Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrilysin (PUMP, MMP-7) is a member of the metalloprotease gene family, whose constituents are responsible for the remodeling of extracellular matrix. The matrilysin protein is a 28-kDa zymogen possessing catalytic activities against a broad range of extracellular matrix substrates including proteoglycans, gelatin, fibronectin, laminin, and elastin. To gain insights into the biological expression of matrilysin in human cell types, we generated a monospecific, polyclonal antibody against a 16-amino acid sequence derived from its catalytic domain, a region which lacked significant homology with other matrix metalloenzymes. We found this antibody capable of precipitating a 28-kDa protein from the conditioned media of human bone marrow-derived promonocytes and human peripheral blood monocytes cultivated in vitro. Promonocyte matrilysin was rapidly converted to a 19-kDa form by organomercurial activation. While matrilysin was constitutively synthesized by bone marrow-derived promonocytes, its secretion was markedly up-regulated by the mononuclear phagocyte activator, lipopolysaccharide. Furthermore, despite its expression in monocyte precursors, blood monocytes, and monocyte-derived macrophages, matrilysin was not synthesized by human alveolar macrophages under any tested condition. In situ hybridization studies with matrilysin cRNA confirmed the presence of specific mRNA in both human promonocytes and monocytes. Moreover, a marked increase in hybridizable mRNA was observed with lipopolysaccharide treatment suggesting that matrilysin synthesis is pretranslationally regulated. In summary, this represents the first report documenting constitutive and regulated synthesis of matrilysin by a normal human cell type and suggests that matrilysin is expressed as a significant secreted product of mononuclear phagocytes at an intermediate stage of cellular differentiation.
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PMID:The matrix metalloprotease matrilysin (PUMP) is expressed in developing human mononuclear phagocytes. 137 84

The uterus of the rat contains a small metalloproteinase that digests Azocoll and proteoglycan. The activity of this enzyme is elevated in the postpartum uterus and parallels the rate of breakdown of matrix proteoglycan (Sellers, A. and Woessner, J.F., Jr., Biochem. J. 189: 521, 1980). The enzyme has been purified to homogeneity. Its molecular weight is 28,000 for the latent form of the enzyme and 19,000 for the active form, as determined by SDS/PAGE. The enzyme has no action on collagens of type I, III, IV or V, but it does digest gelatins of these 4 types. Digestion of type I gelatin is most pronounced for the alpha-2 chain, which is cleaved to two major bands. The B chain of insulin is cleaved at Ala14-Leu15 and Tyr16-Leu17. Proteoglycan is degraded, but no action can be detected against elastin. Both zinc and calcium ions are required for activity. Low levels of phosphoramidon or Zincov are not inhibitory. Detailed comparisons with human gelatinase (matrix metalloproteinase 2) and stromelysin (matrix metalloproteinase 3) show that the uterine proteinase has a distinctive pattern of specificity. The properties match those of human Pump-1 as reported by Quantin et al., Biochemistry 28: 5327, 1989. It is proposed to designate this proteinase as matrix metalloproteinase 7.
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PMID:The small matrix metalloproteinase of the rat uterus. 148 88

A small metalloproteinase that digests Azocoll was found in the uterus of the rat. Its activity increased to high levels during the postpartum period in parallel with the breakdown of the extracellular matrix exclusive of collagen (Sellers, A., and Woessner, J.F., Jr. (1980) Biochem. J. 189, 521-531). This enzyme has now been purified almost 7,000-fold to homogeneity from 12 g of tissue using molecular sieve chromatography, blue sepharose chromatography, and zinc-chelate chromatography. Gel electrophoresis with sodium dodecyl sulfate and dithiothreitol gives Mr = 28,000 for the latent form of the enzyme and Mr = 19,000 for the active form that arises spontaneously or by treatment with aminophenylmercuric acetate. The enzyme digests components of the extracellular matrix including gelatins of types I, III, IV, and V, fibronectin, and proteoglycan. It digests the alpha 2(I) chain of gelatin in preference to the alpha 1(I) chain and cleaves dinitrophenyl-Pro-Leu-Gly-Ile-Ala-Gly-Pro-D-Arg. It cleaves the B chain of insulin at two points: Ala14-Leu15 and Tyr16-Leu17. It has no action on collagens of types I, III, IV, or V at 26 degrees C and no action on elastin or phenylazo-Pro-Leu-Gly-Pro-D-Arg. The pH optimum is at pH 7 and the pI at 5.9. The enzyme requires zinc and calcium ions for activity; cobalt and strontium can partially replace these metal ions. The enzyme is not inhibited by low levels of phosphoramidon or Zincov. Its properties clearly distinguish it from collagenase, gelatinase (matrix metalloproteinase 2), and stromelysin (matrix metalloproteinase 3); it therefore constitutes a further member of the family of extracellular matrix metalloendopeptidases. The name matrix metalloproteinase 7 is proposed.
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PMID:Purification and properties of a small latent matrix metalloproteinase of the rat uterus. 318 22

