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:3.4.24.23 (MMP)
4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The matrix metalloproteinases (MMP) are a multigenic family involving 14 enzymes which can cleave most, if not all, the components of the extracellular matrix (interstitium and basement membranes). The present work reports on the main structural characteristics, the substrate preference and the site synthesis of these proteinases and their inhibitors (TIMP). Human MMPs are produced by various cell types and are involved in the remodelling of the extracellular matrix in many physiological and pathophysiological circumstances. Elastolytic MMPs produced by monocytes and/or macrophages (matrilysin, gelatinases, macrophage elastase) are likely to be implicated in the development of acquired pulmonary emphysema.
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PMID:[Metalloproteinases in the extracellular matrix: structure and activity]. 908

Matrix metalloproteinases (MMPs) are a family of proteinases that play a major role in the metabolic degradation of extracellular matrix proteins. In order to examine the expression pattern of different MMP or MMP-inhibitor genes two RNase protection assays (RPAs) were developed that allow the simultaneous and semiquantitative assessment of their respective mRNAs. Probes for the detection of MMPs stromelysin 1, 2 and 3, matrilysin, metalloelastase, gelatinase A and B, collagenase and membrane type MMP (MT1-MMP) were included in the first RPA probe set, while probes for tissue inhibitor of matrix metalloproteinase (TIMP) 1, 2, 3 and alpha 2-macroglobulin (alpha 2-M) were included in the second probe set (inhibitor of matrix metalloproteinase-IMP set). Titration experiments revealed that this method allows the detection of MMP and inhibitor mRNAs present in at least 0.03 microgram of spleen poly(A)+ RNA. Both RPA sets were further evaluated by analyzing the expression of MMP and IMP genes in brain, kidney, spleen and liver in a murine model for endotoxemia after intraperitoneal LPS injection. Control animals showed an organ-specific constitutive expression of one or more MMPs and a high expression of TIMPs. Following LPS injection, an organ-specific upregulation or induction of MMP and TIMP RNA species was found. This change was most pronounced in the spleen, while liver, kidney and brain showed minor or no changes in MMP expression. An IMP upregulation was detected in all organs. These RPA probe sets provide a valuable tool for the simultaneous assessment of MMP and IMP gene expression under physiological and pathological conditions.
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PMID:RNAse protection assays for the simultaneous and semiquantitative analysis of multiple murine matrix metalloproteinase (MMP) and MMP inhibitor mRNAs. 932 62

Angiostatin is one of the most potent inhibitors of angiogenesis. Reports have shown that metalloelastase, pancreas elastase, plasmin reductase, and plasmin convert plasminogen to angiostatin. However, the cleavage sites of plasminogen by those enzymes have not been determined. Here we demonstrate that two members of the human matrix metalloproteinase (MMP) family, matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9), hydrolyze human plasminogen to generate angiostatin fragments. The cleavage sites have been determined. The 58-kDa bands derived from plasminogen by MMP-7 and MMP-9 both have the N-terminal sequence KVYLSEXKTG, which corresponds to that of angiostatin. This N terminus is identical to that of the starting plasminogen itself and corresponds to residues 97-106 of prepro-plasminogen. The 42- and 38-kDa bands generated by MMP-7 both have the N-terminal sequence VVLLPNVETP, which corresponds to the amino acid sequence 467-476 of prepro-plasminogen, between kringle domain 4 and 5. MMP-9 cleaves plasminogen to generate a 42-kDa fragment with the N-terminal sequence PVVLLPNVE, 1 residue upstream of the MMP-7 cleavage site. These results indicate that MMP-7 and MMP-9 may regulate new blood vessel formation by cleaving plasminogen and generating angiostatin molecules.
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PMID:Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9). 936 Sep 44

Programmed expression of matrix metalloproteinases is involved in wound healing in various organs. We have previously demonstrated enhanced expression of collagenase-1, stromelysin-1, matrilysin, and tissue inhibitor of metalloproteinases (TIMP-1) in gastrointestinal ulcerations. To further define the role of matrix-degrading enzymes and their inhibitors in intestinal inflammation and ulcerations, the expression of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (HME, MMP-12), and TIMP-3 mRNAs was studied using in situ hybridization and immunohistochemistry in 38 samples representing ulcerative colitis, Crohn's disease, ischemic colitis, and normal intestine. As controls for normally healing intestinal wounds, 12 postoperative samples of rat experimental jejunal anastomoses were also examined. The colitis types studied did not essentially differ in their MMP expression. We found stromelysin-2 mRNA in laminin-5-positive and Ki-67-negative enterocytes bordering the ulcerations. HME was abundantly expressed by macrophages in the vicinity of shedding mucosal epithelium and beneath the necrotic surface of the ulcers. Collagenase-3 and TIMP-3 were expressed by fibroblast-like cells deeper in the remodeling intestinal wall. Expression for stromelysin-2 and collagenase-3 was observed in granulation tissue, but not the epithelium, of the rat anastomoses. Our results suggest a role for stromelysin-2 in epithelial migration and for metalloelastase in macrophage movement and epithelial cell shedding.
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PMID:Distinct expression profiles of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (MMP-12), and tissue inhibitor of metalloproteinases-3 (TIMP-3) in intestinal ulcerations. 954 61

