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)

Medium conditioned by the culture of porcine gingival explants was shown to contain, in addition to collagenase, proteolytic activity capable of releasing small fragments, devoid of hydroxyproline but containing hydroxynorleucine, from reduced (tritiated) type I collagen in solution at neutral pH. Quantitative comparison of this effect with that of cathepsin D, at pH 4, revealed that the fragments were derived at least in part from the carboxy-terminal, extra-helical portion of the collagen alpha 1-chains. Incubation of concentrated conditioned medium with fibrillar acetic acid-insoluble collagen resulted in the solubilization of the TC 3/4 and TC 1/4 fragments characteristic of the action of collagenase. However, alpha 1-chain fragments isolated from the latter were found to lack the antigenic determinant normally present on the amino-terminal side of the (hydroxy-)lysine residue which is known to be involved in intermolecular cross-linking. It is therefore suggested that the proteolytic activity described above was involved in the solubilization process. Both the release of low molecular fragments from soluble collagen and the solubilization effect were abolished by ethylenediaminetetra-acetic acid.
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PMID:Cleavage of the carboxy-terminal cross-linking region of type I collagen by proteolytic activity from cultured porcine gingival explants. 631 80

Cultured tissue slices from normal immature rabbit articular cartilage released latent neutral metalloproteinases into serum-free medium. On activation with 4-aminophenylmercuric acetate, these metalloproteinases could degrade collagen, proteoglycan, and gelatin. Also produced were an acid proteinase with the properties of cathepsin D and an inhibitor of the neutral metalloproteinases. The appearance of both the proteinases and the inhibitor in the culture medium could be prevented by incubation of cultures with cycloheximide. The active and latent forms of the proteinases were characterized using Ultrogel AcA 54 chromatography.
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PMID:Characterization of latent and active forms of cartilage proteinases produced by normal immature rabbit articular cartilage in tissue culture. 634 45

The activities of four lysosomal and two nonlysosomal hydrolases were studied in skeletal muscle biopsy samples from patients with neuromuscular diseases and from controls. beta-Glucosaminidase activity was increased in polymyositis. beta-Glucuronidase and alkaline protease activities were elevated in muscular dystrophy in adults, whereas cathepsin D activity was increased in amyotrophic lateral sclerosis. There were significant correlations between the activities of lysosomal and nonlysosomal hydrolases. The activity of beta-glucuronidase, beta-glucosaminidase, alkaline protease, and dipeptidyl aminopeptidase IV showed a positive correlation with the severity of muscular atrophy. The activities of these hydrolases and the activity of dipeptidyl aminopeptidase I correlated positively with the activities of muscular galactosylhydroxylysyl glucosyltransferase and with the serum concentration of type III procollagen aminoterminal propeptide. The results suggest that in neuromuscular diseases the lysosomal and nonlysosomal pathways for muscle degradation are affected concomitantly with collagen biosynthesis.
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PMID:Lysosomal and nonlysosomal hydrolases of skeletal muscle in neuromuscular diseases. 635 16

Preferential labeling of COOH-terminal sequences in newly synthesized fibronectin was achieved by short term incorporation of radiolabeled amino acids in the presence of pactamycin, an inhibitor of polypeptide chain initiation. The labeled fibronectin was then cleaved with cathepsin D under conditions that yield a large (137,000-dalton) fragment that lacks collagen-binding properties, and a smaller (72,000-dalton) fragment that retains the ability of fibronectin to bind to collagen. Determination of the relative specific radioactivities of the two fragments leads us to conclude that the collagen-binding domain in fibronectin is located in the NH2-terminal third of the polypeptide chain and not in a COOH-terminal region as previously indicated by other structural studies.
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PMID:Location of a collagen-binding domain in fibronectin. 644 47

