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:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteinase activity in the cellular slime mould Dictyostelium discoideum has been analyzed by electrophoresis on polyacrylamide gels containing denatured hemoglobin. At least eight bands due to acid proteinases have been defined using extracts of myxamoebae, four bands A-D which move faster than the fifth and major band E, a minor band E' which moves just behind E and two slow bands G and H. Fruiting body formation was accompanied by the appearance of one new proteinase band F. The proteinases were present in extracts of both axenically-grown and bacterially-grown cells. Differences between the pH dependence and stability of the individual proteinases were detected. Inhibitor studies suggested that the faster proteinases A-D may be cathepsin B-like, whilst the slower enzymes E, E' and F do not fit readily into any known group of proteinases since they were sensitive to HgCl2 but not to other inhibitors of cathepsin B and not to inhibitors of cathepsin D-like proteinases under standard conditions. None of the proteinases was apparently formed during or after preparation of extracts and the proteinases could be re-run on polyacrylamide gels to give only the band expected from the first run. The bands are believed to reflect multiple proteinase activities within the cell.
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PMID:Multiple acid proteinases in the cellular slime mould Dictyostelium discoideum. 3 40

Proteinase activities in rat thioglycollate elicited peritoneal cells and the cell-free supernatant (lavage fluid) were measured by using the following substrates: Suc-Ala-Ala-Pro-Phe-Methyl-Coumarin-Amide (for cathepsin G or chymase), Suc-Ala-Ala-Ala-AMC (for elastase or elastase-like), Z-Arg-Arg-AMC (for cathepsin B), haemoglobin (for cathepsin D) and Ala-AMC (for alanine-aminopeptidase: AAP). The enzyme activities were correlated to the quantitative distribution of various cell types in the exudate from 0 to 192 nd h. In the supernatant all the examined activities showed a higher value at 72nd h. In the cells activity of chymase and AAP proved to be very high at 0 h but after four h the activities were dropped. From this time all enzyme activities started to elevate till the 24th h. At the 96th h only the activity of cathepsin B and AAP had a high value. We conclude that the intracellular activation and secretion of proteolytic enzymes characteristic for the various peritoneal cell types involved in the acute and chronic inflammatory reaction can be followed by activity measurements using enzyme-specific substrates and inhibitors.
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PMID:Proteolytic enzyme activities in rat peritoneal exudate. 168 30

Proteinase yscA is an intracellular aspartic proteinase located in the lysosome-like vacuole of the yeast cell. The specificity towards denatured protein substrates was determined by separation and identification of cleavage products after digestions with proteinase yscA, and compared to that obtained with pepsin used under similar conditions. Proteinase yscA is more selective towards the peptide bonds it cleaves than pepsin, but shows the same preference for large hydrophobic residues on both sides of the cleaved bond as pepsin and lysosomal cathepsin D. Phe, Leu and Glu are favoured in substrate subsite P1 and Phe, Ile, Leu and Ala in P'1, whereas Val is unfavoured in P'1. The implications for the role of proteinase yscA as hydrolase maturase are discussed.
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PMID:Substrate specificity of proteinase yscA from saccharomyces cerevisiae. 247 40

Proteinase A, a yeast aspartyl protease that is highly homologous to the mammalian lysosomal aspartyl protease, cathepsin D, was expressed in Xenopus oocytes and its biosynthesis and post-translational modifications were characterized. While 29-45% of the proteinase A was secreted from oocytes, approximately 37% of the cell-associated proteinase A underwent proteolytic cleavage, characteristic of delivery to a lysosomal organelle. Although proteinase A is not targeted to the yeast vacuole by a mannose 6-phosphate receptor-dependent pathway, 2-5% of the proteinase A molecules expressed in oocytes bound to a Man-6-P receptor column. However, analysis of its [2-3H]mannose-labeled oligosaccharides revealed that 14-23% of these units contain phosphomannosyl residues. A hybrid molecule (H6), in which the propiece and first 12 amino acids of proteinase A were changed to the cathepsin D sequence, was also expressed in oocytes. The binding of H6 to the Man-6-P receptor was approximately 12-fold greater than observed for proteinase A. This increased level of receptor binding could be accounted for by three factors: 1) a small increase in the total amount of phosphorylated oligosaccharides, 2) an increase in the number of oligosaccharides which acquire two phosphomonoesters, and 3) the presence of a greater percentage of oligosaccharides with one phosphomonoester which exhibit high affinity binding to the Man-6-P receptor. These results demonstrate that proteinase A is recognized by UDP-GlcNAc:lysosomal enzyme N-acetylglucosaminylphosphotransferase. However, this interaction is altered by the addition of cathepsin D sequences, resulting in the generation of a higher affinity ligand for binding to the Man-6-P receptor.
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PMID:Expression of the yeast aspartyl protease, proteinase A. Phosphorylation and binding to the mannose 6-phosphate receptor are altered by addition of cathepsin D sequences. 252 Dec 20

