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)

A neutral proteinase secreted by rabbit synovial fibroblasts in parallel with specific collagenase was partially purified by ion-exchange chromatography. At pH 7.6 this proteinase degraded 35S-labelled bovine nasal proteoglycan and azo-casein. The enzymic activity was inhibited by EDTA, 1,10-phenanthroline and serum, whereas di-isopropyl phosphorofluoridate and soya-bean trypsin inhibitor had little effect. By gel filtration the apparent mol.wt. of the enzyme was 25000. The fibroblast neutral proteinase was compared with the proteoglycan-degrading neutral proteinases of rabbit polymorphonuclear-leucocyte granules. Two distinct activities were found in the granules: one was inhibited by soya-bean trypsin inhibitor and the other by EDTA. The proteoglycan-degrading proteinases of rabbit fibroblasts and polymorphonuclear leucocytes at acid pH also were examined. Both cathepsin D and a thiol-dependent proteinase contributed to the degradation of proteoglycan at pH 4.5.
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PMID:Proteoglycan-degrading enzymes of rabbit fibroblasts and granulocytes. 3 Apr 51

Cathepsin D was purified from rat liver using a new affinity chromatographic method, based on the coupling to the specific inhibitor pepstatin. This preparation was used for the production of specific antibodies from rabbit. The purified IgG fraction was conjugated to horseradish peroxidase in a two-step coupling procedure and used for electron microscopic immunohistochemistry of the odontoblast-predentine region of the rat incisor. Precipitates, indicating the presence of cathepsin D, were seen in the odontoblast, odontoblast process, and in the extracellular unmineralized matrix, the predentine. The observations are discussed in relation to proteoglycan degradation at the mineralization front simultaneous with crystal formation, and in relation to the function of lysosomal enzymes in the turnover of connective tissue.
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PMID:Cathepsin D: ultra-immunohistochemical localization in dentinogenesis. 11 89

Connective tissue cells are capable of both synthesizing and degrading the macromolecular components of the extracellular matrix. The degradation of proteoglycan and collagen has been shown to be associated with the extracellular release of proteolytic enzymes, some of which are of lysosomal origin. The identity in carilage of two previously unrecognized proteases, capable of proteoglycan breakdown (CPGases), has recently been achieved by the use of a new assay for proteoglycan degradation. These enzymes have been shown to be synthesized and released in response to vitamin A. The third proteoglycan degrading enzyme of connective tissue cells, cathepsin D, has been located in the pericellular environment by trapping with specific antibody and the pattern of release studied in organ culture, experimental arthritis and in human rheumatoid tissues. The secretion of this enzyme and possibly also of the other CPGases is thought to be of importance in the local (pericellular) turnover of matrix macromolecules and, in association with collagenase, to be the cause of the excessive degradation in the pannus erosion of articular cartilage in rheumatoid arthritis.
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PMID:The secretion of enzymes into the pericellular environment. 23 25

1. Proteoglycan was obtained from bovine nasal cartilage by a procedure involving sequential extraction with a low-ionic-strength KCl solution, then a high-ionic-strength CaCl2 solution. Purification was by CsCl-density-gradient centrifugation. 2. The CaCl2- extracted proteoglycan was subjected to proteolytic degradation by papain, trypsin, cathepsin D, cathepsin B, lysosomal elastase or cathepsin G. Degradation was allowed to proceed until no further decrease in viscosity was detectable. 3. The size and chemical composition of the final degradation products varied with the different proteinases. Cathepsin D and cathepsin G produced glycosaminoglycan-peptides of largest average size, and papain produced the smallest product. 4. The KCl-extracted proteoglycan was intermediate in molecular size and composition between the CaCl2-extracted proteoglycan and the largest final degradation products, and may have been formed by limited proteolysis during the extraction procedure. 5. It is postulated that the glycosaminoglycan chains are arranged in groups along the proteoglycan core protein. Proteolytic cleavage between the groups may be common to the majority of proteinases, whereas clevage within the groups is dependent on the specificity of each individual proteinase.
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PMID:The degradation of cartilage proteoglycans by tissue proteinases. Proteoglycan structure and its susceptibility to proteolysis. 60 25

1. CaCl2-extracted proteoglycan from bovine nasal cartilage was degraded by four tissue proteinases till no further decrease in hydroynamic size was obtained. The proteoglycan and its final degradation products were then fractionated by Sepharose 2B chromatography. 2. The average size of the degradation products was least for cathepsin B and lysosomal elastase, and greatest for cathepsin D and cathepsin G. The latter two proteinases also produced degradation products that showed the widest range of sizes. 3. The structure of the degradation products ranged from peptides containing a single glycosaminoglycan chain to those containing twelve or more chains. Of the four proteinases, only cathepsin B produced peptides that contained a single chondroitin sulphate chain. 4. The proteoglycan was very heterogeneous with respect to size and chemical composition. Its behaviour on electrophoresis suggested that at least two genetically distinct core proteins might exist. 5. Irrespective of their structural variations, all proteoglycan molecules were able to interact with hyaluronic acid. In contrast, none of the degradation products were capable of this type of interaction. 6. A pathway for the proteolytic degradation of proteoglycans is postulated in which the sites of initial cleavage may be common to the majority of proteinases, whereas the production of the final clusters is dependent on the specificity of the proteinase. Only those proteinases of broadest specificity can produce single-chain chondroitin sulphate-peptides.
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PMID:The degradation of cartilage proteoglycans by tissue proteinases. Proteoglycan heterogeneity and the pathway of proteolytic degradation. 60 26