Protein degradation was measured as tyrosine release rate from proteins of extensor digitorum longus (EDL) muscles and as urinary excretion of 3-methylhistidine in freely fed adult nongrowing C57BL/6J mice with sarcomas, to study protein degradation in cancer-induced wasting of skeletal muscles. Whole muscle protein breakdown rate was unchanged, whereas protein synthesis was depressed, leading to an increased net degradation of skeletal muscles with loss of soluble, myofibrillar, and collagen proteins. Starvation for 24 hours elevated whole muscle protein breakdown in mice with and without sarcomas. Subsequent refeeding for 24 hours normalized the degradation. Adaptation to anorexia in pair-fed controls was achieved by a decrease in muscle protein turnover evaluated by urinary excretion of 3-methylhistidine over 5 days. The measurement of "catabolic decrease" of muscle protein breakdown protected the muscle mass in mice without tumors, but it was ineffective in tumor-bearing animals. The unchanged rate of breakdown of proteins in whole EDL muscles from tumor-bearing mice was accompanied by increased maximum cathepsin D activity and by elevated autolytic activity at acid pH in some muscles. Therefore, cathepsin D activity and net protease activities did not reflect whole muscle protein degradation in tumor-induced malnutrition. The results demonstrate that wasting of skeletal muscles in experimental cancer was not dependent on increased degradation but was dependent on depressed protein synthesis.
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PMID:Lack of evidence for elevated breakdown rate of skeletal muscles in weight-losing, tumor-bearing mice. 657 91

Local or systemic prostaglandin (PG) administration leads to the known softening and dilatation of the cervix uteri. Lysosomal enzymes are involved in connective tissue degradation. The question arises whether the effect of PG on the cervix uteri is mediated by lysosomes. Five pregnant women (volunteers after informed consent) in the first trimester received 500 micrograms of PGE2-derivative (Nalador) i.m. at 12 and 8 h before termination by curettage. Five pregnant women without PG-treatment served as controls. Small biopsies were obtained from the endocervical canal and were immediately immersed in cold 2.5% glutaraldehyde and after further preparations examined under a Zeiss electron microscope 9S-2. A second portion of tissue was sliced and prepared for histochemical analysis of the acid phosphatase on lysosomes. Examination of the ultrastructure of the cervix uteri showed vesicles in the extracellular matrix. These were surrounded by a single membrane and contained either fine granular material of myelin-like whorls of membranes. These vesicles lay between collagen fibers, showed the reaction product of acid phosphatase and were often surrounded by an electron-lucent halo. We conclude that these matrix vesicles were "matrix lysosomes" extruded from the cervical myo-fibrocytes into the extracellular space as a result of the PG-E2-administration. Here they are not under cellular control and can initiate the proteolytic degradation of connective tissue. This might be the crucial step in cervical dilatation which, on ultrastructural examination, can be seen as decreasing electron density of the extracellular ground substance near the matrix lysosomes. The relationship between PGE2 and collagenase production is generally accepted. If one believes that lysosomal cathepsin D and cathepsin B act synergistically with collagenase, it can be assumed that PGE2 is involved in a lysosomal degradation of the connective tissue. The morphological sign of this occurrence is the release of matrix lysosomes by PGE2 as described in the present study. Extracellular lysosomes and their physiological significance in cervical function are discussed in detail.
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PMID:The effect of prostaglandins on the lysosomal function in the cervix uteri. 666 Sep 24

1. Cathepsin D, purified from bovine thymus, has a limited proteolytic effect on types I and III bovine collagens. The alpha 1 (I) chain was cleaved in native or denatured collagen only within the carboxy-terminal extra-helical sequence, the major site being between resides C6 (Leu) and C7 (Ser). The alpha 2 chain was unaffected in native collagen but was slowly cleaved between residues 782 (Phe) and 783 (Leu) in the denatured form. Cleavages, at 45 degrees C, in type III collagen occur within the extra-helical amino-terminal sequence, on the carboxy-terminal side of the lysine residue involved in intermolecular cross-linking. All three sites of action are within sequences of general hydrophobic character. 2. The very restricted cleavage of peptide bonds in denatured collagens can be ascribed to the infrequent occurrence of groupings of more than two hydrophobic residues and to the high content of the conformation-limiting residues proline and hydroxyproline. 3. The previously demonstrated failure of cathepsin D to solubilize a representative proportion of type III collagen from the fibres of bovine skin collagen [P.G. Scott and C.H. Pearson (1978) Biochem, Soc, Trans. 6, 1197-1199] may be explained by lack of ability of the enzyme to act on this collagen at 25 degrees C, in such a manner as to separate molecules joined by intermolecular cross-links involving the amino-terminal extrahelical region of the molecule.
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PMID:Cathepsin D: specificity of peptide-bond cleavage in type-I collagen and effects on type-III collagen and procollagen. 678 4

