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 otosclerotic stapes footplate exhibits higher activities of cathepsin D and H and collagenase-like peptidase than those of normal cortical bone. The elevated enzyme activities of osteoblastic origin (Cl-peptidase and cathepsin D) emphasize the essential and probably primary role of the bone-forming cells, not only in bone formation, but in resorption as well. The highest activity of cathepsin D from among the measured enzymes highlights the adjuvant role of acidic glucosaminoglycans in the otosclerotic demineralization process. As the osteoblastic osteoid synthesis is known to be sharply reduced in otosclerotic bone remodelling, and the above data emphasize the role of proteolytic enzymes of osteoblastic origin too, indirectly, osteoblasts seem to be the otosclerosis signal-transducing cells.
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PMID:Proteolytic enzymes in otosclerosis. Significance of proteolytic enzymes in otosclerotic bone remodelling. 332 89

p-Nitroanilides of amino acids and peptides were used to study the specificity of cathepsins H and B from human and bovine brain, respectively. The specific activity of cathepsin H decreased in the following order: Arg-pNa greater than or equal to Leu-pNa greater than Ala-pNa greater than or equal to Phe-pNa greater than Pro-pNa greater than Glu-pNa; Arg-pNa was split by the enzyme 12 times as fast as Bz-Arg-pNa. Among other oligopeptide p-nitroanilides tested (Ala-Ala, Ala-Leu, Ala-Ala-Ala, Ala-Ala-Leu, Gly-Gly-Leu, Gly-Gly-Phe, Gly-Leu-Phe, pGlu-Phe-Leu, pGlu-Phe-Ala, pGlu-Phe), PGlu-Phe-Leu and pGlu-Phe-Ala appeared to be the best substrates for cathepsin B; Km for hydrolysis were 0.1 mM and 0.165 mM, respectively, kcat were 5.1 and 8.3 s-1, respectively. A comparative study of substrate specificity of cathepsin D and high molecular weight aspartic peptidase with the use of fluorescent substrate with inner fluorescence quenching, Abz-Ala-Ala-Phe-Phe-pNa, revealed that both peptidases hydrolyzed the single bond between two phenylalanine residues, resulting in the increase of fluorescence (4.5-5-fold) of anthraniloyl tripeptide. The Km values for the substrate hydrolysis by cathepsin D and high molecular weight aspartic peptidase were 6.2 microM and 11.2 microM; kcat were 7.2 s-1 and 1.3 s-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[p-Nitroanilides of amino acids and peptides and fluorescence peptide with inner fluorescence quenching as substrates for cathepsins H, B, D and high molecular weight aspartic peptidase in the brain]. 332 84

The properties and subcellular localization of the elastase-like activities of smooth muscle cells cultured from pig aortas have been investigated. Homogenates of the cells hydrolysed N-succinyl-L-alanyl-L-alanyl-L-alanine-p-nitroanilide, a synthetic substrate for elastases, with a distinct pH optimum of 8.2 and hydrolysed insoluble elastin with a distinct pH optimum of 8.5. Both enzyme activities were directly proportional to the concentration of homogenate in the assay mixture. The activities toward both substrates were inhibited by phenylmethylsulphonyl fluoride and were therefore probably due to a serine peptidase(s). The activities were also inhibited by EDTA and, in a dose-related manner, by alpha 1-antiprotease. Pepstatin, which inhibits cathepsin D, and leupeptin, which inhibits cathepsin B, did not significantly inhibit the elastase-like activities in these cells. The cells were homogenized and a post-nuclear supernatant subjected to sucrose density gradient centrifugation. The distribution of elastase-like activity toward both substrates was similar to that of the plasma membrane marker 5'-nucleotidase, and distinct from those of marker enzymes for the other organelles. Cells were also homogenized with digitonin, which selectively increases the equilibrium density of the plasma membrane. The equilibrium densities of both 5'-nucleotidase and of the elastase-like activities were increased considerably, confirming the plasma membrane localization of the elastase-like activities. The subcellular localization of the elastase-like activities of arterial smooth muscle cells is therefore consistent with a role for them in the degradation of elastin in the normal arterial wall and in atherosclerotic lesions.
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PMID:Properties and subcellular localization of elastase-like activities of arterial smooth muscle cells in culture. 655 16

