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)

Many parasites have deployed proteinases to accomplish some of the tasks imposed by a parasitic life style, including tissue penetration, digestion of host tissue for nutrition and evasion of host immune responses. Information on proteinases from trematodes, cestodes and nematode parasites is reviewed, concentrating on those worms of major medical and economical importance. Their biochemical characterization is discussed, along with their putative biological roles and, where available, their associated genes. For example, proteinases expressed by the various stages of the schistosome life-cycle, in particular the well-characterized cercarial elastase which is involved in the penetration of the host skin and the variety of proteinases, such as cathepsin B (Sm31), cathepsin L1, cathepsin L2, cathepsin D, cathepsin C and legumain (Sm32), which are believed to be involved in the catabolism of host haemoglobin. The various endo- and exoproteinases of Fasciola hepatica, the causative agent of liver fluke disease, are reviewed, and recent reports of how these enzymes have been successfully employed in cocktail vaccines are discussed. The various proteinases of cestodes and of the diverse superfamilies of parasitic nematodes are detailed, with special attention being given to those parasites for which most is known, including species of Taenia, Echinococcus, Spirometra, Necator, Acylostoma and Haemonchus. By far the largest number of papers in the literature and entries to the sequence data bases dealing with proteinases of parasitic helminths report on enzymes belonging to the papain superfamily of cysteine proteinases. Accordingly, the final section of the review is devoted to a phylogenetic analysis of this superfamily using over 150 published sequences. This analysis shows that the papain superfamily can be divided into two major branches. Branch A contains the cathepin Bs, the cathepsin Cs and a novel family termed cathepsin Xs, while Branch B contains the cruzipains, cathepsin Ls, papain-like and aleurain/cathepsin H-like proteinases. The relationships of the helminth proteinases, and similar proteinases from protozoan parasites and other organisms, within these groups are discussed.
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PMID:Proteinases and associated genes of parasitic helminths. 1021 92

The beta amyloid peptide derives from its precursor protein via proteolytic cleavage of yet unidentified proteases (beta- and gamma-secretases). Cathepsin D is an intracellular protease with in-vitro beta-secretase-like features. An exonic polymorphism of the cathepsin D gene (alanine to valine transition at position 224, exon 2) has been associated with altered enzyme function. We tested the hypothesis that this polymorphism is associated with an increased risk for Alzheimer's disease in 102 demented patients, 191 healthy subjects, and 160 depressed patients. There was a highly significant overrepresentation of the cathepsin D*T allele in demented patients (14.2%) compared to non-demented controls (6.7%, P = 0.0012). Carriers of the cathepsin D*T allele had a 2.4-fold increased risk for developing AD than non-carriers. Carriers of the apolipoprotein E epsilon 4 allele had a 4.1 -fold increased risk than non-carriers. The odds ratio for subjects with the apolipoprotein E epsilon 4 and the cathepsin D*T allele was 5.9. Our data suggest that the cathepsin D genotype is strongly associated with the risk for Alzheimer's disease.
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PMID:Genetic polymorphism of cathepsin D is strongly associated with the risk for developing sporadic Alzheimer's disease. 1021 83

The present study examines age-related changes in the subcellular localization of cathepsin B (cath B) and cathepsin D (cath D), as well as morphological features of the cathepsin-immunoreactive (ir) neurons in rat cerebral cortex. Sprague-Dawley rats were studied at 3 and 26 months. By immunoelectron microscopy cath B- or cath D-immunoreactivities were found in many, but not all, pyramidal neurons. In young rat cerebral cortical neurons, cath B was observed not only in lysosomal systems such as multivesicular bodies, dense bodies, and lipofuscin granules, but also in extralysosomal sites. By contrast, cath D was confined mainly to lysosomal systems in young rats. In aged rats, cath B showed a similar pattern in its subcellular localization compared to the young control, but some of the dense bodies containing cath B was closely apposed to the outer nuclear envelope. These cells exhibited a relatively normal appearance. Regardless of subcellular localization, approximately 10% of cath B-ir neurons displayed ultrastructural disturbances presumed to indicate an early stage of degeneration. The nucleus was indented, nuclear boundary was indistinct, nuclear pore structures appeared separately with high frequency, and the endoplasmic reticulum appeared to be affected. In addition to its presence in lysosomal structures, cath D-immunoreactivity in aged cerebral cortex was noted prominently in the cytosol as diffuse granules. About 37% of cath D-ir cells showed this age-related change. Among the neurons with the diffusely scattered form of cath D, approximately 70% of cells exhibited the degenerating features. These cells were characterized by large amounts of diffuse cath D, reduced cellular size, loss of the nuclear boundary, scattered nuclear pore structures, an often fragmentation of the nucleus, disturbances of endoplasmic reticular system, and in advanced stages, condensed nucleus and poor preservation of almost cytoplasmic organelles. Though some of these features were also found in cath B-ir neurons, findings of overt degeneration, such as fragmented and condensed nuclei and impaired almost cytoplasmic organelles, were generally not observed in cath B-ir neurons. In addition, lipofuscin aggregates containing cath D were observed frequently in the extracellular space close to sites of ruptured plasma membrane, whereas in the sections stained with anti-cath B antibodies, large-sized lipofuscin aggregates showed only very weak or no cath B-immunoreactivity at all. Taken together, the present results suggest that cath D and cath B may be regulated differently and play their specific roles in the aging of the brain, especially, the change in location of cath D from the lysosomal system to the cytosol in the aged brain may play an important role in age-related cell death.
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PMID:Age-related changes in ultrastructural features of cathepsin B- and D-containing neurons in rat cerebral cortex. 1053 60

