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:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two proteinases (2A and 2B) purified from the granular fraction of horse blood leucocytes degrade casein (Km values 12.8 and 6mg/ml respectively) with maximum activity at pH 7.4 and in the presence of 2m-urea. Urea-denatured haemoglobin, fibrinogen, albumin and resorcin/fuchsin-stained elastin are digested at a slower rate. The enzymes hydrolyse synthetic substrates of elastase, N-benzyloxycarbonyl-L-alanine 4-nitrophenyl ester (Km 0.114 and 0.178 mM) and N-acetyl-tri-L-alanine methyl ester (Km 5.55 and 0.98 mM), but they do not hydrolyse synthetic substrates of trypsin, chymotrypsin and thrombin. The examined proteinases are completely inhibited by 2 mM-di-isopropyl phosphorfluoridate and show a sensitivity to butyl and octyl isocyanates similar to that of pancreatic elastase. The pH-dependence of their photoinactivation in the presence of Rose Bengal indicates the presence of histidine in the active centre. Proteinase 2A rather insensitive to iodination by IC1 as is pancreatic elastase, whereas proteinase 2B is totally inactivated after incorporation of five iodine atoms per enzyme molecule.
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PMID:Substrate specificity and modifications of the active centre of elastase-like neutral proteinases from horse blood leucocytes. 0 9

The ubiquitous connective tissues contain a wide range of cells including fibroblasts, osteoblasts and chondroblasts. Recently it has been demonstrated that another principal cell of the connective tissue is the smooth muscle cell in several organ systems. These have been shown to be responsible for the synthesis of the connective tissue matrix components of the uterine myometrium and of the arterial system, including collagen, both elastic fibre proteins and glycosaminoglycan. Microtubule inhibitors such as colchicine and vinblastine, and iron chelators such as alpha,alpha -dipyridyl have been used to study their morphologic and chemical effects on collagen synthesis and secretion. Colchicine produces an increase in large Golgi-associated vacuoles, which sometimes contain material reminiscent of aggregates of collagen macromolecules. Vinblastine produces alterations in the endoplasmic reticulum cisternae similar to alterations seen in ascorbic acid deficiency, and alpha,alpha-dipyridyl increases the frequency of regions in cells, interpretable as potential sites of communication of rough endoplasmic reticulum cisternae with the cell surface. Ferritin conjugated anti-procallagen sera were used to localize procollagen in cells and demonstrated procollagen not only in the cisternae of rough endoplasmic reticulum but in all of the elements of the Golgi complex as well. The studies reported in this review have shown that in cell culture arterial smooth muscle will produce not only the microfibrillar protein of the elastic fibre but soluble and/or insoluble elastin as well. Recent studies on serum factors responsible for the proliferation of connective tissue cells have demonstrated that at least one of the principal factors responsible for fibroblast and/or smooth muscle cell proliferation in culture is derived from thrombocytes. Medium containing serum derived from cell-free plasma lacks most of this proliferative effect which can be reinstated when platelets are present during recalcification to form serum. This effect is due to the platelet release reaction as shown by combining supernatant factors derived from platelets exposed to purified thrombin to cell-free, plasma derived serum. Studies with macrophages have also suggested that phagocytic macrophages release factor(s) into a cell culture medium that may also participate in stimulating fibroblasts to proliferate in vitro. The means by which these factors stimulate fibroblast proliferation and connective tissue synthesis remains to be elucidated.
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PMID:Connective tissue cells, cell proliferation and synthesis of extracellular matrix-a review. 23 19

SR 26831 ([[5-(2-chloro-benzyl-2-(terbutyloxycarbonyl)]-4,5,6,7- tetrahydrothieno(3,2-c)pyridine]N-oxide) is the first member of a new class of human leukocyte elastase inhibitors. SR 26831 inhibited in a dose-dependent manner elastases from human leukocytes or pancreas with IC50 values of 80 +/- 2.6 nM and 4.8 +/- 0.12 microM, respectively. Steady-state studies revealed that SR 26831 behaved like a noncompetitive, irreversible inhibitor of both types of enzymes. SR 26831 inhibited in a dose-dependent manner degradation of [3H]elastin and [3H]collagens (types I and IV) by human leukocyte elastase (IC50 values were between 1.2 and 1.8 microM). In this respect, SR 26831 was 3- to 20-fold more active than alpha-1-antitrypsin. SR 26831 was also highly selective for elastases inasmuch as it did not inhibit pepsin, collagenase, trypsin, alpha-chymotrypsin, factor Xa, plasmin, kallikrein, cathepsins B, C, D and G and thrombin. In the rabbit, SR 26831 was cleared rapidly from blood after i.v. injection, but affected intracellular leukocyte elastase activity shortly after either i.v. or p.o. administration. In the rat, i.v. or p.o. administration of SR 26831 prevented in a dose-dependent manner acute lung injury induced by intratracheal instillation of human leukocyte elastase. SR 26831 (1 mg/kg) was still efficient when it was administered 90 min before elastase instillation and was also able to limit further hemorrhage development in response to elastase, after it had begun. SR 26831 may therefore be of therapeutic value in the treatment of diseases such as rheumatoid arthritis or pulmonary emphysema thought to be due to the destructive action of leukocyte elastase.
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PMID:Biochemical and pharmacological activities of SR 26831, a potent and selective elastase inhibitor. 173 26