Using immunohistochemical or histochemical techniques lysosomal proteases have been localized in muscle cells. These include two exopeptidases (dipeptidyl peptidase I and II) and three endopeptidases (cathepsins B, D, and H). In general, the enzymes varied in apparent activities with the soleus muscle always more reactive than the extensor digitorum longus (EDL) of the rat. Cathepsin B and dipeptidyl peptidase I were localized primarily in subsarcolemmal regions whereas cathepsin H and dipeptidyl peptidase II were scattered throughout the sarcoplasm consistent with other observation of two populations of muscle lysosomes. However, cathepsin D could not be localized in either type of lysosome by similar histochemical techniques. Using immunohistochemical techniques, the protease inhibitors alpha 1-antitrypsin and alpha 1-inhibitor3 were recognized in intracellular compartments within muscle cells. alpha 1-antitrypsin appeared scattered throughout the cytoplasm while alpha 1-inhibitor3 was localized in discrete subsarcolemmal regions. Both inhibitor content and protease activity were diminished in skeletal muscles following streptozotocin-induced diabetes.
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PMID:Identification and possible regulation of muscle cell lysosomal protease activity by exogenous protease inhibitors. 704 96

1. Growing rats were fed either ad lib. or with six (equal) meals offered every 4 h (from 10.00 hours). Rats of each group were killed at intervals of 4 h beginning at 11.00 hours. Activities of cathepsin A (carboxypeptidase A; EC 3.4.12.2), C (dipeptidyl peptidase; EC 3.4.14.1) and D (endopeptidase D EC 3.4.23.5) were measured in liver and muscle homogenates and free amino acids in blood were determined. 2. In the rats fed ad lib. activities of carboxypeptidase A and endopeptidase D in liver and muscle showed significant variation, with maximum activity in the light period. In general, meal-feeding only caused minor differences in cathepsin activities; although significant differences occurred for carboxypeptidase A. For the later enzyme a peak in activity occurred in the dark as well as in the light period. 3. Irrespective of the feeding schedule, the lower concentration of free essential amino acids of blood occurred generally during the night period. With the controlled-feeding schedule there is an increase of essential amino acids and a slight decrease of non-essentail amino acids of blood.
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PMID:Variations through the day of hepatic and muscular cathepsin A (carboxypeptidase A; EC 3.4.12.2), C (dipeptidyl peptidase; EC 3.4.14.1) and D (endopeptidase D; EC 3.4.23.5) activities and free amino acids of blood in rats: influence of feeding schedule. 719 24

MHC class II molecules associate with peptides in the endocytic pathway. Different endosomal locations for peptide loading of class II molecules, varying from early endosomes (EE) to lysosomes, have been assigned on the basis of subcellular fractionation experiments. We have determined the intracellular location of HLA-DM, a molecule that supports peptide loading of class II molecules, by separating vesicles from the melanoma cell line Mel JuSo on the basis of buoying density and surface charge. In both fractionations, HLA-DM co-fractionated with a lysosomal compartment containing beta-hexosaminidase (beta-hex) activity and not with endosomes. Further analysis showed that HLA-DM mainly co-fractionated with a sub-lysosomal structure characterized by a relative low density and containing both pro- and mature cathepsin D and MHC class II molecules. Fluid phase markers first enter this compartment before entering high-density lysosomes that contain exclusively mature cathepsin D, some HLA-DM and no detectable MC class II molecules. Finally we determined the intracellular location of neutral and acidic peptidases. Whereas neutral peptidase activity was detected in the endoplasmic reticulum and/or plasma membrane fractions, acidic peptidase activity exclusively migrated at the position of HLA-DM containing lysosomal vesicles. Our results show that class II molecules co-migrate with HLA-DM, pro- and mature cathepsin D, beta-hex and acidic peptidase activity. HLA-DM, cathepsin d and class II molecules were not observed at the position of EE. Our data suggest that HLA-DM-mediated peptide loading of class II molecules occurs in a lysosomal subcompartment.
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PMID:HLA-DM and MHC class II molecules co-distribute with peptidase-containing lysosomal subcompartments. 867 50

Human dipeptidyl peptidase I was expressed in the insect cell/baculovirus system and purified in its active (rhDPPI) and precursor (pro-rhDPPI) forms. RhDPPI was very similar to the purified enzyme (hDPPI) with respect to glycosylation, enzymatic processing, oligomeric structure, CD spectra, and catalytic activity. The precursor, which was a dimer, could be activated approximately 2000-fold with papain. Cathepsin L efficiently activated pro-rhDPPI in vitro at pH 4.5 (k(app) approximately 2 x 10(3) min(-)(1) M(-)(1)), and two cleavage pathways were characterized. The initial cleavage was within the pro region between the residual pro part and the activation peptide. Subsequently, the activation peptide was cleaved from the catalytic region, and the latter was cleaved into the heavy and light chains. Alternatively, the pro region was first separated from the catalytic region. Cathepsin S was a less efficient activating enzyme. Cathepsin B and rhDPPI did not activate pro-rhDPPI, and the proenzyme was incapable of autoactivation. Incubation of both pro-rhDPPI and rhDPPI with cathepsin D resulted in degradation. Cystatin C and stefins A and B inhibited rhDPPI with K(i) values in the nanomolar range (K(i) = 0.5-1.1 nM). The results suggest that cathepsin L could be an important activator of DPPI in vivo and that cathepsin D and possibly the cystatins may contribute to DPPI downregulation.
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PMID:Human recombinant pro-dipeptidyl peptidase I (cathepsin C) can be activated by cathepsins L and S but not by autocatalytic processing. 1132 26

