Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two thrombolytic agents are mainly used in patients: streptokinase (SK) and urokinase (UK). UK from human origin is an endopeptidase which is able to convert plasminogen into plasmin. UK is only secreted by the kidney and is only found in urine which is presently the only source of extraction. Studies in man have shown that UK produces a highly reproducible state of enhanced plasma thrombolytic activity with a high fibrinolysis/fibrnogenolysis ratio and a lack of toxicity and antigenicity. The half life in Animal is short as well as the duration of fibrinolytic activity in Man. In clinical experience, positive results have been reported in pulminary embolism while the issues in myocardial infarction are controversial. Suggestive results have been registered in deep vein thrombosis, in ophthalmologic field and in desobstruction of arterio-venious shunts. No evident benefit has been noted in cerebral vascular disease. Up to now, UK has been very well tolerated.
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PMID:[Urokinase. Biochemical therapeutical and therapeutical data (author's transl)]. 6 58

The activation of procollagenase and prostromelysin by mechanisms that might be functional in vivo has been investigated. Studies with cell monolayers plated onto collagen films have indicated key roles for plasmin and TIMP in these processes. Prostromelysin activation could be rapidly effected by fibroblast monolayers in the presence of plasminogen, with identical kinetics to plasminogen-streptokinase generated plasmin. Procollagenase activation by plasmin was shown to be poor, although an M(r) shift of 11,000 occurred. Activation was enhanced ten-fold by the presence of active stromelysin even at a very low molar ratio. A tumour cell line secreting procollagenase but not stromelysin was found to be dependent upon the addition of both stromelysin and plasminogen to effect degradation of collagen films. Biochemical studies of metalloproteinase activation were carried out using other purified proteinases synthesized by connective tissue cells including endopeptidase 24.11, endopeptidase-2, cathepsin B and cathepsin L. None was a particularly effective activator relative to plasmin, but cathepsin B was shown to activate stromelysin. By use of both cell model systems and biochemical studies of purified enzymes we have found that the role of plasmin as the major metalloproteinase activator in normal connective tissue cells remains unchallenged.
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PMID:Physiological mechanisms for metalloproteinase activation. 148 31

A soluble 80-kDa endopeptidase has been isolated from Trypanosoma brucei brucei. The enzyme, which has a pI 5.1, is optimally active at about pH 8.2 and has apparent pKa values of 6.0 and greater than or equal to 10. It is inhibited by the serine protease inhibitor diisopropylfluorophosphate and by the serine protease mechanism-based inhibitor 3,4-dichloroisocoumarin. Unexpectedly, the enzyme is inhibited by the cysteine protease inhibitor benzyloxycarbonyl-Leu-Lys-CHN2 but not by the related diazomethane, butoxycarbonyl-Val-Leu-Gly-Lys-CHN2, nor by other cysteine protease specific compounds. Specificity studies with a variety of amidomethylcoumaryl (AMC) derivatives of small peptides show that the enzyme has a highly restricted trypsin-like specificity. The best substrate, based on the magnitude of kcat/Km, was benzyloxycarbonyl-Arg-Arg-AMC; other good substrates were benzyloxycarbonyl-Phe-Arg-AMC, benzoyl-Arg-AMC, and compounds with Arg at P1 and Ala or Gly at P2. The hydrolysis of most substrates obeyed classical Michaelis-Menton kinetics but several exhibited pronounced substrate inhibition. The enzyme did not activate plasminogen nor decrease blood clotting time; it was inhibited by aprotinin but not by chicken ovomucoid. We conclude that the enzyme is a trypsin-like serine endopeptidase with unusually restricted subsite specificities.
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PMID:Characterization of an endopeptidase of Trypanosoma brucei brucei. 173 36

Plasma membrane and lysosomal proteases, gamma-glutamyl transferase and extracellular matrix proteases were investigated by qualitative cytochemical means in the mature placenta of mice, rats, guinea-pigs and marmosets. These studies revealed similarities, which concerned primarily the lysosomal proteases in different structures of the placenta and all proteases and gamma-glutamyl transferases in the zone of placental shedding. However, species differences predominated. They were observed especially for amino-peptidase A and M, dipeptidyl peptidase IV and gamma-glutamyl transferase in the plasma membranes and extracellular matrix of the placental barrier and decidual cells of all species and the cells of the basal zone in rats and mice. Plasma membrane and extracellular matrix proteases in other parts of the placenta, e.g. the placenta stem of guinea-pigs and basal plate, amniotic and chorionic plate of marmosets occurred only in these species. Elastase substrates hydrolysing endopeptidase I and kallikrein-, thrombin-, plasmin-, plasminogen- and cathepsin B substrates hydrolysing endopeptidase II were not observed in any of these species. A general comparison of the species revealed similarities for the mouse, rat and guinea-pig placental barrier, but not for that of marmosets. The proteases of this zone in the marmoset placenta are more similar to the human situation, but do not correspond to it completely.
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PMID:Protease cytochemistry in the murine rodent, guinea-pig and marmoset placenta. 287 14