Human rheumatoid synovial cells in culture secrete at least three related metalloproteinases that digest extracellular matrix macromolecules. One of them, termed matrix metalloproteinase 2 (MMP-2), has been purified as an inactive zymogen (proMMP-2). The final product is homogeneous on SDS/PAGE with Mr = 72,000 under reducing conditions. The NH2-terminal sequence of proMMP-2 is Ala-Pro-Ser-Pro-Ile-Ile-Lys-Phe-Pro-Gly-Asp-Val-Ala-Pro-Lys-Thr, which is identical to that of the so-called '72-kDa type IV collagenase/gelatinase'. The zymogen can be rapidly activated by 4-aminophenylmercuric acetate to an active form of MMP-2 with Mr = 67,000, and the new NH2-terminal generated is Tyr-Asn-Phe-Phe-Pro-Arg-Lys-Pro-Lys-Trp-Asp-Lys-Asn-Gln-Ile. However, following 4-aminophenylmercuric acetate activation, MMP-2 is gradually inactivated by autolysis. Nine endopeptidases (trypsin, chymotrypsin, plasmin, plasma kallikrein, thrombin, neutrophil elastase, cathepsin G, matrix metalloproteinase 3, and thermolysin) were tested for their abilities to activate proMMP-2, but none had this ability. This contrasts with the proteolytic activation of proMMP-1 (procollagenase) and proMMP-3 (prostromelysin). The optimal activity of MMP-2 against azocoll is around pH 8.5, but about 50% of activity is retained at pH 6.5. Enzymic activity is inhibited by EDTA, 1,10-phenanthroline or tissue inhibitor of metalloproteinases, but not by inhibitors of serine, cysteine or aspartic proteinases. MMP-2 digests gelatin, fibronectin, laminin, and collagen type V, and to a lesser extent type IV collagen, cartilage proteoglycan and elastin. Comparative studies on digestion of collagen types IV and V by MMP-2 and MMP-3 (stromelysin) indicate that MMP-3 degrades type IV collagen more readily than MMP-2, while MMP-2 digests type V collagen effectively. Biosynthetic studies of MMPs using cultured human rheumatoid synovial fibroblasts indicated that the production of both proMMP-1 and proMMP-3 is negligible but it is greatly enhanced by the treatment with rabbit-macrophage-conditioned medium, whereas the synthesis of proMMP-2 is constitutively expressed by these cells and is not significantly affected by the treatment. This suggests that the physiological and/or pathological role of MMP-2 and its site of action may be different from those of MMP-1 and MMP-3.
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PMID:Matrix metalloproteinase 2 from human rheumatoid synovial fibroblasts. Purification and activation of the precursor and enzymic properties. 226 96

Proteasic systems are largely incriminated in tumoral invasion in breast carcinomas. They are numerous and ranged in three classes. Serine-proteinases include plasmin, elastases, thrombin and trypsine which after activation, attack some structural glycoproteins and elastin. Plasmin system is involved more in stromal invasion than in the disruption of basement membranes. Plasminogen activators do not seem to come under the influence of hormonal factors. The action of these various enzymes is limited by more or less specific anti-proteases. The activity of elastases is parallel to the abundance of elastin in the stroma. The second group is composed of cystein-proteinases. Cathepsin B has a lysosomial origin and represents the most active system. Invasive territories of mammary carcinomas contain this enzyme which can degrade collagens and activate collagenases. Metallo-proteinases with collagenases, constitute the most important proteasic system in the degradation of extra-cellular matrix. Physicochemical properties of collagenases, ionic and cellular environment condition their activity which is also enzyme dependent (activation by plasmin, cathepsin B...) Type IV collagenase activity is related to the invasive and metastatic ability of tumor cells. All these enzymatic productions are closely linked and intermittent, and moreover limited by seric and tissular anti-proteinases.
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PMID:[Proteases and breast carcinoma]. 284 88

Monomers of fibrin generated from fibrinogen by thrombin reacted with elastin to give a new addition product or adduct. The adduct formation results from a covalent bond between both proteins, formation of which is dependent on elastin, fibrinogen and Ca2+ concentrations; but, Factor XIIIa did not intervene. Addition of fibronectin, together with fibrinogen, as cold insoluble proteins from human plasma, and of soluble collagen from rat tail tendon did not inhibit the first reaction. This enabled us to elaborate a new artificial connective matrix.
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PMID:Adduct formation between soluble fibrin monomers and elastin. 288 58

