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:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibitory effects of anthracyclines on bacterial collagenase were examined. Daunomycin, doxorubicin, and aclarubicin potently inhibited the collagenase, but mitomycin C and 5-fluorouracil did not inhibit. Inhibitory activities of anthracyclines were constant regardless of the concentrations of Ca2+, activator of collagenase, or of Zn2+, active center of collagenase. These results suggest that the inhibitory mechanisms of anthracyclines were independent of a chelate effect on Ca2+ or Zn2+.
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PMID:[Studies on collagenase inhibitors. III. Inhibitory effects of anthracyclines on bacterial collagenase]. 164 53

Tetracyclines have long been considered useful adjuncts in peridontal therapy based on their antimicrobial efficacy against putative periodontopathogens. However, recently these drugs were found to inhibit mammalian collagenases and several other matrix metalloproteinases (MMPs) by a mechanism independent of their antimicrobial activity. Evidence is presented that this property may be therapeutically useful in retarding pathologic connective tissue breakdown, including bone resorption. The experiments leading to this discovery are described and possible mechanisms are addressed, including the specificity of tetracyclines' anti-collagenase activity, the role of the drugs' metal ion (Zn2+, Ca2+)-binding capacity, and the site on the tetracycline molecule responsible for this nonantimicrobial property. Of extreme interest, the tetracycline molecule has been chemically modified in multiple ways, generating a new family of compounds called CMTs (chemically modified tetracyclines) that lack antimicrobial but still retain anti-collagenase activity. The first of these CMTs, 4-de-di-methylaminotetracycline, was found not to produce a major side-effect of antimicrobial tetracycline therapy--its administration to experimental animals did not result in the emergence of tetracycline-resistant microorganisms in the oral flora and gut. Numerous examples of the clinical potential of this non-antimicrobial property of tetracyclines in the treatment of periodontal and several medical diseases (e.g., sterile corneal ulcers, rheumatoid arthritis, skin bullous lesions, tumor-induced angiogenesis and metastasis) are discussed.
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PMID:Tetracyclines inhibit connective tissue breakdown: new therapeutic implications for an old family of drugs. 165 39

To develop a potent and specific collagenase inhibitor, a series of tetrapeptidyl hydroxamic acids were synthesized, based on the previous findings with tripeptidyl derivatives (Chem. Pharm. Bull., 38, 1007-1011, 1990). Among the series of tetrapeptidyl derivatives synthesized, R-Gly-Pro-Leu-Ala-NHOH and R-Gly-Pro-D-Leu-D-Ala-NHOH were found to be highly specific and potent inhibitors against vertebrate collagenase with an IC50 of 10(-6) M order, where R stands for Boc or acyl group. Analysis of their structure-activity relationships showed a characteristic feature of the substrate-binding site of collagenase as follows: 1) the S1 subsite forms a shallow hydrophobic pocket, although glycine residue corresponds to the subsite of the natural collagen substrate: 2) the S2 subsite constitutes a bulky pocket with less requirement for hydrophobicity: 3) the S3 subsite preferentially accommodates Pro residue: and 4) the accommodation of the P4-P1 subsites of peptidyl collagenase inhibitor to the S4-S1 subsites is required to form a tight binding of its hydroxamic acid moiety to the zinc ion at the catalytic site of the enzyme. The introduction of an enantiometric dipeptide unit, D-Leu-D-Ala, to the P2-P1 subsites demonstrated an increased binding capacity to the extended S4-S1 subsites of collagenase, thus providing proteinase-resistant inhibitor.
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PMID:Vertebrate collagenase inhibitor. II. Tetrapeptidyl hydroxamic acids. 165 22

Activation of procollagenase constitutes a crucial event in collagenolytic activity regulation. In this study we have purified by DEAE-cellulose, Ultrogel AcA-44, and zinc chelate sepharose chromatographies, a procollagenase-activator from the culture medium of the guinea pig carrageenin granuloma model. On SDS-PAGE, the activator migrates as a principal band of Mr approximately 44,000. The molecule activates procollagenase from human lung fibroblasts in a concentration dependent manner and an enhancement of collagenase activity of trypsin-treated crude culture medium was observed. A loss of about 50% of its activity occurs after heating. In addition, this activator degrades gelatin and casein. All these data suggest that this procollagenase-activator might be stromelysin. The activator was found in both phases of the granuloma, at 7 days when collagen is actively deposited and an important proportion of the collagenolytic activity remains in latent form; and at 14 days, when this enzymatic activity is fully expressed.
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PMID:Purification of a procollagenase-activator present in medium of cultured guinea pig carrageenin granuloma. 166 Aug 1