We show that in the rat basophilic leukemia cell line RBL, the physiological stimulation of the IgE receptor or direct activation of PKC leads to the missorting of proteins to the plasma membrane, diverting them from their normal intracellular destination. This is demonstrated for two classes of proteins that are normally targeted to the secretory lysosomes via completely different mechanisms, i.e. proteoglycans and the aspartic protease cathepsin D. In the latter case, normal processing of the enzyme is also affected, leading to secretion of the immature form of cathepsin. The present study shows how completely different sorting mechanisms, such as those for delivering proteoglycans and cathepsin D to secretory lysosomes, might share common regulatory signals and are similarly affected when the levels of these signals are perturbed. Finally, protein kinase C appears to be a major player in the signal transduction pathways, leading to proteoglycan and cathepsin D missorting.
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PMID:Regulation of protein sorting at the TGN by plasma membrane receptor activation. 1065 66

Lysosomal proteinases, cathepsins D, B, and L have been associated with malignant tumor progression and with prognosis in various human carcinomas. In the current study, the immunohistochemical localization of cathepsins in tumor cells was correlated with cathepsin protein concentration in breast carcinoma cytosols from 77 patients. Significant correlation was found for cathepsin D (P < .041) and borderline correlation for cathepsin B (P < .055) but not for cathepsin L. We hypothesize that the poor correlation of cysteine cathepsins was attributable to the fact that they were present not only in malignant epithelial cells, but also in infiltrating macrophages and stromal fibroblasts. In addition, tumor-surrounding myoepithelial cells (42% of tumors) and myofibroblasts (26% of tumors) as well as endothelial cells of neovasculature (10% of tumors) all stained specifically for cathepsin B. Two thirds of tumors co-expressed cathepsins B and L in tumor cells, whereas only 17% of tumors co-expressed all 3 cathepsins. Intense immunostaining for cathepsin D of tumor cells was observed in tumors at high TNM stage and tumors having positive lymph nodes. The expression of cathepsin B was independent of established prognostic factors, whereas intense cathepsin L staining in tumor cells was associated with high histological grade. With respect to prognosis of patient survival, only tumor cell-associated cathepsin D (P = .042) and myoepithelial cell-associated cathepsin B (P = .061) showed borderline significance. Cathepsins B and L immunostaining in tumor cells was not prognostic. In contrast, cytosolic levels of cathepsin B correlated with higher rate of relapse. Taken together, these results show the diversity in the cellular distribution of cathepsins in human breast carcinoma, presumably reflecting specific regulation and function of each of the cathepsins during tumor progression.
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PMID:Cells producing cathepsins D, B, and L in human breast carcinoma and their association with prognosis. 1068 28