The receptor for urokinase-type plasminogen activator (uPA-R) localizes uPA to the cell surface. The receptor-bound uPA converts plasminogen to the trypsin-like endopeptidase plasmin. Thus uPA is involved in the initiation of pericellular proteolysis. Pericellular proteolysis is assumed to facilitate the cellular infiltration into surrounding tissue. The uPA-R has recently been identified as a surface antigen of activated human T lymphocytes. We have characterized the uPA-R of the human CD4 T cell line Jurkat by immunological (flow cytometry), biochemical (ligand blotting), and physico-chemical (Scatchard blotting) methods. The collective data suggest that the human CD4+ T cell line Jurkat expresses a cell surface receptor for uPA similar to that of myelo/monocytes and normal T cells with regard to size, affinity, ligand specificity, and antigenicity. Binding studies using exogenous uPA and subsequent functional assays revealed that receptor-bound uPA retains its enzymatic activity. Saturation of the Jurkat cell uPA-R with exogenous uPA facilitated cellular invasion into fibrin matrices in vitro. uPA-dependent invasion was inhibited in the presence of an anti-catalytic monoclonal anti-uPA antibody. We propose that uPA-R-bound uPA may facilitate the invasiveness of uPA-R-positive T lymphocytes.
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PMID:Urokinase-type plasminogen activator enhances invasion of human T cells (Jurkat) into a fibrin matrix. 791 95

Previous studies established the existence of an FSH-inducible rat granulosa cell-derived insulin-like growth factor binding protein (IGFBP)-5 endopeptidase. It was the objective of this communication to characterize this activity in some detail. Exposure of [125I]rhIGFBP-5 substrate to media conditioned by FSH-treated granulosa cells (a cell-free assay) produced two rhIGFBP-5 cleavage products (estimated size 19.5 and 17.5 kDa). The acquisition of IGFBP-5 endopeptidase activity in culture proved FSH (or PMSG) to be dose and time dependent. The addition of oFSH or rhFSH to the cell-free assay in turn, proved without effect on IGFBP-5 endopeptidase activity, thereby arguing against the possibility of an FSH receptor-independent phenomenon or of contaminating pituitary-derived contribution. The ability of FSH to induce IGFBP-5 endopeptidase activity proved relatively specific in that other granulosa cell agonists such as activin-A, IGF-I, GnRH, interleukin-1beta, TNF alpha, TGF beta1, EGF, or endothelin-1 failed to do so. However, the concurrent provision of GnRH, TNF alpha, EGF, or endothelin-1 proved inhibitory to the IGFBP-5 endopeptidase-inducing property of FSH. Activin-A and TGF beta1 in turn further stimulated the FSH effect. Sensitivity to EDTA, 1,10 phenanthroline, and high concentrations (> or = 0.1 mM) of Zn2+ suggested a Zn2+ metalloprotease. Insensitivity to TIMP-1 and TIMP-2 argued against a matrix metalloprotease (MMP). Relative insensitivity to PMSF, AMPSF, aprotinin, TPCK, and benzamidine argued against the possibility of a serine protease. Insensitivity to pepstatin A and E64 argued against aspartic and cysteine proteases, respectively. Insensitivity to plasminogen activator inhibitor-1 (PAI-1) and the presumed lack of free plasminogen in serum-free culture media argued against plasmin. Proteolysis was completely inhibited over the acid pH range but proceeded unencumbered at neutral and basic pH. Competition studies using unlabeled IGFBPs (1-6) as well as cell-free proteolysis assays of [125I]-labeled IGFBP-1, 2, 3, and 6 suggested a significant level of specificity for the FSH-induced/IGFBP-5-directed endopeptidase. Centricon-mediated fractionation of FSH-conditioned media revealed the IGFBP-5 endopeptidase activity in the fraction representing proteins of molecular weight >100K. Taken together, these observations document a secreted, granulosa cell-derived, high molecular weight, FSH-inducible, IGFBP-5-selective, neutral/basic pH-favoring, non-MMP Zn2+ metalloprotease.
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PMID:Characterization and hormonal regulation of a rat ovarian insulin-like growth factor binding protein-5 endopeptidase: an FSH-inducible granulosa cell-derived metalloprotease. 949 60

