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)

The protease activity in guts of Ornithodoros tholozani females was studied in vitro. The intracellular protease in Ornithodoros tholozani guts has a pH optimum of about 3.0. Hemoglobin is the preferred substrate, and bovine serum albumin is digested very slowly. In this respect the protease resembles cathepsin D. Unfed ticks contain a small amount of protease in the gut. After feeding the level of protease increases gradually for several days until peak protease activity is attained. The level of gut protease activity depends on the size of the blood meal taken and on the interval after feeding. After a period of peak protease activity, the level of protease declines. The level of gut protease in unmated females (kept at 27 degrees C) did not reach prefeeding levels within 100 days. The level of gut proteolytic activity, as determined by in vitro protease assays, does not reflect the degree of blood digestion which takes place in vivo. After a period of rapid digestion, lasting for about two weeks, the undigested part of the blood meal remains unchanged in the lumen of the gut. At that time the gut tissue contains considerable levels of protease, which can be demonstrated by in vitro assays. Presumably, the protease remains active inside the gut cells, although the uptake of hemoglobin from the gut lumen has ceased. The results are compared to those obtained in other tick species.
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PMID:Protease activity in female Ornithodoros tholozani ticks. 1 32

The total cathepsin D activities in the intestinal wall and in venous mesenteric and arterial systemic blood were investigated on the rats in untreated hemorrhagic shock lasting 60 minutes. We observed a decrease in cathepsin D activity in homogenates of respective segments of small and large bowels and an increase in the enzyme activity in blood serum of both origin. The shock resulted in lowering protein concentration in the intestinal wall and its increase in the mesenteric blood. We found a negative correlation between cathepsin D activity in the intestinal wall and its morphological destruction. Molecules of the enzyme, after liberation from lysosomes due to hemorrhagic shock, are translocated to the circulation and probably to the gut lumen. Liberation of the intestinal cathepsin D may contribute to the local damage and multiorgan failure in hemorrhagic shock.
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PMID:Cathepsin D activity in the intestinal wall in experimental untreated hemorrhagic shock. 852 84

Hemorrhagic shock causes release of lysosomal proteolytic enzymes which contribute to intestinal wall destruction and can be moved into the circulation as well as into the gut lumen. The aim of the study was to examine the activity of cathepsin D in relation to the intestinal wall injury after 60 minutes of untreated hemorrhagic shock in rats. The total cathepsin D activity was investigated in duodenum, jejunum, ileum, cecum and colon, as well as in systemic and mesenteric blood serum, and the biochemical results were compared with morphological changes in the respective segments including immunohistochemical expression of cathepsin D. We found an increase in cathepsin D activity in duodenum and significant decrease in other parts of the gut in shocked rats. The enzyme activity increased also in blood serum, especially systemic (p < 0.05) and insignificantly in mesenteric blood. However, sham-operated animals (one-side carotid artery occlusion) revealed a significant increase in cathepsin D activity measured in mesenteric blood. The shock resulted in lowering protein concentration in the intestinal wall and its increase in mesenteric blood. The contents of peptides and amino nitrogen, as potential proteolytic reaction products, changed in different ways in various segments of intestine. Morphologically, the most intensive destruction was observed in ileum, duodenum and jejunum. Lifting of epithelial layer from lamina propria was the most frequently observed lesion of the intestinal wall after 60 minutes of shock. More advanced lesions, such as denuded mucosa with disintegration of lamina propria, occurred rarely and were not observed in colon and rectum. By means of polyclonal antibodies against cathepsin D, we found that the strong expression of this enzyme was in epithelial layer--the part of intestinal wall which was partially detached into gut lumen due to hemorrhagic shock. The changes of cathepsin D activity after 60 minutes of hemorrhagic shock were correlated with signs of morphological damage to the intestinal wall. Cathepsin D liberation in the intestinal wall during shock indicates the lysosomal membranes impairment and can confirm involvement of proteases in the damage to the intestinal tissue. We conclude that liberation of intestinal cathepsin D is an early phenomenon during hemorrhagic shock which may contribute to the local wall disintegration and activation of systemic inflammatory response.
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PMID:Hemorrhagic shock-induced changes in the cathepsin D activity in the intestinal wall and blood serum in rats. 982 39

