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)

GPA1734, an inhibitor of BM collagen biosynthesis, was investigated in the CAM model system for its effect on angiogenesis. Evaluation of angiogenesis was performed by placing a thin plastic coverslip inscribed with concentric circles on the CAM and counting the number of vessels intercepting the circles. The rate of BM collagen biosynthesis was monitored using [U-14C] proline incorporation into CAM proteins and determining the collagenase-digestible protein fraction. A marked depression in the vascular density was observed in the CAM area under a plastic disc containing GPA1734 as compared to control discs placed on the CAM about 1 cm apart from days 9 to 12 of incubation. A concomitant decrease in collagenous protein biosynthesis was observed in the area under the discs containing GPA1734 and [U-14C]proline as compared to control discs containing only the radiolabeled proline. The forementioned effects of GPA1734 on CAM were specific because no similar effects were observed with a closely related compound, 9,10-dihydroxy-7-methyl-benzo[b]quinolizinium bromide or with GPA1734 plus Fe++, which did not affect the rate of BM collagen biosynthesis. These results suggest that inhibitors of BM collagen biosynthesis prevent angiogenesis by interfering with the formation of an essential component of the vessel wall. The search for such inhibitors may be a new approach in the development of antiangiogenic agents.
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PMID:Inhibition of basement membrane biosynthesis prevents angiogenesis. 245 Feb 2

The binding of fn to collagen (type I) fibres has been found to resemble that of vWf in the following respects: Binding is rapid, specific, saturable, similar at 4 and 37 degrees C, and reduced by increasing ionic strength. Binding is not inhibited by native, monomeric collagen, suggesting a multivalent mechanism of interaction. Binding of fn occurs to a variety of collagen fragments (after their renaturation and polymerization), including, for example, the collagenase-derived TCA and TCB 3/4 and 1/4 molecular fragments and the peptides alpha 1(I)CB3, 6b, 7 and 8 obtained by cleavage with cyanogen bromide (CB), suggesting a wide distribution of binding sites on the native collagen molecule. As judged by the effect of heat-treatment, the native conformation of fn is required. Chemical modification indicates the involvement of arginyl residues in collagen and carboxyl groups in fn. However, fn and vWf did not compete with one another in binding to collagen, suggesting the participation of different collagen arginyl residues in the two interactions. Fn-binding differed from that of vWf in that the former was inhibited by denatured monomeric collagen (gelatin). Fn-binding was also inhibited by the fragment TCA in denatured form. The inhibitory activity was lost after chemical modification of arginyl residues in gelatin. Our results suggest that fn binding to collagen fibres and gelatin involves the same widely-distributed spectrum of binding sites.
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PMID:The interaction of fibronectin (fn) with native, polymeric collagen (collagen fibres): comparison with von Willebrand factor (vWf)-binding by collagen. 279 52

The hexameric complex of globular domains of type IV collagen was isolated after collagenase digestion of human placenta and the different monomers and dimers present were chromatographically separated. The ratio of alpha 1(IV)NC1 to alpha 2(IV)NC1 was 2:1. About 50% of the NC1 domains were connected to dimers. Predominantly alpha 1-alpha 1 dimers were found. Only 12% were alpha 2-alpha 2 dimers and no alpha 1-alpha 2 dimers could be detected. The majority (88%) of the intermolecular bonds was found to be disulfide bridges. The remainder could not be cleaved by reduction. To elucidate the arrangement of the disulfide bonds, the unreduced alpha 1(IV)NC1 monomers were treated with cyanogen bromide, the disulfide-bridged peptides isolated and characterized by Edman degradation. Each of the two homologous subdomains within a monomer is stabilized by an identical set of three disulfide bonds. In subdomain I, cysteines at positions 20 and 53 are connected with the C-terminal cysteine pair 108 and 111. Thus formed, the disulfide knot stabilizes two interconnected loops of 32 and 54 residues, respectively. A smaller loop of five residues occurs due to a disulfide bond between the cysteines 65 and 71. A similar disulfide arrangement is indicated for subdomain II which is separated from subdomain I by a segment of 20 amino acid residues. The same arrangement of disulfide bonds has been strongly suggested for the alpha 2(IV)NC1 monomer by the isolation and characterization of its disulfide-bridged tryptic fragments. Similar investigations on the dimeric alpha 1(IV)NC1 domain established the arrangement of the intermolecular disulfide bonds. They are formed by a complete disulfide exchange between corresponding disulfide knots of two monomeric NC1 domains.
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PMID:The arrangement of intra- and intermolecular disulfide bonds in the carboxyterminal, non-collagenous aggregation and cross-linking domain of basement-membrane type IV collagen. 284 31

