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)

In cultured human fibroblasts we observed that monensin, a Na+/H+-exchanging ionophore, (i) inhibits mannose 6-phosphate-sensitive endocytosis of a lysosomal enzyme, (ii) enhances secretion of the precursor of cathepsin D, while inhibiting secretion of the precursors of beta-hexosaminidase, (iii) induces secretion of mature beta-hexosaminidase and mature cathepsin D, and (iv) inhibits carbohydrate processing in and proteolytic maturation of the precursors remaining within the cells; this last effect appears to be secondary to an inhibition of the transport of the precursors. If the treated cells are transferred to a monensin-free medium, about half of the accumulated precursors are secreted, and the intracellular enzyme is converted into the mature form. Monensin blocks formation of complex oligosaccharides in lysosomal enzymes. In the presence of monensin, total phosphorylation of glycoproteins is partially inhibited, whereas the secreted glycoproteins are enriched in the phosphorylated species. The suggested inhibition by monensin of the transport within the Golgi apparatus [Tartakoff (1980) Int. Rev. Exp. Pathol. 22, 227-250] may be the cause of some of the effects observed in the present study (iv). Other effects (i, ii) are rather explained by interference by monensin with the acidification in the lysosomal and prelysosomal compartments, which appears to be necessary for the transport of endocytosed and of newly synthesized lysosomal enzymes.
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PMID:Effect of monensin on intracellular transport and receptor-mediated endocytosis of lysosomal enzymes. 623 17

Biosynthesis, transport, and maturation of cathepsin D and beta-hexosaminidase was examined in fibroblasts exposed to 1-deoxynojirimycin, a glucose analogue known to inhibit trimming glucosidases (Saunier, B., Kilker, R. D., Jr., Tkacz, J. S., Quaroni, A., and Herscovics, A. (1982) J. Biol. Chem. 257, 14155-14161; Hettkamp, H., Bause, E., and Legler, G. (1982) Biosci. Rep. 2, 899-906). Cells treated with 1-deoxynojirimycin contained precursors of cathepsin D and beta-hexosaminidase larger by about 1-2 kDa than control cells. The shift in molecular size was probably due to glucose residues that were rapidly removed from the precursors in the absence but not in the presence of 1-deoxynojirimycin. In addition, 1-deoxynojirimycin inhibited the glycosylation of the beta-chain precursor of beta-hexosaminidase and the synthesis of glycoproteins, including that of cathepsin D. The proteolytic processing of the larger precursors was retarded by several hours. The delay in proteolytic maturation was secondary to the accumulation of the larger precursors in organelles, which fractionated with membranes of the endoplasmic reticulum and Golgi complex. The accumulated cathepsin D precursor contained neither mannose 6-phosphate residues nor complex type oligosaccharides, which are formed in the cis and trans aspects of the Golgi complex. Cathepsin D precursors eventually released from the site of accumulation were apparently deglucosylated, acquired mannose 6-phosphate residues and complex type oligosaccharides, and were transferred into lysosomes as efficiently as in control cells. Our results suggest that transport of cathepsin D from the endoplasmic reticulum to the Golgi complex depends on removal of glucose residues from its carbohydrate.
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PMID:Cathepsin D and beta-hexosaminidase synthesized in the presence of 1-deoxynojirimycin accumulate in the endoplasmic reticulum. 623 13

Precursors of cathepsin D and beta-hexosaminidase synthesized in the U937 monocyte line are processed to mature forms with similar kinetics as in fibroblasts. In U937 cells the processing of the precursor of the beta-chain of beta-hexosaminidase, however, results in a larger fragment that resembles a processing intermediate in fibroblasts. This difference is explained by differences in the equipment of the cells with proteinases, since cross-feeding of the precursors to the cells results in a processing characteristic for the recipient cell type. In sucrose gradients the precursors are found partly in a low- and partly in a high-density region. Mature polypeptides and activity of lysosomal enzymes fractionate mainly in the higher density region. In U937 cells the transport and maturation of endogenous lysosomal enzymes are less sensitive to bases (NH4Cl, chloroquine, tilorone) and to antibody against the mannose 6-phosphate specific receptors than in fibroblasts. A small portion of enzymes released from U937 cells contains the markers recognized by the mannose-6-phosphate specific receptors. U937 cells express these receptors and utilize them for transport of endogenous and exogenous lysosomal enzymes. It appears, however, that a fraction of lysosomal enzymes is transported in U937 cells independent of the mannose-6-phosphate-specific receptors.
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PMID:Processing and transport of lysosomal enzymes in human monocyte line U937. 623 73

