Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cathepsin E is an intracellular aspartic proteinase of the pepsin family predominantly expressed in cells of the immune system and believed to contribute to homeostasis by participating in host defense mechanisms. Studies on its enzymatic properties, however, have been limited by a lack of sensitive and selective substrates. For a better understanding of the importance of this enzyme in vivo, we designed and synthesized a highly sensitive peptide substrate for cathepsin E based on the sequence of the specific cleavage site of alpha2-macroglobulin. The substrate constructed, MOCAc-Gly-Ser-Pro-Ala-Phe-Leu-Ala-Lys(Dnp)-D-Arg-NH2 [where MOCAc is (7-methoxycoumarin-4-yl)acetyl and Dnp is dinitrophenyl], derived from the cleavage site sequence of human alpha2-macroglobulin, was the most sensitive and selective for cathepsin E, with k(cat)/K(m) values of 8-11 microM(-1) s(-1), whereas it was resistant to hydrolysis by the analogous aspartic proteinases cathepsin D and pepsin, as well as the lysosomal cysteine proteinases cathepsins B, L, and H. The assay allows the detection of a few fmol of cathepsin E, even in the presence of plasma and cell lysate, and gives accurate results over a wide enzyme concentration range. This substrate might represent a useful tool for monitoring and accurately quantifying cathepsin E, even in crude enzyme preparations.
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PMID:A new selective substrate for cathepsin E based on the cleavage site sequence of alpha2-macroglobulin. 1584 76

Protein oligomerization and aggregation are key events in age-related neurodegenerative disorders, causing neuronal disturbances including microtubule destabilization, transport failure and loss of synaptic integrity that precede cell death. The abnormal buildup of proteins can overload digestive systems and this, in turn, activates lysosomes in different disease states and stimulates the inducible class of lysosomal protein degradation, macroautophagy. These responses were studied in a hippocampal slice model well known for amyloidogenic species, tau aggregates, and ubiquitinated proteins in response to chloroquine-mediated disruption of degradative processes. Chloroquine was found to cause a pronounced appearance of prelysosomal autophagic vacuoles in pyramidal neurons. The vacuoles and dense bodies were concentrated in the basal pole of neurons and in dystrophic neurites. In hippocampal slice cultures treated with Abeta(142), ultrastructural changes were also induced. Autophagic responses may be an attempt to compensate for protein accumulation, however, they were not sufficient to prevent axonopathy indicated by swellings, transport deficits, and reduced expression of synaptic components. Additional chloroquine effects included activation of cathepsin D and other lysosomal hydrolases. Abeta(142) produced similar lysosomal activation, and the effects of Abeta(142) and chloroquine were not additive, suggesting a common mechanism. Activated levels of cathepsin D were enhanced with the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK). PADK-mediated lysosomal enhancement corresponded with the restoration of synaptic markers, in association with stabilization of microtubules and transport capability. To show that PADK can modulate the lysosomal system in vivo, IP injections were administered over a 5-day period, resulting in a dose-dependent increase in lysosomal hydrolases. The findings indicate that degradative responses can be modulated to promote synaptic maintenance.
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PMID:Cellular responses to protein accumulation involve autophagy and lysosomal enzyme activation. 1631 22

The proteins cathepsin D, encoded by CTSD gene, and alpha2-macroglobulin, encoded by A2M gene, are involved in the biochemical pathway leading to deposition of beta-amyloid. In these proteins two amino acid polymorphisms (CTSD-Ala/Val C-->T and A2M-Ile/Val A-->G) have been associated with an increased risk for Alzheimer's disease (AD), but conflicting results have been reported. We studied the association and the mutual interactions of the CTSD-C/T and A2M-A/G polymorphisms with sporadic AD in 100 patients with late-onset AD and 136 healthy elderly subjects as controls. The CTSD-T allele and the CTSD-C/T genotype are significantly more frequent in AD than in controls. The odds ratio (OR) for CTSD-T subjects is 1.93 [95% confidence interval (CI)=1.01-3.72], and 2.07 (95% CI=1.01-4.21) after adjustment for age, sex and APOE epsilon4+ status, while no significant association was found for the A2M-A/G polymorphism. The coexistence of the CTSD-T with the A2M-G allele synergistically increased the OR for AD to 2.69 (95% CI=1.13-6.34) [2.82 (95% CI=1.12-7.17) after adjustment], and to 3.29 (95% CI=1.33-8.16) if estimated for the allelic combination. Our data suggest that the CTSD-T allele of the CTSD-C/T polymorphism is associated with an increased relative risk for late-onset AD and, more interestingly, the combination of CTSD-T with the A2M-G allele seems to increase this risk.
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PMID:Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease. 1678 55