The proteinase A structural gene of Saccharomyces cerevisiae was cloned by using an immunological screening procedure that allows detection of yeast cells which are aberrantly secreting vacuolar proteins (J. H. Rothman, C. P. Hunter, L. A. Valls, and T. H. Stevens, Proc. Natl. Acad. Sci. USA, 83:3248-3252, 1986). A second cloned gene was obtained on a multicopy plasmid by complementation of a pep4-3 mutation. The nucleotide sequences of these two genes were determined independently and were found to be identical. The predicted amino acid sequence of the cloned gene suggests that proteinase A is synthesized as a 405-amino-acid precursor which is proteolytically converted to the 329-amino-acid mature enzyme. Proteinase A shows substantial homology to mammalian aspartyl proteases, such as pepsin, renin, and cathepsin D. The similarities may reflect not only analogous functions but also similar processing and intracellular targeting mechanisms for the two proteins. The cloned proteinase A structural gene, even when it is carried on a single-copy plasmid, complements the deficiency in several vacuolar hydrolase activities that is observed in a pep4 mutant. A strain carrying a deletion in the genomic copy of the gene fails to complement a pep4 mutant of the opposite mating type. Genetic linkage data demonstrate that integrated copies of the cloned proteinase A structural gene map to the PEP4 locus. Thus, the PEP4 gene encodes a vacuolar aspartyl protease, proteinase A, that is required for the in vivo processing of a number of vacuolar zymogens.
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PMID:PEP4 gene of Saccharomyces cerevisiae encodes proteinase A, a vacuolar enzyme required for processing of vacuolar precursors. 302 36

Sporothrix schenckii, mainly in the yeast form of the organism, produced extracellular proteinases when cultivated in liquid media containing albumin or collagen as a nitrogen source, but did not do so in brain heart infusion medium. Isolation of two extracellular proteinases from albumin-containing medium was performed by chromatography on DEAE-Sepharose CL-6B and Sephacryl S-200. Proteinase I had a molecular weight of 36,500, an optimal pH at 6.0, and a pI at 4.8. Despite its activities in weakly acidic conditions, proteinase I demonstrated chymotrypsinlike characteristics, these being indicated by strong inhibitory activity by phenylmethylsulfonyl fluoride and chymostatin and good kinetic constants for a synthetic chymotrypsin substrate, Suc-Ala-Ala-Pro-Phe-MCA. Proteinase II had a molecular weight of 39,000, an optimal pH at 3.5, and a pI at 3.8. Proteinase II showed cathepsin D-like characteristics, these being indicated by strong inhibitory activity by pepstatin, an acidic optimal pH, and good kinetic constants for hemoglobin. These two enzymes hydrolyzed natural substrates such as stratum corneum, type I collagen, and elastin although not type IV collagen. Proteinase production and cell growth in collagen-containing medium and the enzymatic digestion of skin constituents by isolated proteinases suggested that these two proteinases cooperatively enable the organism to invade skin and to obtain peptides from insoluble proteins.
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PMID:Isolation and properties of extracellular proteinases from Sporothrix schenckii. 330 79

The proteinase activity of the low molecular weight cytotoxin of Entamoeba histolytica was correlated with its cytotoxicity. Gel-filtered amebal toxin (mol wt 10-30,000) proteinase activities could be assayed on azocasein at pH 6 or on hemoglobin at pH 4.5. Proteinase activity was inhibited by serum fractions, thiol reagents, heavy metals, leupeptin, and antipain. The cytotoxic activity of gel-filtered amebal toxin was inhibited by serum fractions, leupeptin, and antipain. Increased proteinase and cytotoxic activity was produced by treatment with cysteine. These data support the action of a thiol proteinase in the production of cytopathic effects by gel-filtered amebal toxin in vitro. The cytotoxic and proteinase activities were further purified using a combination of column chromatography and preparative isoelectric focusing. Two low molecular weight cytotoxins with proteinase activity on both substrates were isolated. The major cytotoxin had an isoelectric point of 4.5 and a molecular weight of 22,000; the other cytotoxin had a basic isoelectric point. These substances may be cathepsin B-like proteinase and elastase or cathepsin G-like proteinases of E. histolytica. The major proteinase activity in the high molecular weight fraction was not cytotoxic. The isoelectric points of the high molecular weight proteinase activities corresponded to that of mammalian cathepsin D. The major cell rounding cytotoxic activity of E. histolytica extracts in vitro is probably due to the activity of a thiol-containing cathepsin B-like proteinase.
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PMID:Proteinase activities of Entamoeba histolytica cytotoxin. 632 55