Schistosomes feed on human blood. They employ proteases to degrade hemoglobin from ingested erythrocytes, using the residues released for amino acid metabolism. However, the identity and the role of the participating protease(s) are unclear and controversial. Confocal microscopy localized schistosomal cathepsin D to the parasite gastrodermis, and revealed elevated protease expression in females. At sub-cellular level, cathepsin D was localized to superficial digestive vacuoles of the gut and to cisternae of the gastrodermal rough endoplasmic reticulum. Schistosome cathepsin D, expressed in insect cells, autoactivated at pH 3.6 to a approximately 40 kDa form that cleaved the substrates o-aminobenzoyl-Ile-Glu-Phe-nitroPhe-Arg-leu-NH(2) and hemoglobin. The NH(2)-terminal residues of mature cathepsin D of Schistosoma japonicum and Schistosoma mansoni were Asn1 and Gly1, respectively, revealing that the proregion peptide was comprised of 35 residues. The proteases cleaved hemoglobin at pH 2.5--4.6, releasing numerous fragments. S. Japonicum cathepsin D cleaved at 13 sites, S. mansoni cathepsin D at 15 sites. Early cleavage sites were alpha Phe33-Leu34 and beta Phe41-Phe42, while others included alpha Leu109-Ala-110 and beta Leu14-Trp15, demonstrating a preference for bulky hydrophobic residues at P1 and P1'. Most of the schistosomal cathepsin D cleavage sites were discrete from those of human cathepsin D. The gastrodermal location, elevated expression in females, acidic pH optima, similar substrate preferences in two species, and the discrete substrate preferences compared with human cathepsin D together provide compelling support for the hypothesis that schistosomal cathepsin D plays an integral role in hemoglobin proteolysis, and might be selectively targeted by drugs based on protease inhibition.
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PMID:Proteolysis of human hemoglobin by schistosome cathepsin D. 1116 91

DNA-based vaccine technology was used to immunize against the schistosome digestive enzyme, cathepsin D aspartic proteinase. The cDNA coding for Schistosomajaponicum aspartic proteinase was cloned in a mammalian expression vector under control of the CMV promoter/enhancer and expressed for the first time in transfected mammalian cells as well as in mice immunized--by means of intra-ear pinna injection--with the aspartic proteinase-encoding DNA construct. Mice developed antibodies which recognized the native protein in homogenates of S. japonicum worms and reacted with the gut and, to a much lesser degree, with the parenchyma of the parasites in cryostat sections. It was noteworthy that the vaccinated mouse sera did not detectably cross-react with S. mansoni antigens either in homogenates or on cryostat sections. By contrast, infection sera of mice or humans strongly cross-reacted with both schistosome species. We conclude that DNA vaccination can induce species-restricted antibody responses against schistosome proteins. The implications of this previously unrecognized specificity are discussed.
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PMID:Species-restricted antibody response against a DNA-construct coding for aspartic proteinase from Schistosoma japonicum. 1199 27

Hookworms routinely reach the gut of nonpermissive hosts but fail to successfully feed, develop, and reproduce. To investigate the effects of host-parasite coevolution on the ability of hookworms to feed in nonpermissive hosts, we cloned and expressed aspartic proteases from canine and human hookworms. We show here that a cathepsin D-like protease from the canine hookworm Ancylosotoma caninum (Ac-APR-1) and the orthologous protease from the human hookworm Necator americanus (Na-APR-1) are expressed in the gut and probably exert their proteolytic activity extracellularly. Both proteases were detected immunologically and enzymatically in somatic extracts of adult worms. The two proteases were expressed in baculovirus, and both cleaved human and dog hemoglobin (Hb) in vitro. Each protease digested Hb from its permissive host between twofold (whole molecule) and sixfold (synthetic peptides) more efficiently than Hb from the nonpermissive host, despite the two proteases' having identical residues lining their active site clefts. Furthermore, both proteases cleaved Hb at numerous distinct sites and showed different substrate preferences. The findings suggest that the paradigm of matching the molecular structure of the food source within a host to the molecular structure of the catabolic proteases of the parasite is an important contributing factor for host-parasite compatibility and host species range.
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PMID:Cleavage of hemoglobin by hookworm cathepsin D aspartic proteases and its potential contribution to host specificity. 1220 47

Digestive endoprotease activities of the rice water weevil, Lissorhoptrus brevirostris Suffrian (Coleoptera: Curculionidae), were characterized based on the ability of gut extracts to hydrolyze specific synthetic substrates, optimal pH, and hydrolysis sensitivity to protease inhibitors. Larvae of this species were found to use a complex proteolytic system that includes cathepsin D-, cathepsin B-, trypsin-, and chymotrypsin-like activities. Trypsin-like activity was evenly distributed among the anterior, middle, and posterior portions of the gut, whereas cathepsin B- and cathepsin D-like activities were mainly located in the anterior and middle sections, and the chymotrypsin-like activity was highest in the middle and posterior sections. Gelatin-containing native-PAGE gels indicated the presence of several aspartyl, cysteine, and serine protease forms and confirmed the spatial organization of the proteolytic digestive process.
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PMID:Proteolytic gut activities in the rice water weevil, Lissorhoptrus brevirostris Suffrian (Coleoptera: Curculionidae). 1270 Nov 11

