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

---

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

Six gold(I) salts, some of which are used as drugs in chrysotherapy, are shown to be inhibitors of two forms of human neutrophil collagenase. The IC50 values vary over six orders of magnitude, the lowest being 3.5 nM for Myocrisin. Thus, inhibition is greatly affected by the identity of the ligands to the gold(I) atom. The inhibition of collagenase by these gold(I) salts may be a partial basis for their antiarthritic action.
...
PMID:Inhibition of human neutrophil collagenase by gold(I) salts used in chrysotherapy. 303 41

The substrate specificity of human neutrophil collagenase was examined using both monomeric and fibrillar collagens. The neutrophil enzyme cleaved types I, II, and III collagens, but failed to attack types IV or V. Against monomeric collagen substrates at 25 degrees C, the neutrophil enzyme displayed values for the Michaelis constant (Km) of 0.6-1.8 X 10(-6) M, essentially indistinguishable from the substrate affinities that characterize human fibroblast collagenase. Catalytic rates, however, varied considerably; type I collagen was cleaved with a specificity (kappa cat/Km) some 20-fold greater than type III. Type II collagen was degraded with intermediate selectivity, approximately equal to 25% of the type I rate, but 450% that of type III. This specificity contrasted markedly with that of human fibroblast collagenase, which cleaved human type III collagen 15-fold faster than type I and greater than 500-fold more rapidly than type II. Interestingly, the 20-fold selectivity for type I over type III exhibited by neutrophil collagenase against monomeric collagens was largely abolished following the reconstitution of these substrates into insoluble fibrils, falling to a value of just 1.5-fold. The distinctive and opposite preference by the human fibroblast enzyme for monomeric type III collagen over type I (15-fold) was similarly reduced to less than 2-fold upon substrate aggregation. The transition from native soluble collagen monomers into insoluble fibrils appeared to be handled by both the human neutrophil and fibroblast collagenases with similar facility on type I substrates. By comparison, however, the neutrophil enzyme degraded type III collagen fibrils faster than would have been predicted from solution rates, while the fibroblast enzyme cleaved such fibrils much slower than expected from solution values. In exploring this phenomenon further, solvent deuterium isotope effects were measured. The deuterium studies suggest that neutrophil collagenase, acting on type III fibrils (kappa H2O/kappa D2O = 5.0), is less sensitive to factors which govern the availability of water at the relatively hydrophobic site of peptide bond hydrolysis in the collagen molecule than is fibroblast collagenase (kappa H2O/kappa D2O = 15.0).
...
PMID:The collagen substrate specificity of human neutrophil collagenase. 303 63

Collagenase from human polymorphonuclear leukocytes (neutrophil collagenase) attacks collagen type II in solution at a rate intermediate to those of type I and III collagens. This enzyme alone is not able to initiate degradation of native human articular cartilage. If the cartilage is first treated with leukocyte elastase, collagenase slowly degrades collagen. Confirming earlier findings by other investigators, elastase has a dual action on cartilage: The enzyme removes proteoglycans, thus demasking collagen fibers and giving collagenase access to them, and solubilizes collagen at a sizable rate. Although neutrophil collagenase cleaves collagen type II in solution at a high rate, the native, cross-linked status of collagen in cartilage makes it a relatively poor substrate for this enzyme. On a weight by weight scale, elastase and collagenase display about the same collagenolytic potential on human articular cartilage. The elastase/collagenase system from human polymorphonuclear leukocytes could represent a cooperative proteolytic complex in the destruction of cartilage in rheumatoid arthritis.
...
PMID:Action of collagenase and elastase from human polymorphonuclear leukocytes on human articular cartilage. 629 13