Functional characteristics of the interstitial collagenase purified from the BCl rat mammary carcinoma cell line were examined and compared with literature reports of the corresponding characteristics of collagenase from non-neoplastic cells. BCl collagenase degraded soluble collagen types I, II and III at the same rate and degraded fibrillar tendon collagen with an activation energy of 75 kcal/mol; these characteristics were identical to collagenase from normal rat uterine smooth muscle cells. Degradation of fibrillar collagen by BCl collagenase was completely inhibited by rat alpha 2-macroglobulin which was concomitantly cleaved into half-fragments. BCl collagenase was also inhibited by native and recombinant tissue inhibitor of metalloproteinases, a synthetic peptide collagenase inhibitor (Z-pro-leugly-NHOH), and Zn2+. In all functional characteristics examined, BCl collagenase was the same as interstitial collagenases from non-neoplastic sources.
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PMID:Interstitial collagenase from rat mammary carcinoma cells: interaction with substrates and inhibitors. 166 66

We have established mutant SaOS-2 cell lines that express a cyclic AMP (cAMP)-resistant phenotype to investigate the regulation and functional importance of orthophosphoric-monoester phosphohydrolase alkaline optimum (ALPase) in the action of parathyroid hormone (PTH). Cells were stably transfected with a plasmid that directs the synthesis of a mutant form of the type I regulatory subunit of protein kinase A (PKA) under the control of the metallothionein promotor. There was no significant difference between parental SaOS-2 cells and the mutant lines in the affinity or number of receptors for 125I-Nle8,18Tyr34bPTH1-34NH2, either in the absence or presence of Zn2+. When cAMP-dependent gene transcription was examined using transient transfection with a somatostatin promoter-chloramphenicol acetyl transferase (CAT) reporter plasmid, CAT activity stimulated by human PTH and dibutyryl cAMP (DBcAMP) was inhibited by greater than 90% in the presence of Zn2+ in the mutant cell lines. In contrast, activation by a phorbol ester of a pentameric collagenase promoter/CAT construct containing five tandem copies of the AP-1 response element (5x-TRE-CAT) was unaffected in Zn(2+)-treated mutant cells. The inhibitory actions of PTH and DBcAMP on ALPase release were blunted by up to 80-90% in the mutant cell lines in the presence of Zn2+; there were no significant differences in the magnitude of inhibitory effects between these agonists. We conclude that the inhibitory action of PTH on ALPase release in SaOS-2 cells is mediated via activation of PKA. These cAMP-resistant cell lines will be especially useful in elucidating signal transduction mechanism(s) for PTH in human osteoblastic cells.
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PMID:Protein kinase A-dependent inhibition of alkaline phosphatase release by SaOS-2 human osteoblastic cells: studies in new mutant cell lines that express a cyclic AMP-resistant phenotype. 166 91

When human fibroblast collagenase was incubated with ClCH2CO-(N-OH)Leu-Ala-Gly-NH2 (2-5 mM) in Tris buffer, pH 7.4 at 25 degrees C, a slow, time-dependent inhibition of the enzyme was observed. Dialysis against a buffer to remove free inhibitor did not reactivate the enzyme. A reversible competitive inhibitor, phthaloyl-GlyP-Ile-Trp-NHBzl (50 microM) partially protected the enzyme from inactivation by the compound. From the concentration dependent rates of inactivation Ki = 0.5 +/- 0.1 mM and k3, the rate constant for inactivation = 3.4 +/- 0.3 x 10(-3) min-1 were determined. The inactivation followed the pH optimum (6.5-7.0) for the enzyme activity, suggesting direct involvement of the same active site residue(s). The reaction mode of the inhibitor may be analogous to that of the inactivation of Pseudomonas aeruginosa elastase [Nishino, N. and Powers, J. (1980) J. Biol. Chem., 255, 3482] in which the catalytic glutamate carboxyl was alkylated by the inhibitor after its binding to enzyme through the hydroxamic Zn2+ ligand. All carboxyl groups in the inactivated collagenase were modified with 0.1 M ethyl dimethylaminopropyl carbodiimide/0.5 M glycinamide in 4 M guanidine at pH 5. The inactivator-affected carboxyl group was then regenerated with 1 M imidazole at pH 8.9, 37 degrees C for 12 h and the protein was radiolabeled with 3H-glycine methyl ester and carbodiimide to incorporate 0.9 residue glycine per mol enzyme.
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PMID:Inactivation of human fibroblast collagenase by chloroacetyl N-hydroxypeptide derivatives. 166 36