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a significant role in regulating angiogenesis, the process of new blood vessel formation. Interstitial collagenase (MMP-1), 72 kDa gelatinase A/type IV collagenase (MMP-2), and 92 kDa gelatinase B/type IV collagenase (MMP-9) dissolve extracellular matrix (ECM) and may initiate and promote angiogenesis. TIMP-1, TIMP-2, TIMP-3, and possibly, TIMP-4 inhibit neovascularization. A new paradigm is emerging that matrilysin (MMP-7), MMP-9, and metalloelastase (MMP-12) may block angiogenesis by converting plasminogen to angiostatin, which is one of the most potent angiogenesis antagonists. MMPs and TIMPs play a complex role in regulating angiogenesis. An understanding of the biochemical and cellular pathways and mechanisms of angiogenesis will provide important information to allow the control of angiogenesis, e.g. the stimulation of angiogenesis for coronary collateral circulation formation; while the inhibition for treating arthritis and cancer.
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PMID:Complex role of matrix metalloproteinases in angiogenesis. 979 30

Evidence presented in the accompanying article (Gibbs, D. F., T. P. Shanley, R. L. Warner, H. S. Murphy, J. Varani, and K. J. Johnson. 1999. Role of matrix metalloproteinases in models of macrophage-dependent acute lung injury: evidence for alveolar macrophage as source of proteinases. Am. J. Respir. Cell Mol. Biol. 20:1145-1154) implicates alveolar macrophage matrix metalloproteinases (MMPs) in two models of acute lung inflammation in the rat. As a prerequisite to understanding which specific MMPs might be involved in the injury and how they might function, it was necessary to know the spectrum of enzymes present. To this end, alveolar macrophages were obtained from normal rat lungs by bronchoalveolar lavage, placed in culture with and without various agonists, and assessed by a variety of techniques for MMPs. The identification process involved characterization by gelatin, beta-casein, and kappa-elastin zymography, with confirmation of identity by Western blot/immunoprecipitation. Message levels of detected MMPs were assessed by Northern blot. Rat alveolar macrophages were found to produce a low constitutive level of MMP-2 (72-kD gelatinase A) that was only modestly upregulated following stimulation with phorbol myristate acetate, bacterial lipopolysaccharide, or immunoglobulin A-containing immune complexes. Although control cells were found to produce little or no MMP-9 (92-kD gelatinase B) or MMP-12 (metalloelastase), both enzymes were markedly upregulated upon stimulation. In the same stimulated macrophages there was little activity against type I collagen (associated with MMP-13 [collagenase-3] on the basis of Western blotting), no activity suggestive of stromelysin or matrilysin, and no measurable secretion of the serine proteinases, elastase and cathepsin G. These data demonstrate the ability of rat alveolar macrophages to elaborate certain MMPs under proinflammatory conditions, consistent with their possible involvement in the progression of acute inflammation.
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PMID:Characterization of matrix metalloproteinases produced by rat alveolar macrophages. 1034 Sep 32

Photodamage is characterized by degradation of collagen and accumulation of abnormal elastin in the superficial dermis and several matrix metalloproteinases have previously been implicated in this process. Using immunohistochemistry and in situ hybridization, we have studied the localization of two elastolytic matrix metalloproteinases, matrilysin (matrix metalloproteinase-7) and human macrophage metalloelastase (matrix metalloproteinase-12) in solar damage. Human macrophage metalloelastase protein was detected in the superficial dermis in areas of elastotic material. Matrix metalloproteinase-7 was seen in the mid-dermis in regions with less damaged elastic fibers and morphologically better preserved collagen as well as in a band-like pattern below basal keratinocytes in eight of 18 solar elastosis. In samples taken from healthy volunteers 3 d after repeated ultraviolet A or ultraviolet B photoprovocation, occasional immunopositive cells for human macrophage metalloelastase (stromal) or matrix metalloproteinase-7 (sweat gland epithelium) were detected. In samples taken 1 d after ultraviolet B exposure, however, basal keratinocytes were matrix metalloproteinase-7 immunopositive, explaining the linear immunostaining below basal keratinocytes noted particularly in ultraviolet B treated 3 d specimens. Upregulation of metalloelastase was also demonstrated in the skin of hairless mice after repeated ultraviolet exposure. In normal skin, no staining for human macrophage metalloelastase or matrix metalloproteinase-7 was observed in association with elastin. The amount of immunoreactivity for the substrates of matrix metalloproteinase-7, versican, and tenascin, was clearly increased in solar elastosis and photoprovocated skin; versican but not tenascin was detected in the same areas as matrix metalloproteinase-7. Our results suggest that both matrix metalloproteinase-7 and -12 may contribute to remodeling of elastotic areas in sun-damaged skin.
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PMID:Accumulation of matrilysin (MMP-7) and macrophage metalloelastase (MMP-12) in actinic damage. 1050 57