The heterogeneity of human collagenases has been examined using a monoclonal antibody to neutrophil collagenase. This antibody inhibited collagenase activity and, when covalently coupled to Sepharose, bound both latent and active enzyme. Although human neutrophil collagenase was inhibited by the antibody, the activity of human skin and rheumatoid synovial collagenase was not significantly diminished in the presence of the antibody. Competitive inhibition studies also differentiated between these collagenases. Only human neutrophil collagenase effectively blocked the antibody in a competitive enzyme-linked immunosorbent assay while skin and rheumatoid synovial collagenase again failed to interact with the antibody. The unequivocal recognition of neutrophil collagenase as an immunologically distinct entity from other collagenases supports the hypothesis that neutrophil collagenase is a separate gene product from fibroblast or synovial collagenase.
...
PMID:Heterogeneity among human collagenases demonstrated by monoclonal antibody that selectively recognizes and inhibits human neutrophil collagenase. 632 74

We have developed a monoclonal antibody AF-28 that specifically recognizes a neo-epitope on polypeptides with N-terminal FFGVG ... sequences. This sequence is found at the N-terminus of aggrecan fragments that have been digested with matrix metalloproteinases (MMPs). By immunoblotting, monoclonal antibody AF-28 specifically detected G2 fragments derived from an aggrecan G1-G2 substrate digested with stromelysin, collagenase, gelatinase and matrilysin, but failed to detect G2 fragments obtained from elastase, trypsin or cathepsin B digests. Undigested G1-G2 was not detected. In addition, AF-28 antibody detected fragments derived from whole aggrecan and this detection did not require prior treatment with chondroitinase or keratanase. Competition experiments confirmed that peptides containing internal ... FFGVG ... sequences were not detected by the antibody, while native MMP-digested aggrecan fragments and a synthetic 32-mer peptide with FFGVG ... N-termini were equally competitive on a molar basis. An FFGVG 5-mer, and an FGVGGEEDI9-mer which lacked the N-terminal phenylalanine residue, were 50 times and 230 times respectively less competitive than the FFGVG ... 32-mer. Two fragments from the interglobular domain, F342-F373 and F342-D441, that are predicted products of G1-G2 digestion by neutrophil collagenase but have not previously been detected, could be detected with AF-28. The epitope recognized by AF-28 was also detected in human synovial fluids by Western blot analysis. A broad band of 100-200 kDa was detected in some patients and a dominant band of 40-60 kDa was found in two patients. The size of this small fragment corresponds with that seen for the porcine F342-E373 product and may represent the natural physiological product of aggrecan cleaved in vivo at both the MMP site (... DIPEN341 decreases F342FGVG ...) and the aggrecanase site (... ITEGE373 decreases A374RGSVI ...).
...
PMID:Development of a cleavage-site-specific monoclonal antibody for detecting metalloproteinase-derived aggrecan fragments: detection of fragments in human synovial fluids. 754 17

Matrix metalloproteinases are a family of zinc endopeptidases involved in tissue remodeling. They have been implicated in various disease processes including metastasis, joint destruction, and neurodegeneration. Human neutrophil collagenase (HNC, MMP-8) represents one of the three "interstitial" collagenases that cleave triple-helical collagens types I, II, and III. Its 163-residue catalytic domain (Met80 to Gly242) has been expressed in Escherichia coli and crystallized as a noncovalent complex with the hydroxamate inhibitor batimastat. The crystal structure, refined to 2.1 A, demonstrates that batimastat binds to the S1-S2' sites and coordinates to the catalytic zinc in a bidentate manner via the hydroxyl and carbonyl oxygens of the hydroxamate group. The batimastat-collagenase complex is described in detail, and the activities of batimastat analogues are discussed in the light of the protein-inhibitor interactions revealed by the crystallography studies.
...
PMID:Structure determination and analysis of human neutrophil collagenase complexed with a hydroxamate inhibitor. 757 99