A small uterine metalloproteinase of the rat has been shown by amino acid and cDNA sequencing to be orthologous to human pump-1. Both proteinases are now designated as matrilysin or matrix metalloproteinase 7. The properties of purified uterine metalloproteinase and recombinant pump-1 were compared. Their specificities on substrates (gelatins, fibronectin, transferrin, elastin, Azocoll, and (7-methoxycoumarin-4-yl)acetyl-Pro-Leu-Gly-Leu-(3,[2, 4-dinitrophenyl]-L-2, 3-diaminopropionyl)-Ala-Arg-NH2) are similar and distinct from those of the stromelysins and gelatinases. The two matrilysins have similar sensitivity to hydroxamate and pseudopeptide inhibitors. Rat matrilysin selectively cleaves the alpha 2(I) chain of rat gelatin, producing major cuts at Gly713-decreases-Ile714, Gly775-decreases-Leu776, and Gly809-decreases-Ile810. Rat matrilysin produces maximum activation of latent human interstitial collagenase 1 (pro-matrix metalloproteinase 1) when added in the presence of 4-aminophenylmercuric acetate (APMA) by cleaving the Gln80-decreases-Phe81 bond. Rat and human matrilysin do not directly activate latent rat collagenase 3 (matrix metalloproteinase 13) and do not enhance its activation when added together with APMA. Autoactivation of collagenase 3 in the presence of APMA results in cleavage at Val81-decreases-Tyr82 corresponding to the Gln80-decreases-Phe81 cleavage in collagenase 1. Thus collagenase 3 is capable of maximal autoactivation, whereas collagenase 1 is dependent upon another matrix metalloproteinase in order to be activated to its full potential.
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PMID:Characterization of rat uterine matrilysin and its cDNA. Relationship to human pump-1 and activation of procollagenases. 760 62

Human macrophages are believed to damage host tissues in chronic inflammatory disease states, but these cells have been reported to express only modest degradative activity in vitro. However, while examining the ability of human monocytes to degrade the extracellular matrix component elastin, we identified culture conditions under which the cells matured into a macrophage population that displayed a degradative phenotype hundreds of times more destructive than that previously ascribed to any other cell population. The monocyte-derived macrophages synthesized elastinolytic matrix metalloproteinases (i.e., gelatinase B and matrilysin) as well as cysteine proteinases (i.e., cathepsins B, L, and S), but only the cathepsins were detected in the extracellular milieu as fully processed, mature enzymes by either vital fluorescence or active-site labeling. Consistent with these observations, macrophage-mediated elastinolytic activity was not affected by matrix metalloproteinase inhibitors but could be almost completely abrogated by inhibiting cathepsins L and S. These data demonstrate that human macrophages mobilize cysteine proteinases to arm themselves with a powerful effector mechanism that can participate in the pathophysiologic remodeling of the extracellular matrix.
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PMID:Pericellular mobilization of the tissue-destructive cysteine proteinases, cathepsins B, L, and S, by human monocyte-derived macrophages. 773 94

Matrilysin is a recently described metalloproteinase with strong catalytic activity against a variety of extracellular matrix substrates including proteoglycans, elastin, laminin, fibronectin, gelatin, and entactin. Production of this metalloproteinase appears to be limited only to a few normal human cell types including glandular epithelium, mononuclear phagocytes, and renal mesangial cells. Furthermore, matrilysin expression in vivo has been demonstrated only in glandular epithelium, especially the endometrium. In the process of examining various cutaneous and lung inflammatory disorders for matrilysin expression by immunohistochemistry and in situ hybridization, we occasionally found monocytes within blood vessels and newly extravasated tissue-associated macrophages that exhibited matrilysin production. In specimens characterized by severe inflammation and, in particular, cystic fibrosis, this feature was commonly observed. We therefore studied the production of matrilysin by monocyte-derived macrophages in vitro in response to various physiologic signals such as endotoxin, phagocytosable material, cytokines, and hormones. We found that matrilysin expression was stimulated by LPS and opsonized zymosan. Up-regulation of matrilysin by LPS was PGE2-dependent, because indomethacin blocked production, an effect at least partially reversed by the addition of exogenous prostaglandin. LPS stimulated matrilysin production pretranslationally and, furthermore, when cultured cells were subjected to in situ hybridization after LPS exposure, considerable variability in matrilysin mRNA expression was observed on an individual cell basis, with some cells having strong signal and others being completely negative. We also found that matrilysin biosynthesis was inhibited by the lymphokines IL-4, IL-10, and IFN-gamma. Other cytokines such as IL-1, TNF-alpha, and IL-6 failed to modulate the production of matrilysin. Finally, matrilysin biosynthesis was suppressed by glucocorticoids and retinoids. Our studies indicate that matrilysin is produced in vivo by mononuclear phagocytes and is a highly regulated metalloproteinase whose production can be modified by a variety of physiologic and pharmacologic signals.
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PMID:Matrilysin expression by human mononuclear phagocytes and its regulation by cytokines and hormones. 775 83