In continuation of previous studies, which showed a catabolic defect in proteoglycan metabolism, enzymes which degrade the proteoglycan macromolecules, e.g. proteinases (cathepsin D, elastase, and cathepsin G) and glycoisidases (arabinosidase and xylosidase) have been assayed in leucocytes of DMC patients. The regulator of lysosomal proteinases, cyclic AMP and serum antiproteinases, e.g. alpha1-AT and alpha2-M, have also been assayed. The proteinases assayed were normal in DMC patients. Arabinosidase activity in leucocytes of the patients was found to be decreased three fold, while xylosidase activity was increased three fold. A four-fold increased concentration of cyclic AMP in leucocytes of the patients and an increased serum concentration of alpha2-M associated with its abnormal pattern in crossed immunoelectrophoresis have been found. The abnormality in serum alpha2-M of DMC patients may be explained by a complex formation of alpha2-M with collagenase released from the lysosomes. Finally, an abnormal peptidoglycan has been demonstrated in DMC urine.
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PMID:Biochemical abnormalities in Dyggve-Melchior-Clausen syndrome. 63 1

It is evident that human articular cartilage possesses, in addition to multiple forms of cathepsin D, multiple forms of other acid cathepsins, and, most important, a family of at least four closely related neutral protease enzyme forms, all of which degrade proteoglycan. In addition, caseinase and histonase activities are present. The search for these enzymes in human cartilage ahs been presented in some detail in order to give an idea of some of the problems faced in such research, as well as the hypotheses and hopes that flow from it and prepare the ground for further research. The actual role of proteolytic enzymes in the physiologic and pathologic condition of cartilage remains to be determined. It is hoped that these enzymes, especially the neutral protease forms, will be sufficiently purified to enable preparation of antibodies to them. This will help to clarify what controls their release from the chondrocytes and where they function in the cartilage. Meanwhile, it seems appropriate to study the neutral protease forms and their role in initiating the degradation of proteoglycan in the early stages of osteoarthritis. The chief role of cathepsin D and the new acid cathepsins is most likely in intracellular digestion. One may hypothesize a three-step sequence of the degradation of the matrix proteoglycan: (1) initial extracellular attack by the neutral matrix, (2) endocytosis of the fragments by the cells, and (3) completion of their degradation within the lysosomal digestive system of the cell. The initial degradation of the matrix proteoglycan would facilitate the entrance of other degrading enzymes from the synovium to aid in total destruction of the cartilage. While awaiting knowledge of the primary events that trigger the development of osteoarthritis, enzymatic research offers the real hope of finding a way to control the enzymatic degradation of proteoglycan occurring in the early stages of the disease. Research into the nature of these degrading enzymes will lead to the development of therapeutically suitable inhibitors.
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PMID:Proteolytic enzymes in human cartilage: the pathogenesis of osteoarthritis. 97 57

A single intraarticular injection of carrageenin into the rabbit knee joint initiates an inflammatory reaction in the synovial tissues. the exudate from the joint was able to degrade proteoglycan at pH 5.2 and pH 7.2. Further characterization of proteolytic enzymes in the inflamed synovial tissues showed the presence of cathepsin D, a neutral protease, and cathepsin B1. Maximum activities of two lysosomal enzymes, acid phosphatase and cathepsin D, were observed within 7 days of injection. Most of this activity was found to be associated with cells in the synovial fluid.
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PMID:Carrageenin-induced arthritis. III. Proteolytic enzymes present in rabbit knee joints after a single intraarticular injection of carrageenin. 99 38

The proteinase cathepsin D which degrades proteoglycan was never demonstrated in extracellular sites in tissues from patients with traumatized meniscoid cartilage, either before or after culture with an antiserum to human cathepsin D. In contrast, in synovia (but not usually cartilage) from the knees of 6 of 11 rheumatoid patients, extracellular cathepsin D was commonly detected by culturing tissues with an antiserum to this enzyme.
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PMID:Secretion and localization of cathepsin D in synovial tissues removed from rheumatoid and traumatized joints. An immunohistochemical study. 103 89

Cytolytic lymphocytes contain specialized lytic granules whose secretion during cell-mediated cytolysis results in target cell death. Using serial section EM of RNK-16, a natural killer cell line, we show that there are structurally distinct types of granules. Each type is composed of varying proportions of a dense core domain and a multivesicular cortical domain. The dense core domains contain secretory proteins thought to play a role in cytolysis, including cytolysin and chondroitin sulfate proteoglycan. In contrast, the multivesicular domains contain lysosomal proteins, including acid phosphatase, alpha-glucosidase, cathepsin D, and LGP-120. In addition to their protein content, the lytic granules have other properties in common with lysosomes. The multivesicular regions of the granules have an acidic pH, comparable to that of endosomes and lysosomes. The granules take up exogenous cationized ferritin with lysosome-like kinetics, and this uptake is blocked by weak bases and low temperature. The multivesicular domains of the granules are rich in the 270-kD mannose-6-phosphate receptor, a marker which is absent from mature lysosomes but present in earlier endocytic compartments. Thus, the natural killer granules represent an unusual dual-function organelle, where a regulated secretory compartment, the dense core, is contained within a pre-lysosomal compartment, the multivesicular domain.
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PMID:The lytic granules of natural killer cells are dual-function organelles combining secretory and pre-lysosomal compartments. 227 62


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