Blood-feeding parasites, including schistosomes, hookworms, and malaria parasites, employ aspartic proteases to make initial or early cleavages in ingested host hemoglobin. To better understand the substrate affinity of these aspartic proteases, sequences were aligned with and/or three-dimensional, molecular models were constructed of the cathepsin D-like aspartic proteases of schistosomes and hookworms and of plasmepsins of Plasmodium falciparum and Plasmodium vivax, using the structure of human cathepsin D bound to the inhibitor pepstatin as the template. The catalytic subsites S5 through S4' were determined for the modeled parasite proteases. Subsequently, the crystal structure of mouse renin complexed with the nonapeptidyl inhibitor t-butyl-CO-His-Pro-Phe-His-Leu [CHOHCH(2)]Leu-Tyr-Tyr-Ser- NH(2) (CH-66) was used to build homology models of the hemoglobin-degrading peptidases docked with a series of octapeptide substrates. The modeled octapeptides included representative sites in hemoglobin known to be cleaved by both Schistosoma japonicum cathepsin D and human cathepsin D, as well as sites cleaved by one but not the other of these enzymes. The peptidase-octapeptide substrate models revealed that differences in cleavage sites were generally attributable to the influence of a single amino acid change among the P5 to P4' residues that would either enhance or diminish the enzymatic affinity. The difference in cleavage sites appeared to be more profound than might be expected from sequence differences in the enzymes and hemoglobins. The findings support the notion that selective inhibitors of the hemoglobin-degrading peptidases of blood-feeding parasites at large could be developed as novel anti-parasitic agents.
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PMID:Hemoglobin-degrading, aspartic proteases of blood-feeding parasites: substrate specificity revealed by homology models. 1149 96

Breast cancer cells oversecrete the lysosomal peptidase cathepsin D as a pro-enzyme. In this study, we assessed the effect of media conditioned by MRC-5 fibroblasts or MCF-7/6 breast cancer cells on cathepsin D (CD) production and secretion by these two cell types. We also considered the influence of estrogens and matrix components (type I or type IV collagen, or Matrigel) on the expression and activity of CD produced by breast cancer cells of different invasive potentials (MCF-7/AZ, MCF-7/6, MDA-MB-231). In our system, fibroblasts conditioned medium does not significantly affect CD levels produced and secreted by the MCF-7/6 cells. However, we found that fibroblasts are able to capture the pro-CD secreted by these tumor cells by a mannose 6-phosphate-dependent process. We also found a positive correlation between the proportion of extracellular CD levels and the invasive potentials of the tumor cell types considered. If estrogens are able to upregulate CD production and secretion by receptor-positive cells, it is not the case of extracellular matrix components. On the other hand, our results indicate that matrix components are able to influence the distribution of the different CD forms in and out of the cells. Our data suggest that tumor fibroblasts, by enhancing their intracellular CD levels, could assist cancer cells in the digestion of extracellular matrix during the invasion of tissues.
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PMID:Fibroblasts capture cathepsin D secreted by breast cancer cells: possible role in the regulation of the invasive process. 1189 22

Lysosomal serine and cysteine proteases are reported to play a role in collagen degradation. In this study, the activities of the lysosomal cysteine proteases cathepsin B and H, dipeptidyl peptidase I, and the serine protease tripeptidyl peptidase I and dipeptidyl peptidase II, all ascribed a role in collagen digestion, were compared with those of the aspartate protease cathepsin D, and lysosomal glycosidases in leukocytes from rheumatoid arthritis patients at different stages of the disease. In all patients the activities of cysteine protease cathepsin B, dipeptidyl peptidase I, aspartate protease cathepsin D, and two glycosidases were elevated, but the activities of the serine proteases tripeptidyl peptidase I, dipeptidyl peptidase II, and the cysteine protease cathepsin H was unchanged. The magnitude of the increased activity was correlated with the duration of the disease. Patients with long-standing RA (10 years or more) had higher cysteine protease activity in their leukocytes than did those with disease of shorter duration. This tendency suggests that elevated lysosomal cysteine protease activities, together with aspartate protease cathepsin D and lysosomal glycosidases (but not serine proteases), are associated with progression of rheumatoid arthritis.
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PMID:Lysosomal peptidases and glycosidases in rheumatoid arthritis. 1210 54


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