Matrix metalloproteinase 7 (MMP-7) has been purified as an inactive zymogen of M(r) 28,000 (proMMP-7) from the culture medium of CaR-1 human rectal carcinoma cells. The NH2-terminal sequence of proMMP-7 is Lys-Pro-Lys-Pro-Gln-Glu, which is identical to that of matrilysin. The zymogen is activated by 4-aminophenylmercuric acetate (APMA), yielding an intermediate form of M(r) 21,000 and an active species of M(r) 19,000 which shows the new NH2-terminal sequence of Tyr78-Ser-Leu-Phe-Pro-Asn-Ser. Although trypsin fully activates the zymogen, the activation rate by plasmin or leukocyte elastase is confined to approximately 50%. ProMMP-7 can be activated by MMP-3 (stromelysin 1) to its full activity in a single-step mechanism and generates the same NH2 terminus obtained by APMA activation, whereas MMP-1 (tissue collagenase), MMP-2 (gelatinase A), and MMP-9 (gelatinase B) do not have such an effect. On the other hand, proMMP-1 is activated by MMP-7 to an activity similar to that obtained by APMA and the activation by MMP-7 is enhanced up to approximately 6.5 fold in the presence of APMA. This enhanced activity is donated by specific cleavage at the Gln80-Phe81 bond of proMMP-1. MMP-7 can also activate proMMP-9 up to approximately 50% of the full activity with a new NH2 terminus of Leu16-Arg-Thr-(Asn)-Leu. Incubation of proMMP-2 or proMMP-3 with MMP-7 results in no activation of these proMMPs. MMP-7 degrades type IV collagen, laminin-1, fibronectin, proteoglycan, type I gelatin, and insoluble elastin. These results suggest that in vivo MMP-7 may play a role in degradation of extracellular matrix macromolecules in concert with MMP-1, -3, and -9 under pathological conditions.
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PMID:Matrix metalloproteinase 7 (matrilysin) from human rectal carcinoma cells. Activation of the precursor, interaction with other matrix metalloproteinases and enzymic properties. 789 11

Mononuclear phagocytes have the capacity to produce an array of MMPs. Several of these proteinases are capable of degrading insoluble elastin, an important component for the structural stability of the lung. Matrilysin is a low molecular weight proteinase with a broad substrate specificity produced at highest levels in in vitro differentiated monocytes. The 92-kD gelatinase is a major product of human alveolar macrophages that is also an elastase. The most newly described member of the MMP family is human macrophage metalloelastase. This enzyme is also expressed in alveolar macrophages derived from cigarette smokers. Determining the contribution of these and other elastolytic proteinases to the pathogenesis of emphysema is a focus of ongoing research.
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PMID:Elastolytic metalloproteinases produced by human mononuclear phagocytes. Potential roles in destructive lung disease. 795 53

Several matrix metalloproteinases, including the 92-kDa and 72-kDa gelatinases, macrophage metalloelastase (MME), and matrilysin degrade insoluble elastin. Because elastolytically active MME and matrilysin consist only of a catalytic domain (CD), we speculated that the homologous CDs of the 92-kDa and 72-kDa gelatinases would confer their elastolytic activities. In contrast to the MME CD, the 92 and 72 CDs expressed in Escherichia coli (lacking the internal fibronectin type II-like repeats) had no elastase activity, although both were gelatinolytic and cleaved a thiopeptolide substrate at rates comparable to the full-length gelatinases. To test the role of the fibronectin type II-like repeats in elastolytic activity, we expressed the 92-kDa gelatinase CD with its fibronectin type II-like repeats (92 CD/FN) in yeast. 92 CD/FN degraded insoluble elastin with activity comparable to full-length 92-kDa gelatinase. 92 and 72 CDs lacking the fibronectin type II-like repeats did not bind elastin, whereas the parent enzymes and 92 CD/FN did bind elastin. Furthermore, recombinant 92-kDa fibronectin type II-like repeats inhibited binding of the 92-kDa gelatinase to elastin. We conclude that the 92- and 72-kDa gelatinases require the fibronectin type II-like repeats for elastase activity.
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PMID:The structural basis for the elastolytic activity of the 92-kDa and 72-kDa gelatinases. Role of the fibronectin type II-like repeats. 862 82

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


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