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)

The cellular basis of the age-related decline in the functional capacity of many mammalian organs is still poorly understood. In this paper, the rat liver is presented as a promising model for studying cellular phenomena underlying organ ageing. The recent development of methods for isolation and purification of parenchymal, Kupffer and endothelial cells from the rat liver makes possible the comparison of functional and metabolic changes in the intact liver with changes in distinct liver cell classes isolated from rats of various age groups. An attempt has been made to correlate age changes in some important liver-specific functions, such as bromsulophthalein uptake and albumin synthesis, at the organ and at the cellular level. To compare cellular ageing phenomena in long-lived cells (parenchymal cells) and short lived cells (Kupffer and endothelial cells) from the same organ, the role of lysosomes in cellular ageing processes was investigated, with secial reference to the functioning of the lysosomal enzyme cathepsin D. The specific cathepsin D activity in Kupffer cells was abour 3 times higher than in endothelial cells and about 20 times higher than in parenchymal cells. The enzyme activity in the latter cell type showed a significant increase with age.
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PMID:Model systems for studies on cellular basis of organ ageing. 1 45

A chymotrypsin-like esterase was purified from beef lung. This lysosomal enzyme, not previously characterized, seemed to be composed of two or more forms with molecular weights of about 52 000. It hydrolysed N-benzoyl-DL-phenylalanine beta-naphthol ester at acid and neutral pH; it polymerized L-phenylalanine methyl ester(Phe-OMe) at neutral pH; and it transferred the Phe-residue from Phe-OMe to hydroxylamine at neutral pH. Phenylmethanesulfonyl fluoride, an inhibitor of hydrolytic enzymes with serine in their catalytic site, inhibited this enzyme, but pepstatin, the cathepsin D (EC 3.4.4.23) inhibitor, did not. Sulfhydryl reagents were not required for activity. Macrophages, especially pulmonary alveolar macrophages, were a rich source of this esterase, so it is likely that the enzyme purified from lung came from its macrophages. The esterase hydrolysed and transferred monoamino acid esters, especially those of the aromatic type. Cathepsin C, the dipeptidyl peptide hydrolase (EC 3.4.14.1), acted only on dipeptide esters and amides. Pancreatic chymotrypsin acted on both monoamino acid and dipeptide esters. The chymotrypsin-like esterase did not hydrolyse hemoglobin, casein, or plasma albumin. Thus its proteolytic activity, if present, must be limited to specific substrates, as yet unknown.
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PMID:Macrophage esterase: identification, purification and properties of a chymotrypsin-like esterase from lung that hydrolyses and transfers nonpolar amino acid esters. 24 Apr 26

The purity of cathepsin D has been increased from 150 units/mg to over 200 units/mg. Peptides such as Ala-Phe-NH2, His-Phe-NH2 and Phe-Phe were split by impure enzyme and activity was blocked by pepstatin and diazoacetylnorleucine methyl ester. Pure preparations no longer digested these peptides. This points to the presence of a second peptidase activity similar to cathepsin D in specificity and inhibition properties, but distinct from it . Cathepsin D splits the peptides Leu-Phe-NH2, Leu-Tyr-NH2, Ac-Phe-TyrI2, and Ala-Leu-Tyr-Leu upon overnight incubation. More rapid splitting is found with phenyl sulfite, Glu-Ala-Leu-Tyr-Leu-Val, and Bz-Arg-Gly-Phe-Phe-Leu-4-methoxy-beta-naphthylamide. Digestion of bovine hemoglobin and human serum albumin by ruptured rat liver tritosomes was studied over the pH range 2.5-6.5. The combined action of cathepsin D and thiol proteinases accounted for most of the digestion. Cathepsin D accounted for 75% of the hemoglobin digestion at pH 3 and 45% at pH 5. Thiol proteinase accounted for 85% of the albumin digestion at pH 5. The role of cathepsin D in the development of embryonic limbs and skin, in uterine involution, and in cartilage degradation was reviewed. The activity of cathepsin D on cartilage matrix proteoglycans is limited to acid pH values. Human articular cartilage also contains metalloproteases active at pH 4.5 and 5.7.
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PMID:Specificity and biological role of cathepsin D. 59 4