A novel single polypeptide endopeptidase of 24 kDa (24k-endopeptidase) was purified with a yield of 300-400 microg/L from conditioned medium of a bacterial strain which was identified as a new species in the genus Chryseobacterium Sp. on the basis of its 16S rDNA sequence and DNA:DNA hybridizations. The NH(2)-terminal amino acid sequence (Val-Ala-Thr-Pro-Asn-Leu-Glu-.) was not found in the availabe databases. The 24k-endopeptidase specifically hydrolyzed the Ser(441)-Val(442) peptide bond in human plasmin(ogen), with additional cleavage of the Lys(78)-Val(79) and Pro(447)-Val(448) peptide bonds, and a secondary cleavage at Lys(615)-Val(616). Thereby, plasminogen is converted into an angiostatin-like fragment containing kringles 1-4 (K1-4) and miniplasminogen (kringle 5 and the serine proteinase domain). The purified K1-4 fragment showed a comparable cytotoxicity toward endothelial cells as the elastase-derived K1-3 fragment (12.7% versus 10.6% at a concentration of 10 microg/mL). Plasminogen, bound to monocytoid THP-1 cells, was also cleaved by the 24k-endopeptidase, resulting in generation of an angiostatin-like fragment and in a decreased capacity to generate cell-associated plasmin following activation by urokinase. The 24k-endopeptidase was not efficiently neutralized by specific inhibitors against the serine, cysteine, aspartic, or matrix metalloproteinase classes of enzymes. In human plasma or serum, however, it induced only very limited plasminogen degradation, apparently due to neutralization of its activity by alpha(2)-macroglobulin. Interaction of this novel 24k-endopeptidase with plasminogen thus yields an angiostatin-like fragment and affects plasmin-mediated cellular proteolytic activity.
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PMID:Specific proteolysis of human plasminogen by a 24 kDa endopeptidase from a novel Chryseobacterium Sp. 1063 Oct 10

Deposition of amyloid beta (A beta) into extracellular plaques is a pathologic characteristic of Alzheimer's disease. Plasmin, neprilysin, endothelin-converting enzyme and insulin-degrading enzyme (IDE) have each been implicated in A beta degradation; data supporting the role of the latter three enzymes have included increased levels of endogenous murine A beta in mice genetically deficient for the respective enzyme. In this study, we sought to determine if plasminogen deficiency increases endogenous A beta. We report that plasminogen deficiency did not result in an A beta increase in the brain or in the plasma of adult mice. Hence, although plasmin is potentially important in the degradation of A beta aggregates, we interpret these data as suggesting that plasmin does not regulate steady-state A beta levels in non-pathologic conditions.
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PMID:Plasmin deficiency does not alter endogenous murine amyloid beta levels in mice. 1536 12

In Alzheimer's disease (AD) Abeta accumulates because of imbalance between the production of Abeta and its removal from the brain. There is increasing evidence that in most sporadic forms of AD, the accumulation of Abeta is partly, if not in some cases solely, because of defects in its removal--mediated through a combination of diffusion along perivascular extracellular matrix, transport across vessel walls into the blood stream and enzymatic degradation. Multiple enzymes within the central nervous system (CNS) are capable of degrading Abeta. Most are produced by neurons or glia, but some are expressed in the cerebral vasculature, where reduced Abeta-degrading activity may contribute to the development of cerebral amyloid angiopathy (CAA). Neprilysin and insulin-degrading enzyme (IDE), which have been most extensively studied, are expressed both neuronally and within the vasculature. The levels of both of these enzymes are reduced in AD although the correlation with enzyme activity is still not entirely clear. Other enzymes shown capable of degrading Abetain vitro or in animal studies include plasmin; endothelin-converting enzymes ECE-1 and -2; matrix metalloproteinases MMP-2, -3 and -9; and angiotensin-converting enzyme (ACE). The levels of plasmin and plasminogen activators (uPA and tPA) and ECE-2 are reported to be reduced in AD. Reductions in neprilysin, IDE and plasmin in AD have been associated with possession of APOEepsilon4. We found no change in the level or activity of MMP-2, -3 or -9 in AD. The level and activity of ACE are increased, the level being directly related to Abeta plaque load. Up-regulation of some Abeta-degrading enzymes may initially compensate for declining activity of others, but as age, genetic factors and diseases such as hypertension and diabetes diminish the effectiveness of other Abeta-clearance pathways, reductions in the activity of particular Abeta-degrading enzymes may become critical, leading to the development of AD and CAA.
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PMID:Abeta-degrading enzymes in Alzheimer's disease. 1836 35

The steady state concentration of the Alzheimer's amyloid-beta peptide in the brain represents a balance between its biosynthesis from the transmembrane amyloid precursor protein (APP), its oligomerisation into neurotoxic and stable species and its degradation by a variety of amyloid-degrading enzymes, principally metallopeptidases. These include, among others, neprilysin (NEP) and its homologue endothelin-converting enzyme (ECE), insulysin (IDE), angiotensin-converting enzyme (ACE) and matrix metalloproteinase-9 (MMP-9). In addition, the serine proteinase, plasmin, may participate in extracellular metabolism of the amyloid peptide under regulation of the plasminogen-activator inhibitor. These various amyloid-degrading enzymes have distinct subcellular localizations, and differential responses to aging, oxidative stress and pharmacological agents and their upregulation may provide a novel and viable therapeutic strategy for prevention and treatment of Alzheimer's disease. Potential approaches to manipulate expression levels of the key amyloid-degrading enzymes are highlighted.
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PMID:Amyloid-degrading enzymes as therapeutic targets in Alzheimer's disease. 1839 6


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