Dental plaque is the major aetiological factor in periodontal diseases and contains several proteolytic enzymes. The origin of these proteinases is, however, poorly studied. This study was undertaken to characterize collagenase present in dental plaque of adult periodontitis patients. Vertebrate-type rather than bacterial-derived collagenase activity was detected in extracts of both supra- and subgingival dental plaque extracts of adult periodontitis patients. Dental plaque collagenase was found to exist predominantly in autoactive form. Dental plaque collagenase from periodontally healthy individuals existed in latent from. Latent dental plaque collagenase from periodontitis lesions could be activated by a 95 kD chymotrypsin-like proteinase from Treponema denticola and human leukocyte cathepsin G but not by human plasmin. Incubation of purified latent leukocyte collagenase with whole cells of Fusobacterium nucleatum, Eubacterium saburreum, Prevotella buccae and Porphyromonas gingivalis, however, did not result to the activation of the enzyme. Doxycycline in vitro inhibited dental plaque collagenase with an IC50-value of 20 microM. Dental plaque collagenase degraded more efficiently type I and II collagens than type III collagen. Western-blot analysis with specific anti-human neutrophil collagenase-antibody revealed that both in supra- and subgingival dental plaque extracts dental plaque collagenase had undergone proteolytic conversion from an 80 kD proform to a 58 kD active form which is associated with catalytic autoactivity as measured by functional collagenase assay. This reflects proteolytic activation of leukocyte collagenase in dental plaque probably by other proteases derived from potent periodontopathogenic bacteria such as T. denticola or other PMN proteases such as cathepsin G.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Cellular source, activation and inhibition of dental plaque collagenase. 759 2

In this study, structure-based drug design of matrix metalloproteinase inhibitors [human fibroblast collagenase (HFC), human fibroblast stromelysin (HFS), and human neutrophil collagenase (HNC)] was utilized in the development of potent hydroxamates which contain novel, heteroatom-based modifications of the P1' group. A series containing a P1' butyramide group resulted in a nanomolar potent and selective HNC inhibitor as well as a dual HFS/HNC inhibitor. Benzylic ethers with a four- or five-carbon methylene linker in the P1' position also produced nanomolar potent HFS/HNC inhibition and micromolar potent HFC inhibition as expected. Surprisingly, the phenolic ethers of the same overall length as the benzylic ethers showed nanomolar potencies against HFC, as well as HFS and HNC. The potency profile of the phenolic ethers was optimized by structure-activity relationships of the phenolic group and the C-terminal amide. These inhibitors may help elucidate the in vivo roles of matrix metalloproteinases in normal and disease states.
...
PMID:Inhibition of matrix metalloproteinases by hydroxamates containing heteroatom-based modifications of the P1' group. 762 97

The crystal structure of the catalytic domain of human neutrophil collagenase complexed with a peptide transition state analogue has been determined to a resolution of 2.1 A. The structure of the neutrophil enzyme, when compared with the three dimensional structure of the corresponding human fibroblast collagenase, shows differences in the first, S1', of the three enzyme specificity subsites on the carboxy-terminal side of the substrate scissile bond. The S1' pocket in the neutrophil collagenase is significantly larger than the equivalent site in the fibroblast enzyme, suggesting that the former enzyme has a broader range of possible substrates. Such differences also suggest approaches for the design of selective matrix metalloproteinase inhibitors.
...
PMID:Structure of human neutrophil collagenase reveals large S1' specificity pocket. 765 15

In order to investigate the role of neutrophil collagenase in the periodontal disease, human neutrophil collagenase was purified and two monoclonal antibodies against this enzyme were obtained. This enzyme was purified by four step-affinity chromatography: heparin-aminocellurofine, gelatin Sepharose 4B, collagen-Sepharose and collagenase inhibitor column chromatographies. To produce the monoclonal antibody against the enzyme, the Balb/c mouse was immunized and its spleen cells were fused with the mouse myeloma cells. Two monoclonal antibodies to the enzyme, 2F3 (IgG1) and 3F12 (IgG1), which recognized a conformational structure of the enzyme apart from its catalytic site were obtained. Both antibodies were monospecific to leukocyte collagenase and did not cross-react with the other metalloproteinases such as leukocyte gelatinase, skin fibroblast collagenase, gelatinase and stromelysin. Using these monoclonal antibodies, collagenase was stained granularly in gingival crevicular neutrophils.
...
PMID:[Purification of human neutrophil collagenase, establishment of its monoclonal antibodies and application to gingival crevicular neutrophils]. 768 27


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---