1. Renin was purified 30 000-fold from rat kidneys by chromatography on DEAE-cellulose and SP-Sephadex, and by affinity chromatography on pepstatinyl-Sepharose. 2. The enzymatic properties of isorenin from rat brain, pseudorenin from hog spleen, cathepsin D from bovine spleen, and renin from rat kidneys were compared: Isorenin, pseudorenin and cathepsin D generate angiotensin from tetradecapeptide renin substrate with pH optima around 4.9, renin at 6.0. With sheep angiotensinogen as substrate, isorenin, pseudorenin and cathepsin D have similar pH profiles (pH optima at 3.9 and 5.5), in contrast to renin (pH optimum at 6.8). 3. The angiotensin-formation from tetradecapeptide by isorenin, pseudorenin and cathepsin D was inhibited by albumin, alpha-and beta-globulins. These 3 enzymes have acid protease activity at pH 3.2 with hemoglobin as the substrate. Renin is not inhibited by proteins and has no acid protease activity. 4. Renin generates angiotensin I from various angiotensinogens at least 100 000 times faster than isorenin, pseudorenin or cathepsin D, and 3000 000 times faster than isorenin when compared at pH 7.2 with rat angiotensinogen as substrate. 5. The 3 'non-renin' enzymes exhibit a high sensitivity to inhibition by pepstatin (Ki less than 5.10(-10) M), in contrast to renin (Ki approximately 6-10(-7) M), at pH 5.5. 6. It is concluded from the data that isorenin from rat brain and pseudorenin from hog spleen are closely related to, or identical with cathepsin D.
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PMID:Isorenin, pseudorenin, cathepsin D and renin. A comparative enzymatic study of angiotensin-forming enzymes. 62 74

1. 'Inhibitor fragment' isolated from human serum albumin degraded by rabbit cathepsin D is composed of one peptide chain with two intrachain disulphide bonds. There are two kinds of inhibitor molecules having different N-terminal amino acids: one is threonine and the other glutamine. 2. Fragment F1, isolated from inhibitor degraded by trypsin, is composed of two chains linked by a disulphide bond. There are three kinds of fragment F1. All have one alpha chain in common, which has an intrachain disulphide bond. They differ by the nature of the chain, which is linked to the alpha chain by a disulphide bond. The epsilon chain is present in trace amounts. The two other chains, beta and gamma, differ by their C-terminal amino acid, which is respectively arginine and lysine. 3. Inhibitor is composed of the last 92 or 89 residues of the human albumin molecule and fragment F1 is composed of two parts of this C-terminal portion of the albumin molecule.
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PMID:Chemical structure of two fragments of human serum albumin and their location in the albumin molecule. 116 60

An acid proteinase has been detected in culture supernate of the 9.2.27 murine hybridoma. This enzyme extensively degrades albumin and transferrin during short incubations at pH 3 and below. Limited proteolysis of the 9.2.27 IgG2a appears to occur in the culture supernate. Proteolysis in enhanced at low pH in the presence of urea or 1 M acetic acid. The proteinase activity accumulates in continuous perfusion, total cell recycle cultures, beginning during exponential growth of the hybridoma. It is destroyed by boiling and blocked by pepstatin, but not by inhibitors of cysteine or serine proteinases or by EDTA. The low pH optimum may distinguish this enzyme from the known rat and mouse aspartic acid proteinases including cathepsin D and cathepsin E.
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PMID:A novel acid proteinase released by hybridoma cells. 136 94

Incubation of bovine serum albumin (BSA), rat serum albumin or rat plasma with medium conditioned by endotoxin stimulated rat peritoneal macrophages produced an activity that released histamine from isolated rat serosal mast cells. The amount of histamine-releasing activity (HRA) produced increased with the length of the incubation period, with the concentration of albumin, with the number of macrophages stimulated, and with the duration of exposure of the macrophages to endotoxin. Moreover, the formation of the HRA showed a dependency on the pH of the incubation medium with an optimum at pH 4.5. Boiling the medium conditioned by stimulated macrophages before its incubation with albumin or including the acid protease inhibitor, pepstatin with the conditioned medium prevented the formation of HRA. The generation of HRA was not inhibited by pretreatment of the macrophages with the inhibitor of protein synthesis, cycloheximide. Media from macrophages not stimulated with endotoxin failed to generate HRA. Histamine release from mast cells in response to the HRA was inhibited by pretreatment of the cells with antimycin A and deoxyglucose or by preincubation in Ca-free Locke's solution containing a calcium chelating agent. When injected intradermally into anesthetized Evan's Blue treated rats, the generated HRA produced a change in vascular permeability that was prevented by the H1 antagonist, diphenhydramine. Treatment of the HRA with carboxypeptidase A reduced its ability to stimulate histamine release from mast cells. Histamine-Releasing Peptide (HRP), a neurotensin-related octapeptide, shown previously by us to be formed by the action of cathepsin D or pepsin on albumin, was identified by radioimmunoassay in acid:acetone extracts of the histamine-releasing activity. It is concluded that the formation of HRA is due to the actions of enzymes released from macrophages acting on albumin. It is suggested that such histamine-releasing activity could be formed during the later stages of the inflammatory response and that HRP is one of the peptides present.
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PMID:Formation of histamine-releasing activity from albumin by medium conditioned by endotoxin-stimulated rat peritoneal macrophages. 138 Jul 64

