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:3.4.24.35 (matrix metalloproteinase 9)
2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activation of human neutrophil progelatinase B (pro-HNG) by a variety of proteolytic and non-proteolytic activators has been investigated. A quantitative comparison of the activation efficiencies of treatments previously reported to activate pro-HNG or the related gelatinase B species produced by other cells demonstrates that stromelysin and trypsin are good activators. HgCl2 is a moderately effective activator, while p-chloromercuribenzoate and NaOCl are poor activators. It is also shown that human matrilysin and human fibroblast-type collagenase can activate pro-HNG by a mechanism that is very similar to that of stromelysin. Initially, these proteinases hydrolyze the Glu40-Met41 bond in the propeptide domain to generate an 88 kDa inactive HNG species. Collagenase also generates a 68 kDa HNG species through hydrolysis of the Ala74-Met75 bond. Ultimately, treatment with either matrilysin, collagenase or trypsin results in the production of a 65 kDa active form of HNG that arises from hydrolysis of the Arg87-Phe88 bond. This is the same active species produced on activation by stromelysin. This cleavage site is downstream of the 'cysteine-switch' residue located at position 80 and releases it, accounting for the permanent activation of the enzyme. These results suggest that matrilysin and collagenase may be physiologically relevant activators of pro-HNG and/or other progelatinase B species. Activation by HgCl2 produces an active 68 kDa enzyme due to autolytic hydrolysis of the Ala74-Met75 bond. This species retains the cysteine switch residue; however, it is shown that it is only active in the continued presence of HgCl2. Removal of the HgCl2 restores latency, indicating that this species is reversibly activated by HgCl2, which functions by complexing the sulfhydryl group of the cysteine switch residue and keeping it dissociated from the active site zinc atom. Thus, in spite of reports to the contrary, the cysteine switch mechanism can account for the latency and activation of pro-HNG.
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PMID:Proteolytic and non-proteolytic activation of human neutrophil progelatinase B. 766 17

The network of both intra- and intercellular, either physical (bioconductive connectional system) and/or chemical signals, plays a significant role in the maintenance of tissue architecture and integrity of epithelial cell layers. The basement membrane is not only a static barrier but a dynamic regulator of the urothelium. Any change in the basement membrane can lead, by the extracellular matrix-cytoskeleton-nuclear matrix interaction, to altered gene regulation of the urothelial cells. Abnormal production and deposition or proteolytic degradation of the extracellular matrix components correlate with tumour stage and progression. In some experimental models, tissue inhibitors of metalloproteinases or anti-proteinase antibodies can abrogate the proteolytic activity of those matrix metalloproteinase enzymes (collagenase IV, cathepsin, stromelysin, etc.) which promote tumour invasion. Finally, the current researches investigating the use of biologic protein (e.g., TIMP-1 e-2; agents that affect angiogenesis and spread of neoplasias) are aimed at offer new therapeutic opportunities in oncology.
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PMID:[Urothelial tumors and the extracellular matrix]. 768 89

The actions of human recombinant stromelysins-1 and -2, collagenase, gelatinases A and B and matrilysin on neonatal human proteoglycan aggregates were examined. With the exception of gelatinase B, aggrecan was degraded extensively by most metalloproteinases studied, whereas link protein showed only limited proteolysis. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Cleavage at the former bond generated a link protein component with the same N-terminus as that isolated from newborn human cartilage. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.
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PMID:Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. 769 69