The effects of two spleen proteinases, cathepsin D and thiol proteinase I active in neutral media--on the structural properties of fibronectins from blood plasma on adult animals and their embryos were investigated. Proteinase I and cathepsin D caused rapid fragmentation of all fibronectins under study. Fibronectin from calf embryonic serum was more sensitive to proteinase I than that from adult animal serum. The molecular weight and the correlation between the proteolytic products formed under the influence of each enzyme, on the embryonic and "adult" fibronectins, are very similar but not identical. Similar results were obtained in experiments with proteolytic products of chicken serum and embryo fibronectins. Fragmentation of embryonic fibronectin occurs more rapidly than that of chicken fibronectin; the fibronectin proteolytic products differ both qualitatively and quantitatively. However, the determination of structural differences between these fibronectins is considerably hampered by the presence of protein contaminations in chicken fibronectin preparations.
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PMID:[Comparative study of the proteolytic products of fibronectins in the serum of adult and embryonic animals formed under the effects of proteinases of the spleen]. 639 54

Amyloid beta (A beta) is a 39-43-residue protein that originates from proteolysis of the beta-protein precursor (beta PP) and accumulates in senile plaques in brains of Alzheimer's disease (AD) patients. Mutant beta PP, which incorporates an AD-causing double mutation at positions 687-688, has been shown to enhance A beta production in transfected cells. In this work we investigate the susceptibility of the mutant beta PP sequence to proteolytic cleavage by proteinases from human brain. Internally quenched fluorogenic substrates were used that encompass the NH2-terminal sequence of A beta from wild-type beta PP, the double mutant, and the two single substitutions. Proteinase activity in brain extract cleaved the mutant substrate 100-fold faster than the wild-type substrate and the partial mutants 25-fold faster. The major cleavage site in all substrates was at the amyloidogenic Asp1 site. The brain activity appeared to be cathepsin D (CD), as indicated by similarities to purified CD in 1) the rate and site of substrates cleavage, 2) the pH optima, and 3) the sensitivity to pepstatin A. The increased activity against the mutant substrate was not shared by cathepsins B and C, pepsin, HIV proteinase, and Candida albicans Asp-proteinase. Furthermore, CD cleaved a substrate that incorporates the COOH terminus of A beta at positions equivalent to Thr43 and Ala42, at ratios of 68% and 32%, respectively. CD degraded A beta 1-40 into six fragments but A beta 1-42 was completely resistant to digestion, probably because of its aggregation characteristics. These results indicate that CD is capable of producing the cleavages resulting in A beta production and that it may prove to be a suitable therapeutic target.
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PMID:Cleavage at the amino and carboxyl termini of Alzheimer's amyloid-beta by cathepsin D. 803 90

Proteinase levels are increased in multiple sclerosis (MS) lesions and are implicated in demyelination. The cellular origins of the activity are not known, but inflammatory cells of hematogenous origin are one possibility. We studied the levels of two lysosomal proteinases implicated in the proteolysis of myelin basic protein, cathepsin B (CB) and cathepsin D (CD), in peripheral blood mononuclear cells (PBMCs) of 20 stable relapsing-remitting MS patients. We prepared and assayed cell lysates of PBMCs from the MS patients, 10 patients with other neurologic diseases (OND), and 12 normal controls (NC). Mean CB activity expressed as milliunits of activity per million cells was significantly increased in MS patients (7.86 +/- 0.54) compared with OND (6.80 +/- 0.74) and NC (5.94 +/- 0.28) cells (p < 0.05). CD levels were not significantly increased. To determine whether the increase was generalized or limited to a subset of cells, PBMCs were fractionated by plate adherence. CB levels in the adherent fraction (AD) of the 20 MS patients were higher than in the nonadherent fraction (NA), and the AD:NA ratio of CB in MS was higher than that in controls. This would be consistent with an increase in CB levels in monocytes and macrophages, cells known to be activated in the peripheral blood of MS patients and implicated as effectors of demyelination.
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PMID:Increased cathepsin B activity in peripheral blood mononuclear cells of multiple sclerosis patients. 816 36


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