Forssman antigen, a neutral glycosphingolipid carrying five monosaccharides, was localized in epithelial MDCK cells by the immunogold technique. Labeling with a well defined mAb and protein A-gold after freeze-substitution and low temperature embedding in Lowicryl HM20 of aldehyde-fixed and cryoprotected cells, resulted in high levels of specific labeling and excellent retention of cellular ultrastructure compared to ultra-thin cryosections. No Forssman glycolipid was lost from the cells during freeze-substitution as measured by radio-immunostaining of lipid extracts. Redistribution of the glycolipid between membranes did not occur. Forssman glycolipid, abundantly expressed on the surface of MDCK II cells, did not move to neighboring cell surfaces in cocultures with Forssman negative MDCK I cells, even though they were connected by tight junctions. The labeling density on the apical plasma membrane was 1.4-1.6 times higher than basolateral. Roughly two-thirds of the gold particles were found intracellularly. The Golgi complex was labeled for Forssman as were endosomes, identified by endocytosed albumin-gold, and lysosomes, defined by double labeling for cathepsin D. In most cases, the nuclear envelope was Forssman positive, but the labeling density was 10-fold less than on the plasma membrane. Mitochondria and peroxisomes, the latter identified by catalase, remained free of label, consistent with the notion that they do not receive transport vesicles carrying glycosphingolipids. The present method of lipid immunolabeling holds great potential for the localization of other antigenic lipids.
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PMID:Subcellular localization of Forssman glycolipid in epithelial MDCK cells by immuno-electronmicroscopy after freeze-substitution. 195 53

Antibodies specific for the insulin-regulatable glucose transporter (GLUT 4) were used to immunolocalize this protein in brown adipose tissue from basal- and insulin-treated rats. Cryosections of fixed tissue were incubated with antibodies, which were subsequently labeled with Protein A/gold and examined by EM. Antibodies against albumin and cathepsin D were also used with gold particles of different sizes to identify early and late endosomes, respectively. Under basal conditions 99% of the GLUT 4 labeling was located within the cell. Labeling was predominantly in the trans-Golgi reticulum and tubulo-vesicular structures elsewhere in the cytoplasm. In insulin-stimulated cells approximately 40% of the GLUT 4 labeling was at the cell surface, where it was randomly distributed, except for occasional clustering in coated pits. Moreover, after insulin treatment, GLUT 4 was also enriched in early endosomes. We conclude that translocation of GLUT 4 to the cell surface is the major mechanism by which insulin increases glucose transport. In addition, these results suggest that in the presence of insulin GLUT 4 recycles from the cell surface, probably via the coated pit-endosome pathway that has been characterized for cell surface receptors, and also that insulin causes the redistribution of GLUT 4 by stimulating exocytosis from GLUT 4-containing tubulo-vesicular structures, rather than by slowing endocytosis of GLUT 4.
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PMID:Immuno-localization of the insulin regulatable glucose transporter in brown adipose tissue of the rat. 200 17

The degradation of native albumin by human spleen cathepsin D was inhibited by GSH, cysteine and cysteamine. The thiols existing physiologically also inhibited reduced-carboxymethylated albumin, indicating that these thiols react preferentially with the enzyme itself rather than the substrate. The inhibitions of native albumin proteolysis were dose-dependent. These effects of thiols which have not been observed in other animal cathepsin D, suggest an essential function for cathepsin D in the human spleen.
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PMID:Inhibitory effect of thiols on the degradation of albumin by human spleen cathepsin D. 240 72


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