We have compared the effects of a general matrix metalloproteinase (MMP) inhibitor (CT435) with those of a concentration-dependent specific gelatinase inhibitor (CT543; Ki < 20 nM) on bone resorption in vitro. The test systems consisted of measuring: (i) the release of 45Ca2+ from prelabelled mouse calvarial explants; (ii) the release of 45Ca2+ from prelabelled osteoid-free calvarial explants co-cultured with purified chicken osteoclasts; and (iii) lacunar resorption by isolated rat osteoclasts cultured on ivory slices. Both CT435 and CT543 dose-dependently inhibited the release of 45Ca2+ from neonatal calvarial bones stimulated by either parathyroid hormone or 1,25-dihydroxyvitamin D3. Moreover, CT543 produced a 40% inhibition at a concentration (10(-8) M) selective for the inhibition of human gelatinases A and B. CT435 (10(-5) M) and CT543 (10(-5) M) partially inhibited the release of 45Ca2+ from osteoid-free calvarial explants by chicken osteoclasts with a maximum of approximately 25% for unstimulated cultures, and approximately 36% for cultures stimulated by interleukin-1 alpha (IL-1 alpha; 10(-10) M). Neither inhibitor prevented lacunar resorption on ivory by unstimulated rat osteoclasts, but the compounds produced a partial reduction in both the number and total surface area of lacunae in IL-1 alpha-stimulated cultures, with maximal action at 10(-5) M. Neither of the inhibitors affected protein or DNA synthesis, nor the IL-1 alpha-stimulated secretion of the lysosomal enzyme beta-glucuronidase. Immunocytochemistry demonstrated that isolated rabbit osteoclasts constitutively expressed gelatinase A and synthesized gelatinase B, collagenase and stromelysin, as well as the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) following IL-1 alpha stimulation. These experiments have shown that in addition to collagenase, gelatinases A and B are likely to play a significant role in bone resorption. They further suggest that MMPs produced by osteoclasts are released into the sub-osteoclastic resorption zone where they participate in bone collagen degradation.
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PMID:The effects of selective inhibitors of matrix metalloproteinases (MMPs) on bone resorption and the identification of MMPs and TIMP-1 in isolated osteoclasts. 769 5

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

In addition to the known 94-kd gelatinase (matrix metalloproteinase 9, MMP-9), HL-60 leukemia cells release a hither-to undescribed 45-kd metalloproteinase into the culture medium. This enzyme cleaves the synthetic substrate Pro-Gln-Gly-Ile-Ala-Gly-Gln-Arg, which represents the cleavage site for collagenases in collagen type I not between isoleucine and alanine--the typical cleavage site for collagenases--but between alanine and glycine. The enzymatic activity was purified through a combination of zinc-chelate-Sepharose column chromatography, precipitation with Fractogel TSK-AF Red and gelatin-Sepharose, and subsequent sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Microsequence analysis of the NH2-terminus of the purified 45-kd proteinase revealed the sequence Asp-Ile-Ser-Lys-Tyr-Thr-Thr-Thr-, which could not be found in other proteins when searched in several protein data bases. Incubation of the enzyme immobilized on nitrocellulose membranes with polyclonal antibodies to collagenase and stromelysin or gelatinases revealed no cross-reactivity. The proteolytic activity was not increased by treatment with trypsin, 8M urea, acid, or organomercurials. The proteinase, which was inhibited by chemical inhibitors of metalloproteinases, such as phenanthrolene or EDTA, is able to degrade several matrix constituents, such as collagen type IV, fibronectin, gelatin, and proteoglycans. In contrast to all known MMPs, the proteolytic activity of the 45-kd enzyme was not abolished upon incubation with recombinant tissue inhibitors of matrix metalloproteinases (TIMP) 1 or 2. Thus, the novel enzyme may influence extracellular matrix (ECM) turnover in vivo because its activity is not influenced by specific inhibitors of MMPs.
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PMID:Leukemic cells (HL-60) produce a novel extracellular matrix-degrading proteinase that is not inhibited by tissue inhibitors of matrix metalloproteinases (TIMPs). 782 72

Monocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaques. Peripheral blood monocytes in culture can produce certain enzymes that degrade extracellular matrix, known as matrix metalloproteinases (MMPs). Lipid-laden macrophages may thus contribute to weakening of extracellular matrix of rupture-prone atherosclerotic plaques. However, the spectrum and regulation of MMP production by foam cells remain unknown. To investigate this issue, we isolated lipid-laden macrophages from rabbit aortic lesions produced by a combination of hypercholesterolemia and balloon injury. Freshly isolated aortic macrophage foam cells, identified using cell-specific antibodies, contained immunoreactive stromelysin and interstitial collagenase, whereas alveolar macrophages isolated from the lungs of same rabbits did not. Macrophages from both tissue sources released gelatinolytic activity consistent with the 92-kDa gelatinase. In vitro, lipid-laden aortic macrophages, but not alveolar macrophages, synthesized de novo and released immunoprecipitable stromelysin and collagenase, with or without stimulation by phorbol ester or bacterial lipopolysaccharide. These stimuli caused foam cells to release additional gelatinolytic activity that migrated faster than a purified preparation of 92-kDa gelatinase in substrate-containing polyacrylamide gels, indicating activation of the 92-kDa gelatinase or induction of the 72-kDa gelatinase. Our results show that lipid-laden macrophages elaborate MMPs capable of degrading the major constituents of vascular extracellular matrix even without further stimulation. Therefore, these cells may contribute to remodeling of the extracellular matrix during atherogenesis and to the disruption of plaques often responsible for acute clinical manifestations of atherosclerosis.
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PMID:Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. 783 Dec 99