Ageing, melatonin, epithalon (tetrapeptide Ala-Glu-Asp-Gly) and different light conditions effects on protein content and cathepsins B and D activities in rat liver and kidneys lysosomal fractions were studied. Ageing leads to decrease of cathepsins activity in rat liver lysosomal fractions. Constant light and darkness conditions result in earlier age decline of cathepsins activity. Absence of day and night succession in comparison with alternating light conditions causes decline of both general and specific cathepsin D activity. Melatonin and epithalon administration resulted in decrease of cathepsin D activity in liver only under control interchangeable light conditions. Cathepsin B activity in liver and kidneys lysosomal fractions declined in all experimental light conditions. Cathepsins activity decrease under the influence of epiphysial factors is evidently connected with their inhibitory effect on protein and general metabolism.
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PMID:[Effect of age, different light conditions, melatonin, and epitalon on lysosomal proteinase activity in the liver and kidneys of rats]. 1715 24

A number of different ligands have been tested in the course of the development of protein array technology. The most extensively studied example of protein ligands has been based on antibody-antigen interaction. Other examples include protein-protein, protein-nucleic acid, and protein-small molecule interactions. All these ligands can recognize and specifically bind to protein epitopes. In this study, we have developed a novel technology using DNA-based aptamers to detect proteins based on their amino acid sequences. Mouse cathepsin D was used for the proof of principle experiment. Four tripeptides, Leu-Ala-Ser, Asp-Gly-Ile, Gly-Glu-Leu, and Lys-Ala-Ile, were selected based on the published amino acid sequence of mouse cathepsin D. DNA aptamers against the tripeptides were isolated using the systematic evolution of ligands of exponential enrichment method. We have demonstrated that the aptamers specifically interacted with mouse cathepsin D using the structure-switch method. We further performed a proximity-dependent ligation assay to demonstrate that multiple aptamers could specifically detect the protein from cell extracts. In principle, one library containing 8000 aptamers should be enough to detect almost all proteins in the whole proteome in all organisms. This technology could be applied to generate a new generation of protein arrays.
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PMID:Detection of proteins based on amino acid sequences by multiple aptamers against tripeptides. 1722 63

The human liver fluke Opisthorchis viverrini is endemic in Thailand, Laos and Cambodia where long standing infection is associated with cancer of the bile ducts, cholangiocarcinoma. Here we describe a cathepsin D-like aspartic protease from the gut and other tissues in O. viverrini. Phylogenetic analysis indicated that Ov-APR-1 is cathepsin D-like, conforming with Clan AA, Family A1 of the MEROPS classification. Ov-APR-1 is expressed in the gut of the mature hermaphroditic parasite, in the reproductive tissues including the testis and immature spermatids, and the developing miracidium within the eggshell. The enzyme was also detected in the excretory/secretory products of cultured adult flukes, indicating a role in host-parasite relationships. A recombinant form of the enzyme expressed in Escherichia coli and refolded from denatured inclusion bodies underwent autocatalytic activation and demonstrated hydrolytic activity against the peptide substrate 7-methoxycoumarin-4-acetyl-GKPILFFRLK(DNP)-D-Arg-amide with a k(cat)/K(m)=1.7 x 10(4)M(-1)s(-1) and a pH optimum around pH 2.5-3.0. The recombinant enzyme digested hemoglobin and bovine serum albumin. Forty-six serum albumin peptides were detected after digestion with recombinant Ov-APR-1 and sequenced. Like many other aspartic proteases, Ov-APR-1 displayed promiscuous preferences for residues accommodated at the key subsites of the binding pocket although hydrophobic (Leu, Ala, Ile), positively charged (Lys) and bulky aromatic (Phe) residues, in that order, were preferred at P1. Similar residues were accommodated at P1' although even less selectivity was exerted at this position.
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PMID:Ov-APR-1, an aspartic protease from the carcinogenic liver fluke, Opisthorchis viverrini: functional expression, immunolocalization and subsite specificity. 1899 18