Effects of glutamine on whole body and intestinal protein synthesis and on intestinal proteolysis were assessed in humans. Two groups of healthy volunteers received in a random order enteral glutamine (0.8 mmol.kg body wt(-1)x h(-1)) compared either to saline or isonitrogenous amino acids. Intravenous [2H5]phenylalanine and [13C]leucine were simultaneously infused. After gas chromatography-mass spectrometry analysis, whole body protein turnover was estimated from traced plasma amino acid fluxes and the fractional synthesis rate (FSR) of gut mucosal protein was calculated from protein and intracellular phenylalanine and leucine enrichments in duodenal biopsies. mRNA levels for ubiquitin, cathepsin D, and m-calpain were analyzed in biopsies by RT-PCR. Glutamine significantly increased mucosal protein FSR compared with saline. Glutamine and amino acids had similar effects on FSR. The mRNA level for ubiquitin was significantly decreased after glutamine infusion compared with saline and amino acids, whereas cathepsin D and m-calpain mRNA levels were not affected. Enteral glutamine stimulates mucosal protein synthesis and may attenuate ubiquitin-dependent proteolysis and thus improve protein balance in human gut.
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PMID:Enteral glutamine stimulates protein synthesis and decreases ubiquitin mRNA level in human gut mucosa. 1270 96

We describe the neuropathological and biochemical autopsy findings in 3 patients with autosomal dominant adult neuronal ceroid lipofuscinosis (ANCL, Parry type; MIM 162350), from a family with 6 affected individuals in 3 generations. Throughout the brain of these patients, there was abundant intraneuronal lysosomal storage of autofluorescent lipopigment granules. Striking loss of neurons in the substantia nigra was found. In contrast, little neuronal cell loss occurred in other cerebral areas, despite massive neuronal inclusions. Visceral storage was present in gut, liver, cardiomyocytes, skeletal muscle, and in the skin eccrine glands. The storage material showed highly variable immunoreactivity with antiserum against subunit c of mitochondrial ATP synthase, but uniform strong immunoreactivity for saposin D (sphingolipid activating protein D). Protein electrophoresis of isolated storage material revealed a major protein band of about 14 kDa, recognized in Western blotting by saposin D antiserum (but not subunit c of mitochondrial ATPase (SCMAS) antiserum). Electron microscopy showed ample intraneuronal granular osmiophilic deposits (GRODs), as occurs in CLN1 and congenital ovine NCL. These forms of NCL are caused by the deficiencies of palmitoyl protein thioesterase 1 and cathepsin D, respectively. However, activities of these enzymes were within normal range in our patients. Thus we propose that a gene distinct from the cathepsin D and CLN1-CLN8 genes is responsible for this autosomal dominant form of ANCL.
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PMID:Autosomal dominant adult neuronal ceroid lipofuscinosis: a novel form of NCL with granular osmiophilic deposits without palmitoyl protein thioesterase 1 deficiency. 1465 61

Schistosomes are considered the most important of the helminth parasites of humans in terms of morbidity and mortality. Schistosomes employ proteolytic enzymes to digest host hemoglobin from ingested human blood, including a cathepsin D-like, aspartic protease that is overexpressed in the gut of the adult female schistosome. Because of its key role in parasite nutrition, this enzyme represents a potential intervention target. To continue exploration of this potential, here we have determined the sequence, structure and genomic organization of the cathepsin D gene locus of Schistosoma mansoni. Using the cDNA encoding S. mansoni cathepsin D as a probe, we isolated several positive bacterial artificial chromosomes (BAC) from a BAC library that represents an approximately 8-fold coverage of the schistosome genome. Sequencing of BAC clone 25-J-24 revealed that the cathepsin D gene locus was approximately 13 kb in length, and included seven exons interrupted by six introns. The exons ranged in length from 49 to 294 bp, and the introns from 30 to 5025 bp. The genomic organization of schistosome cathepsin D was similar in sequence, structure and complexity to human cathepsin D, including to a greater or lesser extent the conservation of all six exon/intron boundaries of the schistosome gene. It was less similar to aspartic protease genes of the nematodes Caenorhabditis elegans and Haemonchus contortus, and dissimilar to those of plasmepsins from malarial parasites. Examination of the introns revealed the presence of endogenous mobile genetic elements including SR2, the ASL-associated retrotransposon, and the SINE-like element, SMalpha. Phylogenetically, schistosome cathepsin D appeared to be more closely related to mammalian cathepsin D than to other sub-families of eukaryotic aspartic proteases known from mammals. Taken together, these features indicated that schistosome cathepsin D is a platyhelminth orthologue of mammalian lysosomal cathepsin D.
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PMID:Genomic organization of the Schistosoma mansoni aspartic protease gene, a platyhelminth orthologue of mammalian lysosomal cathepsin D. 1530 11


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