Type XIV collagen is a newly described member of the fibril-associated collagens with interrupted triple helices (FACITs). Expression of this collagen has been localized to various embryonic tissues, suggesting that it has a functional role in development. All FACITs thus far described (types IX, XII, XIV, and XVI) contain a highly homologous carboxyl-terminal triple helical domain designated COL1. We have studied the capacity of various matrix metalloproteinases (interstitial collagenase, stromelysin, matrilysin, and 92-kDa gelatinase) to degrade the COL1 domain of collagen XIV. We found that only 92-kDa gelatinase cleaves COL1. Furthermore, digestion of whole native collagen XIV by the 92-kDa gelatinase indicates that this enzyme specifically attacks the carboxyl-terminal triple helix-containing region of the molecule. COL1 is cleaved by 92-kDa gelatinase at 30 degrees C, a full 5-6 degrees C below the melting temperature (Tm) of this domain; native collagen XIV is also degraded at 30 degrees C. In comparison to interstitial collagenase degradation of its physiologic native type I collagen substrate, the 92-kDa enzyme cleaved COL1 (XIV) with comparable catalytic efficacy. Interestingly, following thermal denaturation of the COL1 fragment, its susceptibility to 92-kDa gelatinase increases, but only to a degree that leaves it several orders of magnitude less sensitive to degradation than denatured collagens I and III. These data indicate that native COL1 and collagen XIV are readily and specifically cleaved by 92-kDa gelatinase. They also suggest a role for 92-kDa gelatinase activity in the structural tissue remodeling of the developing embryo.
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PMID:Degradation of the COL1 domain of type XIV collagen by 92-kDa gelatinase. 783 60

The matrix metalloproteinase 92-kDa gelatinase is a major product of inflammatory cells. Macrophages synthesize and secrete this proteinase as a proenzyme in association with tissue inhibitor of metalloproteinases (TIMP) (92TIMP), whereas neutrophils store and release it from secondary granules as a TIMP-free proenzyme (92TIMP-free). Metalloproteinase proenzymes can be activated in vitro by a variety of agents, including organomercurials and proteinases, resulting in loss of an 8-10-kDa NH2-terminal domain which disrupts the interaction of a conserved cysteine residue with the catalytic zinc molecule. We report that the activation and processing of 92-kDa gelatinase differs depending on its association with TIMP and the nature of the activating agent. We observed that 92TIMP undergoes classic activation to 82 kDa by stromelysin, whereas exposure to 4-aminophenylmercuric acetate (APMA) results in a final product of 83 kDa that still contains the "prodomain" cysteine. Association with TIMP appears to stabilize the COOH-terminal domain, whereas 92TIMP-free is converted by APMA to a final product of 67 kDa lacking the COOH-terminal portion. In the continued presence of APMA, which maintains cysteine-zinc disruption, the 67-kDa species is at least as active as the classic 82 kDa. In contrast, activation of 92TIMP-free by stromelysin initially generates the 82-kDa form which is followed by final conversion to a 50-kDa species that lacks the catalytic domain of the parent molecule. Therefore, although stromelysin activation of 92TIMP-free is initially efficient, the active 82-kDa form is short-lived and is replaced by an inactive 50-kDa product. This complex pattern of activation of the 92-kDa gelatinase may serve to restrict its proteolytic capacity following exposure to stromelysin and may serve to regulate proteinase activity in vivo.
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PMID:Activation of the 92-kDa gelatinase by stromelysin and 4-aminophenylmercuric acetate. Differential processing and stabilization of the carboxyl-terminal domain by tissue inhibitor of metalloproteinases (TIMP). 789 Jul 73

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


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