P. gingivalis adheres to A. viscosus on mineral surfaces mimicking teeth. To study whether P. gingivalis proteases contribute to its binding, mutants of P. gingivalis deficient in proteases were compared with their parent strain and a P. gingivalis-type strain for their adherence to A. viscosus on saliva-coated hydroxyapatite by manipulating a radio-isotope binding assay. Adherence of P. gingivalis 2561 to A. viscosus was studied by tests of the effects of incubation temperature and known inhibitors or promoters of proteases. Controls were handled by the assay run in PBS buffer at 22 degrees C. Two mutants deficient in trypsin-like protease were found to be deficient in adherence (% attachment relative to control: 3.2 +/- 0.1% and 11.2 +/- 0.4%), while a collagenase-deficient mutant had an adherence score (51.6 +/- 8.4) closer to that of the parent strain (75.6 +/- 7.2%). Heating P. gingivalis at 70 degrees C decreased its subsequent adherence at 22 degrees C by 80%. Adherence decreased by 60% when the assay was run at 4 degrees C, but increased by 70% at 37 degrees C. Reducing agents (dithiothreitol, cysteine, and mercaptoethanol) enhanced P. gingivalis adherence by 50 to 60%. Protease inhibitors (BZMD, SBTI, TPCK, TLCK, CMPS, PMSF) decreased adherence by 10 to 50%. Also, Hg2+ and Zn2+ decreased adherence by 30 to 50%, and arginine decreased it by 50%. Most of these effects on P. gingivalis adherence were statistically significant (p less than 0.05). Analysis of these data suggests that P. gingivalis proteases may contribute to the cohesion of P. gingivalis and A. viscosus.
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PMID:Association of proteases of Porphyromonas (Bacteroides) gingivalis with its adhesion to Actinomyces viscosus. 184 87

Tetracycline inhibition of neutrophil-associated collagenolysis has been the focus of a number of investigations. Evidence has suggested that this inhibition results from the ability of this family of antimicrobial drugs to bind divalent cations such as Ca2+ and Zn2+, two cations that are required for full expression of activity of metalloproteinases such as collagenase and gelatinase. Data presented in this study demonstrate that tetracyclines can also inhibit neutrophil-mediated RBC lysis, superoxide anion synthesis, degranulation and migration. To some extent, tetracycline inhibition of neutrophil functions is mimicked by the Ca2+ binding agents, EDTA and TMB-8. However, Ca2+ enrichment restored full function to EDTA- and TMB-8-treated cells but not to tetracycline-treated neutrophils. This suggests that Ca2+ binding plays a role but is not the critical effect leading to tetracycline suppression of neutrophil functions. It has been suggested that tetracyclines can suppress leukocyte-associated tissue damage. Host tissues are protected from neutrophil-mediated damage by two mechanisms: 1. Neutrophil granule-associated enzymes are secreted in an inactive state; and, 2. tissues are protected from these enzymes by a potent inhibitor shield. Neutrophils can bypass these protective elements by activating enzymes and by destroying the shield through the synthesis of oxygen radicals. Therefore, tetracyclines may suppress neutrophil-mediated tissue damage by inhibiting their migration and degranulation and, potentially more importantly, by suppressing synthesis of oxygen radicals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Suppression of human neutrophil functions by tetracyclines. 184 18

Matrix metalloproteinases are an important group of zinc enzymes responsible for degradation of the extracellular matrix components such as collagen and proteoglycans in normal embryogenesis and remodeling and in many disease processes such as arthritis, cancer, periodontitis, and osteoporosis. A matrixin family is defined, comprising at least seven members that range in size from Mr 28,000 to 92,000 and are related in gene sequence to collagenase. All family members are secreted as zymogens that lose peptides of about 10,000 daltons upon activation. Latency is due to a conserved cysteine that binds to zinc at the active center. Latency is overcome by physical (chaotropic agents), chemical (HOCl, mercurials), and enzymatic (trypsin, plasmin) treatments that separate the cysteine residue from the zinc. Expression of the metalloproteinases is switched on by a variety of agents acting through regulatory elements of the gene, particularly the AP-1 binding site. A family of protein inhibitors of Mr 28,500 or less binds strongly and stoichiometrically in noncovalent fashion to inhibit members of the family. The serum protein alpha 2-macroglobulin and relatives are also strongly inhibitory.
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PMID:Matrix metalloproteinases and their inhibitors in connective tissue remodeling. 185 Jul 5


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