Protein synthesis and degradation and net uptake and release of amino acids and minerals were examined in the perfused hemicorpus of bilaterally nephrectomized and sham-operated control rats. Animals were studied 30 h after surgery. In comparison with controls, uremic rats had greater urea N appearance (net urea generation) and lower plasma and muscle concentrations of most amino acids. Muscle protein synthesis was not altered, but protein degradation was greater in uremic versus sham rats. There was greater net release of phenylalanine, tyrosine, alanine, total nonessential amino acids, total amino acids, potassium, and phosphorus from the perfused hemicorpus of uremic rats and greater release of citrulline from sham rats. ATP, creatine phosphate, cAMP, and activities of cathepsin B1, cathepsin D, and alkaline protease were not different in muscles of the uremic versus sham rats. Thus, in acutely uremic rats there is increased protein wasting in the hemicorpus due to enhanced protein degradation. The enhanced protein degradation does not appear to be due to increased muscle cathepsin B1, cathepsin D, or alkaline protease activities.
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PMID:Protein and amino acid metabolism in posterior hemicorpus of acutely uremic rats. 630 4

Protein synthesis and degradation and net uptake and release of amino acids and minerals were investigated in the perfused hemicorpus of acutely uremic and control Sprague-Dawley rats. Rats underwent bilateral nephrectomy or sham surgery and were studied 30 hr after surgery. The uremic rats displayed greater urea N appearance (net urea generation), lower plasma and muscle concentrations of most amino acids, and increased muscle protein degradation as compared to control rats. Muscle protein synthesis was slightly but not significantly decreased in the uremic animals. There was greater net release of phenylalanine, tyrosine, alanine, total nonessential amino acids, total amino acids, potassium and phosphorus from the perfused hemicorpus of uremic rats and greater release of citrulline from sham rats. Muscle ATP, creatine phosphate, cyclic-AMP, and activities of cathepsin B1, cathepsin D, and alkaline protease were not different in the uremic and sham rats. These data provide evidence that acutely uremic rats sustain increased muscle protein wasting which is due to enhanced protein degradation. The increased protein degradation does not appear to be due to enhanced activities of muscle cathepsin B1, cathepsin D or alkaline protease.
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PMID:Enhanced muscle protein degradation and amino acid release from the hemicorpus of acutely uremic rats. 636 19

The influence of prostacyclin (PGI2) alone or in combination with intraaortic balloon pumping (IABP) on the levels of energy-rich phosphate compounds was investigated before and after coronary artery ligation in canine myocardium. There was a higher level in creatine phosphate in the ischemic as well as non-ischemic areas of the myocardium after treatment with PGI2, however the most protective effect was registered after a combination of PGI2 and IABP. PGI2 also reduces the release of cathepsin D activity into the blood independently whether or not a mechanical support of the heart after coronary artery ligation was performed.
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PMID:Improved protection in myocardial ischemia by combined prostacyclin administration and intraaortic balloon pumping. 639 62

Cathepsin D from porcine spleen contained mannose (3.3%), glucosamine (1.4%), and mannose 6-phosphate (0.08%). Essentially all of the oligosaccharides of cathepsin D could be released by endo-beta-N-acetylglucosaminidase H, pointing to oligomannoside types of structures. Three neutral oligosaccharide fractions, containing 5, 6, and 7 mannose residues, respectively, were isolated by gel permeation chromatography on Bio-Gel P-2. Studies using exoglycosidase digestions and 500-MHz 1H NMR spectroscopy revealed that their structures are [Man alpha 1 leads to 2]0 or 1 Man alpha 1 leads to 6[Man alpha 1 leads to 3]Man alpha 1 leads to 6[Man alpha 1 leads to 2)0 or 1 Man alpha 1 leads to 3]Man beta 1 leads to 4GlcNAc beta 1 leads to 4 GlcNAc. These structures are identical to what have recently been proposed by Takahashi et al. for the major oligosaccharide units of cathepsin D from the same source (T. Takahashi, P. G. Schimidt, and J. Tang (1983) J. Biol. Chem. 258, 2819-2930), except for the occurrence of two isomeric oligosaccharides containing six mannoses. Only a part (3.4%) of the oligosaccharides were acidic, containing phosphates in monoester linkage. The phosphorylated oligosaccharides also consisted of oligomannoside-type chains which were analogous to, but more heterogeneous in size than the neutral oligosaccharides. Cathepsin D was bound to a mannose- and N-acetylglucosamine-specific lectin (mannan-binding protein) isolated from rabbit liver with the Ki value of 5.4 X 10(-6) M.
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PMID:Oligosaccharides on cathepsin D from porcine spleen. 642 53

