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)

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

(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

Nuclear matrins are proteins that localize to the internal nuclear matrix. In a previous study, we reported that histone deacetylase is a component of the internal matrix, suggesting that histone deacetylase is a nuclear matrin. Here, we demonstrate that the majority of the histone deacetylase activity is associated with the internal nuclear matrices of chicken and trout liver. Thus, the association of the histone deacetylase with the internal nuclear matrix is neither tissue- nor species-specific. Using histone deacetylase as a marker enzyme for the partitioning of the internal nuclear matrix during nuclear fractionations, we show that in contrast to the internal nuclear matrices of trout liver, trout hepatocellular carcinoma and chicken liver, the stability of the chicken erythrocyte internal nuclear matrix is temperature-dependent. Our results support a model that has the histone deacetylase mediating transient interactions between the internal nuclear matrix and chromatin regions undergoing dynamic acetylation, for example transcriptionally active chromatin regions.
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PMID:Nuclear distribution of histone deacetylase: a marker enzyme for the internal nuclear matrix. 156 6

The mesangial cell MMPs and their inhibitor may represent proteins through which biological modifiers such as cytokines and growth factors can control and influence the organization of the glomerulus. At the present we can only speculate on their exact function in glomerular disease. They could conceivably play a role in glomerular conditions where mesangial hypercellularity and cytoplasmic interposition between the endothelium and the basement membrane are frequent occurrences, and in which cytokine-enhanced synthesis of matrix-degrading enzymes could result in severe structural damage. A number of glomerular diseases such as diabetic nephropathy are characterized by the accumulation of glomerular matrix proteins. This could be explained by the inappropriate expression of intrinsic mesangial cell MMPs or TIMP. Further investigation of these proteins in experimental models of glomerular disease or in situ hybridization studies using the available probes promises to be a rewarding area of research during the next few years. For these studies the availability of rTIMP and recent developments in the design of synthetic inhibitors of MMPs may allow more searching investigations into the role of MMP in the pathophysiology of glomerular disease.
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PMID:Proteinases and glomerular matrix turnover. 157 45

The enzyme responsible for the metalloproteinase activity which cleaves the Glu143-Leu144 bond of (pro)urokinase has been isolated from the conditioned medium of cultured normal human kidney cells. Using S-Sepharose and Cibacron Blue-agarose chromatography, then C-4 reversed phase high pressure liquid chromatography, a protein of about 20,000 Da was isolated. Through an identical amino-terminal sequence, the protein was shown to be the matrix metalloproteinase previously referred to in the literature as "pump-1" (putative metalloproteinase). When aprotinin was added during the course of the purification, the major species isolated was the zymogen form (28,000 Da) of pump-1. Pump-1 has been shown to efficiently cleave the susceptible bond of both pro-urokinase (single-chain) and active (two-chain) urokinase and thereby produce the corresponding low molecular weight forms. The amino-terminal sequences of the A and B chains of low molecular weight urokinase prepared by action of pump-1 on recombinant high molecular weight urokinase are identical to those of the low molecular weight urokinase isolated from human kidney cell culture. Since the reaction of urokinase with this metalloproteinase results in separation of its serine proteinase region from the domain which mediates binding to the urokinase receptor, it may be of importance in the regulation of the functional activity of the plasminogen activator in cellular processes.
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PMID:The matrix metalloproteinase pump-1 catalyzes formation of low molecular weight (pro)urokinase in cultures of normal human kidney cells. 162 80

The gene for PUMP (putative metalloproteinase), a human matrix metalloproteinase, was synthesized by a PCR-based method. The DNA fragment of 546 bases containing the PUMP gene was generated by overlap extension of six long oligonucleotides (length ranging from 101 to 116 bases) and subsequent amplification by two short terminal oligonucleotide primers (length from 20 to 48 bases) in one pot without using restriction and ligation enzymes. The synthetic gene was cloned into a T7 expression vector in two ways to express PUMP as a non-fusion protein. Both constructs showed high level expression in E. coli.
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PMID:Gene synthesis and expression in E. coli for pump, a human matrix metalloproteinase. 163 63