Delta(9)-tetrahydrocannabinol (THC) causes an antigen-dependent defect in the ability of macrophages to activate helper T cells, and this drug-induced impairment is mediated through the peripheral CB2 receptor. Various requirements for the processing of the antigen, lysozyme, were examined to determine where along the pathway THC exerts its influence. A THC-exposed macrophage hybridoma inefficiently stimulated interleukin-2 secretion by a helper T cell hybridoma in response to native lysozyme and its reduced form, suggesting that disulfide bond reduction was unaffected. Cell surface expression of major histocompatibility complex class II molecules was normal on THC-exposed macrophages. The drug-exposed macrophages also competently presented a lysozyme peptide to the T cells, indicating that the class II molecules were functional. The proteolytic activity of two thiol cathepsins was unaltered, but aspartyl cathepsin D activity was significantly increased in THC-exposed macrophages. Thus, selective up-regulation of aspartyl cathepsin activity accompanied the deficiency in lysozyme processing and may contribute, at least in part, to the antigen-dependent processing defect in THC-exposed macrophages.
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PMID:Delta(9)-tetrahydrocannabinol selectively increases aspartyl cathepsin D proteolytic activity and impairs lysozyme processing by macrophages. 1070 85

The possibility that brain aging in rats exhibits regional variations of the type found in humans was studied using lysosomal chemistry as a marker. Age-related (two vs 12months; male Sprague-Dawley) differences in cathepsin D immunostaining were pronounced in the superficial layers of entorhinal cortex and in hippocampal field CA1, but not in neocortex and field CA3. Three changes were recorded: an increase in the intraneuronal area occupied by labeled lysosomes; clumping of immunopositive material within neurons; more intense cytoplasmic staining. Western blot analyses indicated that the increases involved the active forms of cathepsin D rather than their proenzyme. Shrinkage of cathepsin-D-positive neuronal cell bodies was observed in entorhinal cortex but not in neocortical sampling zones. Age-related lysosomal changes as seen with cathepsin B immunocytochemistry were considerably more subtle than those obtained with cathepsin D antibodies. In contrast, a set of glial and/or vascular elements located in a distal dendritic field of the middle-aged hippocampus was much more immunoreactive for cathepsin B than cathepsin D. The areas exhibiting sizeable changes in the present study are reported to be particularly vulnerable to aging in humans. The results thus suggest that aspects of brain aging common to mammals help shape neurosenescence patterns in humans.
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PMID:Regionally selective changes in brain lysosomes occur in the transition from young adulthood to middle age in rats. 1079 71

The preservation of the proteolytic activity of a bovine spleen lysosomal-enriched (BSLE) extract was investigated. The BSLE extract (pH = 5.8), was subjected to storage under different conditions: refrigeration at 0 degrees C for 60 days; freezing at -20 degrees C -either directly or previously frozen in liquid nitrogen-, -80 degrees C and in liquid nitrogen; freeze-drying and stored at 0 degrees C; and freezing at -20 degrees C or in liquid nitrogen in the presence of glycerol and sorbitol as cryoprotectants. Freezing at low temperatures (-80 degrees C and in liquid nitrogen) was most effective for preserving about 100% of the initial activity of all cathepsins (B, B+L and D), as well as the activity of the extract on myofibrils, for two years. Freezing at -20 degrees C, on the contrary, led to significant (P < 0.01) losses of activity. Freeze-drying was able to preserve cathepsin activity, while it failed to maintain activity on myofibrils. Both cryoprotectants sorbitol and glycerol significantly (P < 0.01) enhanced enzyme preservation, particularly cathepsin D and the activity on myofibrils, even at a freezing temperature of -20 degrees C.
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PMID:Preservation of the proteolytic activity of a bovine spleen lysosomal-enriched extract using various freezing conditions. 1124 Feb 5

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

We analyzed 53 specimens from primary squamous cell carcinomas of the skin for the expression of collagenase IV, cathepsin D and metallothionein by means of immunohistochemistry along with histological data. We compared tumors that metastasized (30) with tumors that did not (23) during a follow-up period of at least 5 years. The expression of the two proteolytic enzymes cathepsin D and collagenase IV was also assessed at the invading front of the tumors. Statistical analyses revealed significant differences for the overall expression of cathepsin D (P < 0.05), expression of cathepsin at the invading front (P < 0.05) and the tumor thickness (P < 0.01). The results showed that cathepsin D may be a prognostic factor for squamous cell carcinomas of the skin. We then combined the results of parameters with statistically significant differences by multiplication. The prognostic value of such a combined risk-factor score showed higher confidence than any of the single parameters alone: a sensitivity of 63.3%, a specificity of 87.0% and an efficiency of 73.6%. This kind of combined risk-factor score might be used to more accurately detect patients at high risk of metastasis.
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PMID:The prognostic value of the expression of collagenase IV, cathepsin D and metallothionein in squamous cell carcinomas of the skin determined by immunohistochemistry. 1135 24


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