Protein synthesis and degradation and net uptake and release of amino acids and minerals were investigated in the perfused hemicorpus of acutely uremic and sham-operated control Sprague-Dawley rats. Rats underwent bilateral nephrectomy or sham surgery and were studied 30 hours after surgery. The uremic rats displayed greater urea nitrogen appearance (net urea generation), lower plasma and muscle intracellular concentrations of most amino acids, and increased protein degradation in the hemicorpus as compared with control animals. Muscle protein synthesis was slightly but not significantly decreased in the uremic animals as compared with controls. There was greater net release of phenylalanine, tyrosine, alanine, total nonessential amino acids, total amino acids, potassium, and phosphorus from the perfused hemicorpus of uremic rats and greater release of citrulline from sham rats. Muscle ATP, creatine phosphate, and cyclic AMP, and muscle cathepsin B1, cathepsin D, and alkaline protease activities were not different in the uremic and control rats. These data provide evidence that acutely uremic rats have increased muscle protein wasting which is due to enhanced protein degradation. The cause of the increased muscle protein degradation is unknown.
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PMID:Effect of acute uremia on protein degradation and amino acid release in the rat hemicorpus. 658 68

The cathepsin D of Plasmodium lophurae was purified using a combination of CM-Sephadex, pepstatin-agarose and Sephadex G-100 chromatography. The plasmodial enzyme was distinct from that of the host red cell and bovine spleen in its low isoelectric point (pI 4.3). The cathepsin D of P. lophurae, as well as plasmodial extracts demonstrating such proteinase activity, were able to digest the membrane proteins of duckling and human red cells at pH 7.4; proteolysis was not inhibited in phosphate-buffered saline by 100 microM pepstatin. Membrane proteins most susceptible to proteolysis were those of the cytoskeleton, notably bands 1 and 2 (spectrin), bands 2.1-2.6 (spectrin-binding proteins) and band 3. Membrane protein degradation by crude plasmodial extracts was partially inhibited by a combination of 10 mM FeCl3, and 10 mM phenylmethylsulfonyl fluoride in phosphate-buffered saline. The changes induced in erythrocyte membrane proteins by exposure to plasmodial cathepsin D parallel the alterations observed in red cell membranes obtained from malaria infected cells. Since the action of the plasmodial protease was confined to the inner surface of the red cell membrane, it is possible that protease-induced modifications in the red cell cytoskeleton could lead to merozoite release.
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PMID:Purification of Plasmodium lophurae cathepsin D and its effects on erythrocyte membrane proteins. 662 18

Cathepsin D was purified about 1000-fold from human brain cortex by a procedure involving ammonium sulfate fractionation (30-70%), Sephadex G-75 chromatography, affinity chromatography on pepstatin-Sepharose and isoelectric focusing. The enzyme was assayed fluorometrically at pH 3.2, the substrates used were globin or haemoglobin modified with pyridoxal-5'-phosphate. 6 multiple forms of cathepsin D were resolved in the isoelectric focusing step with pI values 4.4, 4.8, 5.3, 6.2, 6.5 and 6.8. Km of pyridoxal-globin and pyridoxal-haemoglobin for all 6 multiple forms is 1.8-2.0 X 10(-5) M and 1.3 to 4 X 10(-6) M, respectively, and Ki of pepstatin is 2-4 X 10(-9) M. Gel filtration of the multiple forms on Sephadex G-100 column showed that each has a molecular weight of about 50 000. Human brain cathepsin D has a pH optimum of 3.2 with a smaller second optimum at pH 4.0 (pyridoxal-haemoglobin being used as substrate). All the multiple forms have the same pH-dependence curve. On SDS-polyacrylamide gel electrophoresis the purified enzyme produced 3 bands approximately corresponding to Mr 50 000, 35 000 and 15 000. Study of the breakdown of substance P and its C-terminal heptapeptide by cathepsin D shows that cleavage occurs at the Phe-Phe linkages of both substrates tested.
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PMID:Cathepsin D from human brain: purification and multiple forms. 667 69


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