Resolution of a cathepsin D digest of plasma fibronectin on heparin-Sepharose yielded, in addition to non-bound and weakly retained material (Fraction I and II), various fragments which were not eluted until 0.25M NaCl (Fraction III) and 0.5M NaCl (Fraction IV) was applied. Fraction III contained predominantly a peptide of Mr 70 000 originating from the N-terminus of the fibronectin subunits as well as high molecular weight precursors yielding the Mr 70 000 peptide by further digestion. All those peptides were retained by immobilized denatured collagen, type I, indicating the presence of the known gelatin-binding domain. In addition, they contained a transamidase-sensitive site as revealed from a digest of fibronectin previously labelled with [14C]putrescine by a transamidase-mediated reaction. Plasminolysis of the fragment of Mr 70 000 resulted in two peptides of Mr 30 000 and 40 000, only the former being retained by heparin-Sepharose. Fraction IV contained a fragment of Mr 140 000 which, after reduction, dissociated into two peptides of Mr 75 000 and 65 000. Apparently, it included the disulfide bond(s) connecting the two fibronectin subunits close to their C-terminal ends. Partial digestion of the two electrophoretically separated peptide chains with protease of Staphylococcus aureus V8 yielded for each chain a number of peptides with equal electrophoretic migration rate. In addition, however, some peptides were different in the two digests. The results were consistent with an identical or homologous structure of the two peptide chains with an additional sequence in the longer chain. The latter (Mr 75 000) uniquely contained a transamidase susceptible site as demonstrated by processing of [14C]putrescine-labelled fibronectin.
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PMID:Location of heparin-binding sites of fibronectin. Detection of a hitherto unrecognized transamidase sensitive site. 723 39

Cells from porcine epithelial rests of Malassez were cultured in vitro with collagen prepared from rat tail tendons. Serial sections of the cultures were prepared for examination in the electron microscope. Some of the material was processed to demonstrate activity of acid phosphatase. Electron microscopy showed that the epithelial cells had phagocytosed collagen in vitro, and study of the serial sections indicated that much of the phagocytosed collagen was contained wholly within the cells. Reaction product indicating sites of acid phosphatase activity was found to be associated with intracellular collagen, and some of the intracellular fibrils exhibited nonsymmetrical loss of material and also localized loss of banding, suggesting intracellular digestion of collagen. A lysosomal fraction was prepared from epithelial cells cultured from the rests of Malassez, and this was shown using biochemical assays to contain activities of thiol-dependent cathepain, cathepsin D, beta-D-glucuronidase, aryl sulfatase, and acid phosphatase. The lysosomal fraction had the capacity in vitro to depolymerize and digest collagen obtained from rat tail tendon. It was concluded from these observations and results that epithelial cells cultured from the rests of Malassez can digest collagen in vitro. The findings suggests a possible mechanism whereby the epithelial cells can destroy the extracellular substance of connective tissue during their well known participation in cyst formation in vivo.
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PMID:Epithelial rests of Malassez in vitro. Phagocytosis of collagen and the possible role of their lysosomal enzymes in collagen degradation. 739 75

Dependence of collagen fractions content from the activities of cathepsin D and acid phosphatase as well as dynamics of their alteration under the influence of choriogonine were studied in cirrhotic liver tissue of rats. Content of the collagen proteins was decreased, with simultaneous increase in amount of their soluble fractions, after treatment of the animals by choriogonine. At the first step of the experiment the activity of the hydrolytic enzymes was decreased but it was normalized to the end of the experiment; at the same time, activity of cathepsin D remained high in the non-sedimentable fraction. Correlation between the activity of cathepsin D and content of collagen fractions was observed in the liver tissue. This enzyme appears to participate in catabolism of collagen.
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PMID:[Effect of lysosomal cathepsin D and acid phosphatase on collagen protein catabolism in cirrhotically altered liver after stimulating regeneration with choriogonin]. 745 75


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