesised as a fluorogenic substrate for the matrix metalloproteinases. The highly fluorescent 7-methoxycoumarin group is efficiently quenched by energy transfer to the 2,4-dinitrophenyl group. The punctuated metalloproteinase (PUMP, EC 3.4.24.23) cleaves the substrate at the Gly-Leu bond with a 190-fold increase in fluorescence (lambda cx 328 nm, lambda cm 393 nm). In assays of the human matrix metalloproteinases. Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 is about 50 to 100 times more sensitive than dinitrophenyl-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2 and continuous assays can be made at enzyme concentrations comparable to those used with macromolecular substrates. Specificity constants (kcat/Km) are reported for both synthetic substrates with PUMP, collagenase, stromelysin and 72 kDa gelatinase.
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PMID:A novel coumarin-labelled peptide for sensitive continuous assays of the matrix metalloproteinases. 153

Tooth eruption is defined as the movement of a tooth from its site of development within the jaws to its position of function within the oral cavity. We present a critical review of evidence for the mechanisms and regulation of the intraosseous and supraosseous phases of eruption, with an emphasis upon the canine premolar model studied by the authors. Analyses at different stages of premolar eruption indicate that selective fragmentation of dental follicle protein DF-95 correlates with the presence of elevated levels of follicular collagenase and stromelysin, and with the onset of premolar movement. A dramatic decrease in these metalloproteinases followed initiation of movement. A biochemical and cell biological model for regulation of tooth eruption is proposed based upon these new and existing data.
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PMID:Current concepts of the biology of tooth eruption. 157 71

Normal and osteoarthritic (OA) human articular cartilage chondrocytes, released enzymatically in the presence of 0.5% fetal calf serum, display constitutive expression of early response activating protein (AP-1) genes; c-fos, c-jun and jun-B. Among the late AP-1 responsive genes, total metallothionein (MT) and stromelysin mRNAs were expressed at high levels in both normal and OA chondrocytes, while collagenase and hMT-IIA mRNA levels were elevated only in OA individuals. Despite the common AP-1 sequences present in their promoter regions, the three late genes were differentially expressed.
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PMID:Expression of c-fos, c-jun, jun-B, metallothionein and metalloproteinase genes in human chondrocyte. 163 72


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