The purpose of these studies was to identify some of the extracellular proteolytic enzymes associated with the development and healing of acute inflammatory lesions. Lesions were produced in the skin of rabbits by the topical application of the military vesicant, sulfur mustard (SM). Full-thickness, 1-cm2 central biopsies of the lesions were organ-cultured for one to three days, and the culture fluids were assayed for proteases with a variety of substrates. When compared to culture fluids from normal skin, the culture fluids from both developing and healing SM lesions had three to six times the levels of proteases hydrolyzing two synthetic peptide substrates: (1) t-butyloxycarbonyl-Leu-Gly-Arg-4-trifluoromethylcoumarin-7-amide(Boc-Leu -Gly- Arg-AFC, herein abbreviated LGA-AFC), and (2) N-benzoyl-phenylalanine-beta-naphthyl ester (BPN). LGA-AFC is a substrate for trypsin, plasmin, plasminogen activator, thrombin, kallikrein, and the C3 and C5 convertases; BPN is a chymotrypsin and cathepsin G substrate. The culture fluids did not consistently hydrolyze four other synthetic peptide substrates or the proteins [14C]-casein and [14C]elastin. In order to determine the likely sources of LGA-AFCase and BPNase activity, we counted the number of granulocytes (PMNs), macrophages (MNs) and activated fibroblasts in histologic sections of developing and healing SM lesions, and we measured the levels of these enzymes in serum, in culture fluids of PMN and MN peritoneal exudate cells, and in culture fluids of two fibroblast cell lines. In SM lesions, serum and fibroblasts seemed to be the major source of LGA-AFCase, and serum alone the major source of BPNase. Tissue PMNs and MNs seemed to be only minor sources. The crusts of healing lesions, which were full of dead PMNs, seemed to be a rich source of both enzymes. In the SM lesion culture fluids, whether LGA-AFC and BPN were hydrolyzed by endopeptidases or only by exopeptidases could be determined by evaluating complex formation with alpha-macroglobulin proteinase inhibitors (alpha M). Endopeptidases, but not exopeptidases, are entrapped and inhibited by alpha M, because an internal peptide band in alpha M must first be hydrolyzed before molecular rearrangement (required for proteinase inhibition) occurs. The catalytic site of endopeptidases that are entrapped and inhibited by alpha M is known to remain active on (and reachable by) small synthetic peptide substrates such as LGA-AFC and BPN.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Proteases released in organ culture by acute dermal inflammatory lesions produced in vivo in rabbit skin by sulfur mustard: hydrolysis of synthetic peptide substrates for trypsin-like and chymotrypsin-like enzymes. 304 42

We have developed a monospecific antiserum directed against a major glycoprotein in the elastin-associated microfibrils with an apparent molecular mass of 128 kDa (GP 128). When immunoblotting or enzyme-linked immunosorbent microassay was used, its IgGs recognized thrombospondin in a platelet lysate, but did not react with several basement-membrane-derived macromolecules, nor with plasma fibronectin. Similar patterns of immunofluorescence and immunoperoxidase were found after incubation of endothelial cells with either anti-GP 128 or anti-(platelet thrombospondin) IgGs. Both antibodies inhibited the microfibrils- and thrombin-induced platelet aggregation, and were without effect on the aggregation by other inducers. These results confirm that there is an antigenic homology between GP 128 and thrombospondin.
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PMID:Characterization of an antibody directed against a 128 kDa glycoprotein involved in the thrombogenicity of the elastin-associated microfibrils. 305 19

Monomers of fibrin generated by thrombin from fibrinogen reacted with elastin to give a new addition product or adduct. Adduct formation resulted from a covalent bond between fibrin monomers and elastin. The kinetic studies of this reaction confirmed that the adduct was formed before fibrin precipitated to produce the clot. The reaction depended on elastin, fibrinogen and thrombin concentrations. When thrombin-induced and reptilase-induced fibrin were compared, it became obvious that fibrin monomers did intervene more commonly as Des AA-fibrin than as Des AA.BB-fibrin. The adduct synthesis was completely inhibited by 150 microM of the peptide Gly-Pro-Arg-Pro which was previously known to stabilize the fibrin monomers and consequently to inhibit the polymerization completely. It is shown that FXIII could intervene directly in the reaction where homological quality of elastin (human versus bovine) and purity of thrombin were other important factors.
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PMID:Biochemical study of adduct synthesis between fibrin monomers and elastin. 322 39

A fibrinogen derivative generated by thrombin was reacted with elastin to yield a new addition product or adduct between the two proteins. Addition of fibronectin, and then of collagen, did not interfere with the basic elastin-fibrinogen reaction and conferred the qualities of an artificial connective tissue to the product. Biochemical, structural and biomechanical aspects of the new matrix were studied. Aprotinin, heparin, thiomersal, and thiourea did not inhibit the main reaction; indeed, some of these ingredients improved the matrix cohesion. Scanning electron microscopy showed the genesis of a true network whose meshes were more reticulated by the addition of thiourea. Biomechanical studies, i.e., strength and elasticity showed the thiourea matrix to be the strongest. These intrinsic properties suggest the product could have biological and clinical applications.
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PMID:A new reconstituted connective tissue matrix: preparation, biochemical, structural and mechanical studies. 365 89


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