The purified collagenase from tadpole (Rana catesbiana) back skin was studied with respect to its activation energy using soluble and fibrillar type I collagen, as well as a synthetic peptide substrate, DNP-Pro-Gln-Gly-Ile-Ala-Gly-Gln-D-Arg. The activation energy appeared to be independent of the nature of the substrate, ranging between 28 and 35 kcal/mol. The peptide was cleaved at the Gly-Ile bond and proved to be a poor substrate (kcat/Km, 1.21 h-1 microM-1) when compared with native type I collagen in solution (kcat/Km, 40.6 h-1 microM-1), consistent with the enzyme's low activity versus gelatin [T. A. Bicsak and E. Harper (1984) J. Biol. Chem. 259, 13145]. The amino acid composition of the collagenase was shown to be high in glycine and glutamic acid, and the preparation was shown not to be contaminated with collagen by digestion with bacterial collagenase. The enzyme was not inhibited by iodoacetic acid or 2-hydroxy-5-nitrobenzyl bromide, suggesting the lack of essential cysteinyl and tryptophanyl residues, but was inhibited by micromolar concentrations of ZnCl2, consistent with the presence of essential histidine(s). Ethoxyformic anhydride irreversibly inhibited the collagenase suggesting the presence of essential lysyl residues.
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PMID:Chemical and kinetic characterization of tadpole back skin collagenase. 299 32

Evidence is presented that, in contrast to the traditional view, a large proportion of the proteins of the tectorial membrane (TM) consists of collagen, primarily type II: characteristic amino acid composition of TM, including high levels of glycine, hydroxyproline and hydroxylysine; comigration of the main TM protein with appropriate collagen standards in two-dimensional gel electrophoresis; digestion of the main TM protein band following treatment with bacterial collagenase; one- and two-dimensional peptide mapping of cyanogen bromide digests of the TM exhibits patterns characteristic for collagen type II.
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PMID:Collagen--the predominant protein of the tectorial membrane. 301 Feb 13

In this study, the ability of peptides, obtained by fragmentation of the collagen type I molecule, to induce platelet aggregation has been examined. In order to satisfy requirements for tertiary and quaternary structure, peptides were first renatured (where necessary) to restore triple-helical configuration and then polymerised. Fragmentation with mammalian collagenase indicated the presence of platelet-reactive sites in both the N-terminal three-quarter and C-terminal one quarter fragment of the collagen molecule. Cleavage with cyanogen bromide indicated the presence in the constituent alpha 1(I)-chain of at least four platelet-reactive sites. Our results suggest a relatively wide distribution of platelet-binding sites situated throughout the length of the collagen (type I) molecule, each probably of relatively low affinity and low structural specificity, at least in terms of amino acid sequence, and probably of a similar nature to those that might be expected to exist in any collagen-like species.
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PMID:The platelet reactivity of collagen type I: evidence for multiple platelet-reactive sites in the type I collagen molecule. 302 15

The role of vascular endothelial cells in the vagal control of hemodynamics was studied in rat gastric mucosa. Vagal stimulation and intra-arterial administration of acetylcholine and of papaverine increased hemoglobin (Hb) and oxygen saturation of hemoglobin (SO2) in the gastric mucosa. The increases induced by vagal stimulation were reduced but not abolished by atropine. The responses to acetylcholine and vagal stimulation were reduced by quinacrine, p-bromophenacyl bromide and nordihydroguaiaretic acid, while indomethacin had no effect. Intra-arterial infusion of collagenase removed the endothelial cells from submucosal vasculatures and depressed the increase in mucosal hemodynamics in response to acetylcholine and vagal stimulation. The response to papaverine was not depressed in rats treated with quinacrine or collagenase. These results suggest that the increase in gastric mucosal blood flow induced by acetylcholine or vagal stimulation is mediated by the endothelium-derived relaxing factor.
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PMID:Endothelium-dependent increases in rat gastric mucosal hemodynamics induced by acetylcholine and vagal stimulation. 303 Jul 72

The amino acid sequences surrounding three major phosphorylation sites in rat and bovine synapsin I have been determined by employing automated gas-phase sequencing and manual Edman degradation of purified phosphopeptide fragments. Site 1 is a serine residue phosphorylated by cAMP-dependent protein kinase and by calcium/calmodulin-dependent protein kinase I. The sequence around site 1 was derived from tryptic/chymotryptic phosphopeptides and overlapping cyanogen bromide cleavage fragments. This sequence, identical in rat and bovine synapsin I, is Asn-Tyr-Leu-Arg-Arg-Arg-Leu-Ser(P)-Asp-Ser-Asn-Phe-Met. Site 1 is located at the NH2 terminus of the protein, within the collagenase-resistant head region. Sites 2 and 3 are serine residues phosphorylated by calcium/calmodulin-dependent protein kinase II. The sequences surrounding bovine site 2 and site 3 were derived from tryptic phosphopeptides and overlapping fragments generated by cleavage with chymotrypsin, collagenase, and endoproteinase Lys-C. The sequence around bovine site 2 is Thr-Arg-Gln-Thr-Ser(P)-Val-Ser-Gly-Gln-Ala-Pro-Pro-Lys, and the sequence around bovine site 3 is Thr-Arg-Gln-Ala-Ser(P)-Gln-Ala-Gly-Pro-Met-Pro-Arg. Sites 2 and 3 are located within the COOH-terminal, collagenase-sensitive tail region of the molecule, separated by 36 amino acids. The sequences surrounding rat site 2 and site 3 were derived from tryptic phosphopeptides. The sequence around rat site 2 is Gln-Ala-Ser(P)-Ile-Ser-Gly-Pro-Ala-Pro-Pro-Lys, and the sequence around rat site 3 is Gln-Ala-Ser(P)-Gln-Ala-Gly-Pro-Gly-Pro-Arg. Thus, the sequences surrounding the four sites that are phosphorylated by calcium/calmodulin-dependent protein kinase II, namely sites 2 and 3 in rat and bovine synapsin I, exhibit a high degree of homology.
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PMID:Amino acid sequences surrounding the cAMP-dependent and calcium/calmodulin-dependent phosphorylation sites in rat and bovine synapsin I. 311 71