We report the discovery, cloning, and characterization of a novel human matrix metalloproteinase 26 (MMP-26) (matrixin) gene, endometase, an endometrial tumor-derived metalloproteinase. Among more than three million expressed sequence tags sequenced, the endometase gene was only obtained from human endometrial tumor cDNA library. Endometase mRNA was expressed specifically in human uterus, not in other tissues/cells tested, e.g. testis, heart, brain, lungs, liver, thymus, and melanoma G361. Endometase protein has a signal peptide, a propeptide domain, and a catalytic domain with a unique "cysteine switch" propeptide sequence, PHCGVPDGSD, and a zinc-binding motif, VATHEIGHSLGLQH. Endometase is 43, 41, 41, and 39% identical to human metalloelastase, stromelysin, collagenase-3, and matrilysin, respectively. The zymogen was expressed and isolated from Escherichia coli as inclusion bodies with a molecular mass of 28 kDa. The identity and homogeneity of the recombinant protein was confirmed by protein N-terminal sequencing, silver stain, and immunoblot analyses. The pro-enzyme was partially activated during the folding process. Endometase selectively cleaved type I gelatin and alpha(1)-proteinase inhibitor; however, it did not digest collagens, laminin, elastin, beta-casein, plasminogen, soybean trypsin inhibitor, or Bowman-Birk inhibitor. It hydrolyzed peptide substrates of matrixins and tumor necrosis factor-alpha converting enzyme. Endometase may selectively cleave extracellular matrix proteins, inactivate serpins, and process cytokines.
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PMID:Identification and characterization of human endometase (Matrix metalloproteinase-26) from endometrial tumor. 1080 41

The capacity of inflammatory cell-derived matrix metalloproteinases (MMPs) to cleave tissue factor pathway inhibitor (TFPI) and alter its activity was investigated. MMP-7 (matrilysin) rapidly cleaved TFPI to a major 35-kDa product. In contrast, MMP-1 (collagenase-1), MMP-9 (gelatinase B), and MMP-12 (macrophage elastase) cleaved TFPI into several fragments including the 35-kDa band. However, rates of cleavage were most rapid for MMP-7 and MMP-9. NH(2)-terminal amino acid sequencing revealed that MMP-12 cleaved TFPI at Lys(20)-Leu(21)(close to Kunitz I domain and producing a 35-kDa band), Arg(83)-Ile(84) (between Kunitz I and II domains), and Ser(174)-Thr(175) (between Kunitz II and III domains). MMP-7 and MMP-9 cleaved TFPI at Lys(20)-Leu(21) with additional COOH-terminal processing. These MMPs did not cleave tissue factor (TF), factor VII, and factor Xa. Proteolytic cleavage by MMP-1, MMP-7, MMP-9, and MMP-12 resulted in considerable loss of TFPI activity. These observations indicate specific cleavage of TFPI by MMPs, which broadens their substrate profile. Co-localization of MMPs, TF, and TFPI in atherosclerotic tissues suggests that release of MMPs from inflammatory cell leukocytes may effect TF-mediated coagulation.
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PMID:Matrix metalloproteinases cleave tissue factor pathway inhibitor. Effects on coagulation. 1085 19

The effects of plasma proteins on controlling the activity of matrix metalloproteinases (MMPs, matrixins) have been the focus of numerous studies, although only a few have examined the influence of matrixins on plasma proteins. Recently, it has been shown that MMPs may play a role in the degradation of fibrin. We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. Our data demonstrate that the catalytic domains of MMP-8, MMP-12, MMP-13, and MMP-14 can proteolytically process fibrinogen and, with the exception of MMP-8, also inactivate Factor XII (Hageman factor). We have identified the amino termini of the major protein fragments. Cleavage of fibrinogen occurred in all chains and resulted in significantly impaired clotting. Moreover, rapid proteolytic inactivation of Factor XII (Hageman factor) by MMP-12, MMP-13, and MMP-14 was noted. These results support the hypothesis of an impaired thrombolytic potential of MMP-degraded Factor XII in vivo. MMP-induced degradation of fibrinogen supports a plasmin-independent fibrinolysis mechanism. Consequently, degradation of these proteins may be important in inflammation, atherosclerosis, and angiogenesis, all of which are known to be influenced by MMP activity.
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PMID:Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII. 1093 Mar 99


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