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

Epithelial cell lines (BC1, BC3, BC4, and BC5), derived from 4 separate invasive and metastatic rat mammary carcinomas, all secreted interstitial collagenase (matrix metalloproteinase 1, MMP 1) in culture. Neither a cloned cell line (A5P/B10), derived from a noninvasive rat epithelial tumor, nor nonneoplastic rat fibroblasts secreted the enzyme. Western blot analyses of proteins extracted from the plasma membranes indicated the presence of interstitial collagenase (MMP 1) on the surface of all of the 6 cell lines. These data suggest that the control of collagenolysis may involve the association of collagenase molecules with the plasma membrane. The aggressiveness of malignant tumors may be due in part to the breakdown of such a control.
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PMID:Interstitial collagenase (matrix metalloproteinase 1) associated with the plasma membrane of both neoplastic and nonneoplastic cells. 165 15

Interleukin 1 (IL-1) mediates many cellular functions, but the signal transduction mechanisms of its actions are not clearly understood. Here, we have examined the exact participation of cAMP in the IL-1-induced production of the precursors of matrix metalloproteinase (MMPs) and their specific inhibitor, tissue inhibitor of metalloproteinases (TIMP) in human uterine cervical fibroblasts. IL-1 significantly augmented the production of proMMP-1 (vertebrate procollagenase), proMMP-3 (prostromelysin), and TIMP without detectable changes in the intracellular level of cAMP. Dibutyryl cAMP (Bt2cAMP) and the cAMP elevating agent (forskolin) did not replace IL-1 as MMP inducers. On the contrary, the IL-1-mediated induction of proMMP-1 and proMMP-3 was significantly suppressed by treatment of the cells with Bt2cAMP, forskolin, or theophylline. The suppressive effect of Bt2cAMP on the IL-1-induced production of proMMP-1 and -3 was not due to the inhibition of zymogen secretion, but resulted from the decrease in the steady-state levels of proMMP-1 and proMMP-3 mRNAs. In contrast, Bt2cAMP slightly enhanced the IL-1-induced production of TIMP. The synthesis of proMMP-2 (72-kDa progelatinase/type IV procollagenase) was not altered by IL-1 and/or Bt2cAMP. These results suggest, first, that induction of proMMP-1 and -3 synthesis may share similar transduction pathways but they are distinct from those for proMMP-2 and TIMP synthesis and, second, that cAMP does not function as a second messenger in the MMPs' induction upon IL-1 stimulation in human uterine cervical fibroblasts. Thus, it is further suggested that the system that increases the intracellular cAMP level may be involved in negative regulation of proMMP-1 and -3 production.
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PMID:Cyclic adenosine 3',5'-monophosphate suppresses interleukin 1-induced synthesis of matrix metalloproteinases but not of tissue inhibitor of metalloproteinases in human uterine cervical fibroblasts. 165 5

Metalloproteinase inhibitors were surveyed with the culture media of 19 kinds of human tumor cell lines, using transin (rat stromelysin) as the target enzyme. This survey showed that most of the cell lines more or less secreted inhibitor activity, and that a human hepatoma cell line, HLE, secreted an extremely high inhibitor activity into the culture medium. Two kinds of metalloproteinase inhibitors were purified from the serum-free conditioned medium of HLE cells. The major inhibitor, which showed a single protein band with a molecular weight (Mr) of 21,000 (21k) (nonreduced) or 24k (reduced) on SDS-polyacrylamide gel electrophoresis, was identified as TIMP-2 (tissue inhibitor of metalloproteinases-2) by the analysis of its N-terminal amino acid sequence. The other was immunologically identified as TIMP. Purified TIMP-2 inhibited the activities of transin, matrin (pump-1), Mr 72k gelatinase, and interstitial collagenase with 1:1 stoichiometry. When the latent precursor form (Mr 57k) of transin was incubated with p-aminophenylmercuric acetate as an activating reagent, TIMP-2 inhibited the conversion of the intermediate form (Mr 45k) into the mature enzyme (Mr 42k). This indicated that TIMP-2 regulates not only the activity of the mature enzyme but also the autolytic processing of the proenzyme. TIMP-2 also inhibited in vitro tumor invasion through reconstituted basement membrane (matrigel) in chemotaxis chambers, showing that the metalloproteinase inhibitors as well as the extracellular matrix metalloproteinases are involved in tumor invasion through basement membrane and other extracellular matrices.
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PMID:Efficient purification of TIMP-2 from culture medium conditioned by human hepatoma cell line, and its inhibitory effects on metalloproteinases and in vitro tumor invasion. 166 1


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