Fluorescent probes have been used to obtain dissociation constants for the fluid-phase interaction of human plasma fibronectin and several of its gelatin-binding fragments with purified alpha chains of type I rat tail collagen, as well as with a cyanogen bromide fragment (CB7) of the alpha 1 chain in 0.02 M Tris buffer containing 0.15 M NaCl at pH 7.4. Addition of fibronectin to fluorescein-labeled collagen chains caused a dose-dependent increase in the fluorescence anisotropy which continued over several logs of titrant concentration. Scatchard-type plots of the anisotropy response were biphasic indicating the presence of one or more weak sites (Kd greater than microM) along the collagen chain in addition to a strong site characterized by Kd = 1.3 X 10(-8) M at 25 degrees C. Gelatin-binding fragments with Mr = 42,000, 60,000, and 72,000 also produced a biphasic response with Kd values for the high affinity site being 10- to 20-fold greater than for intact fibronectin. Binding of fibronectin and its fragments to fluorescent-labeled CB7 was essentially the same as to the whole alpha 1 chain. In all cases, the anisotropy response could be reversed or prevented by addition of excess unlabeled gelatin or CB7, but not by synthetic peptides spanning the collagenase cleavage site of alpha 1 (I). Studies of the temperature dependence of Kd for binding of fibronectin to the high affinity site on alpha 1 produced a value of +16 kcal/mol for the enthalpy of dissociation below 30 degrees C. Above this temperature, fibronectin appeared to undergo a subtle conformational transition characterization by a reduced affinity for collagen. This transition occurred in whole fibronectin but not in the gelatin-binding fragments and may involve disruption of intramolecular interactions between different domains.
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PMID:Interaction of fibronectin and its gelatin-binding domains with fluorescent-labeled chains of type I collagen. 312 86

Mastomys is a rodent which has been reported to develop spontaneous antral endocrine tumors with acid hypersecretion and duodenal ulceration. This study documents the establishment of a breeding colony and the characterization of the tumors and their possible secretagogues. Parietal cell secretory characteristics were studied using isolated gastric glands (IGG) of both normal (n = 5) and tumor-bearing animals. Tumors (n = 6) and control gastric tissue samples were examined by light transmission microscopy and immunohistochemistry. Gastrin was measured by radioimmunoassay in both plasma and tissue. IGG were prepared by collagenase dispersion and acid sequestration assessed by [14C]AP accumulation. Secretory mechanisms of this species were identified by establishment of a histamine dose-response curve and use of 8-bromo-cAMP. Receptor and proton pump inhibitions were assessed using cimetidine (10(-5)M) and the H/K ATPase inhibitor omeprazole (10(-5]. Both reduced [14C]AP accumulation significantly (P less than 0.05). 8-Bromo-cAMP and histamine significantly stimulated [14C]AP accumulation (P less than 0.05). Although parietal cells were substantially increased in tumor animals as compared to controls, the physiological parameters of acid secretion appeared normal in both and were comparable to other species which have been studied. Tumors were Grimelius positive and contained diffuse electron-dense granules. Immunohistochemistry was negative for gastrin, bombesin, serotonin, neuron-specific enolase, calcitonin, and pancreatic polypeptide. Tumor histamine-like immunoreactivity was, however, positive. Normal stomach contained 1001 +/- 185 compared to less than 0.5 pmole/g gastrin in tumors. Plasma gastrin was normal in both groups (29 +/- 5) as compared to 26 +/- 8 pmole/liter. This study characterizes a spontaneous gastric endocrine tumor which is associated with apparent parietal cell hyperplasia and reports of increased acid secretion and duodenal ulceration. The observations are consistent with the elaboration by the tumor of a nongastrin acid-trophic secretagogue.
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PMID:Characteristics of the spontaneous gastric endocrine tumor of mastomys. 334 20


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