A number of new inhibitors of plasmepsin II (PlmII) from Plasmodium falciparum, one of the key factors of malarial parasite survival, were synthesized. The inhibitors are analogues of pepstatin with various variants of Ala residue substitutions. Effects of the inhibitors on human PlmII and cathepsin D were studied. Inhibition of PlmII by the substrate was found, which required the use of the modified Henderson method for the determination of inhibition constants. Two synthesized inhibitors were shown to exhibit a pronounced selectivity to PlmII (K(i) = 5.5 and 5 nM) in comparison with cathepsin D (K(i) = 230 and 3000 nM, respectively).
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PMID:[Selective inhibitors of plasmepsin II from Plasmodium falciparum based on pepstatin]. 1908 46

Two aspartyl proteases activities were identified and isolated from Trypanosoma cruzi epimastigotes: cruzipsin-I (CZP-I) and cruzipsin-II (CZP-II). One was isolated from a soluble fraction (CZP-II) and the other was solubilized with 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CZP-I). The molecular mass of both proteases was estimated to be 120 kDa by HPLC gel filtration and the activity of the enzymes was detected in a doublet of bands (56 and 48 kDa) by substrate-sodium dodecyl sulphate-polyacrylamide-gelatin gel electrophoresis. Substrate specificity studies indicated that the enzymes consistently hydrolyze the cathepsin D substrate Phe-Ala-Ala-Phe (4-NO2)-Phe-Val-Leu-O4MP but failed to hydrolyze serine and other protease substrates. Both proteases activities were strongly inhibited by the classic inhibitor pepstatin-A (> or =68%) and the aspartic active site labeling agent, 1,2-epoxy-3-(phenyl-nitrophenoxy) propane (> or =80%). These findings show that both proteases are novel T. cruzi acidic proteases. The physiological function of these enzymes in T. cruzi has under investigation.
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PMID:Trypanosoma cruzi: isolation and characterization of aspartyl proteases. 1921 6

Peculiarities of the course of metabolic processes in tissues of the bivalve mollusc Anadara inaequivalvis Br. were studied under conditions of experimental anoxia. In the absence of oxygen, in gill and foot the protein catabolism processes were found to be enhanced; this led to a decrease of the protein content and to an increase of the free amino acid and urea levels. Predominantly hydrolyzed were low molecular peptides, which was indicated by a decrease of the cathepsin D activity on the background of a rise of the gamma-glutamyltranspeptidase activity. Anoxia was accompanied by enhancement of the succinate thiokinase and fumarate reductase reactions controlled by alanine and aspartate aminotransferases. They prevented accumulation of toxic lactate in tissues and allowed obtaining an additional macroerg resource. Metabolic processes in the mollusc hepatopancreas were oriented to production of amino acids.
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PMID:[Tissue specificity of metabolism in bivalve mollusc Anadara inaequivalvis Br. under conditions of experimental anoxia]. 1956 53

A specific irreversible inhibitor of both cathepsins B and L, Fmoc-Tyr-Ala-CHN(2) (FYAD) induced apoptosis of neuroblastoma cells but not other tumor cells. Cysteine protease inhibitors that were not efficient inhibitors of both proteases did not cause death of any cell line tested. Apoptosis was preceded by accumulation of large electron dense vesicles and multivesicular bodies in the cytoplasm. Exposure of cells to the cathepsin D inhibitor, pepstatin, failed to rescue cells from FYAD-induced death. These results indicate that inhibition of cathepsins B and L may provide a unique mechanism for selectively inducing death of neuroblastoma with limited toxicity to normal cells and tissues.
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PMID:Induction of cell death in neuroblastoma by inhibition of cathepsins B and L. 2036 89


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