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 formation of inactive complexes in excess molar amounts of human cathepsins H and L with their protein inhibitors human stefin A, human stefin B and chicken cystatin at pH 5.6 has been shown by measurement of enzyme activity coupled with reverse-phase HPLC not to involve covalent cleavage of the inhibitors. Inhibition must be the direct result of binding. On the contrary the interaction of cystatins with aspartic proteinase cathepsin D at pH 3.5 for 60 min followed by HPLC resulted in their inactivation accompanied by peptide bond cleavage at several sites, preferentially those involving hydrophobic amino acid residues. The released peptides do not inhibit papain and cathepsin L. These results explain reported elevated levels of cysteine proteinases and lead to the proposal that cathepsin D exerts an important function, through inactivation of cystatins, in the increased activities of cysteine proteinases in human diseases including muscular distrophy.
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PMID:Cathepsin D inactivates cysteine proteinase inhibitors, cystatins. 326 Nov 70

Cathepsins B, D, H, and L were identified in the extract of 2-day-old rat epidermis and separated by gel filtration from aminoendopeptidase with a Mr of 400,000 and from the low-molecular-weight cysteine proteinase inhibitor. They were further purified by ion exchange column chromatography. The final separation for cathepsins B and H was performed by gel filtration, while cathepsin D was purified by pepstatin affinity chromatography and cathepsin L by fast protein liquid chromatography (FPLC). Substrate specificity, inhibitor susceptibility, and apparent molecular weights of the separated proteinases were determined and values compared to rat liver enzymes. Apparent molecular weights for epidermal cathepsins B, H, and L were higher than those for comparable liver enzymes of adult rats. The cysteine proteinase inhibitor in epidermis was found to inhibit cathepsins B, H, and L but not cathepsin D and aminoendopeptidase of rat epidermis. This study demonstrates the presence of cathepsin L in the epidermis and describes simultaneous separation and comparison of epidermal catheptic proteinases.
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PMID:Separation and identification of cathepsins in newborn rat epidermis. 355 65

Cathepsin L was capable of destroying rabbit muscle aldolase (D-fructose-1,6-bisphosphate D-glyceraldehyde-3-phosphate-lyase, EC 4.1.2.13) activity towards the substrate fructose 1,6-bisphosphate. The rate of loss of activity towards this substrate was stimulated (approx. 2-fold) by physiological concentrations of ATP and to a lesser degree by GTP, CTP, UTP, ADP and cyclic AMP, while PPi and Pi decreased the rate of inactivation. Other proteinases (cathepsin B, cathepsin D, trypsin and chymotrypsin) also decreased aldolase activity toward fructose 1,6-bisphosphate more rapidly in the presence of ATP and more slowly in the presence of Pi. Cathepsin L, at higher concentrations, was capable of inactivating aldolase activity towards fructose 1-phosphate and extensively degrading the enzyme; these reactions were not affected by ATP and Pi. The thermostability of aldolase was also unaffected by these ligands. ATP and Pi had no effect on the rates of hydrolysis of other proteins (hemoglobin, bovine serum albumin, casein and azocasein) by cathepsin L. These data indicate that the effects of ATP and Pi are due to interactions of these ligands with aldolase that make the enzyme more vulnerable to limited but not extensive proteolysis; these ligands do not directly affect cathepsin L activity.
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PMID:Inactivation of fructose-1,6-bisphosphate aldolase by cathepsin L. Stimulation by ATP. 669 88

The specific activity of three lysosomal proteinases (cathepsins B1, D, and L) as well as acid phosphatase and beta-galactosidase has been determined in the liver of both 7-10 day-old and young adult rats. Cathepsin B1 in suckling rats is markedly lower than in adults, while cathepsin D is only moderately lower and cathepsin L does not significantly differ. The activity of acid phosphatase is similar in the two groups of animals whereas that of beta-galactosidase in suckling rats is approx. twice as high as in adults. The activity of lysosomal hydrolases thus appears to be regulated individually during the development. Moreover it is suggested that the low activity of cathepsin B1 may be related to the low rate of cell protein catabolism characteristic of the developing liver (Conde and Scornik, 1977).
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PMID:Lysosomal hydrolase activities in the developing rat liver. 677 67

When leupeptin, a thiol protease inhibitor of microbial origin, was injected into rats, the activity of fructose-1,6-bisphosphate aldolase (D-fructose-1,6-bisphosphate D-glyceraldehyde-3-phosphate-lyase, EC 4.1.2.13) in the liver decreased to about 60% of that in control rats. However, the concentration of aldolase protein in the liver extracts, measured with a specific antibody obtained with enzyme purified on a phosphocellulose column, remained unchanged. Injection of leupeptin also caused a marked increase in the activities of free lysosomal proteases, such as cathepsin B (EC 3.4.22.1), cathepsin L (EC 3.4.22.-), cathepsin D (EC 3.4.23.5) and lysosomal carboxypeptidase A in the cytosol fraction. A clear inverse relationship between aldolase and cathepsin B activities in the cytosol fraction was demonstrated. The possibility that the less active form of aldolase detected in the livers of leupeptin-treated rats was produced during homogenization was excluded by showing that the aldolase activity was not changed by addition of various protease inhibitors to the homogenization medium., When insulin was coinjected with leupeptin, increase in the activity of free cathepsin L and decrease of activity of aldolase produced by the injection of leupeptin was prevented. These findings indicate that modification of aldolase may be due to the action of a lysosomal protease(s). Enhanced sensitivity of lysosomes to osmotic shock was demonstrated in the livers of leupeptin-treated rats, suggesting that the lysosomal membrane is labilized by administration of leupeptin. Incubation of the purified aldolase with the lysosomal fraction produced the same changes in properties of aldolase as those observed in vivo on injection of leupeptin.
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PMID:Proteolytic modification of rat liver fructose-1,6-bisphosphate aldolase by administration of leupeptin in vivo. 702 Jul 65

Two methods have been developed to discriminate simultaneously between the main part of cysteine proteinase activity (cathepsin L) and all aspartic proteinase activity (mainly cathepsin D) in rat organs, using Z-Phe-Phe-CHN2 which at 5 mumol/l completely inhibits cathepsin L from rat liver and, on the other hand, pepstatin which at 0.5 mumol/l completely inhibits cathepsin D. Substrates are double-labeled cytosol proteins from rat liver at pH 3.0 or azocasein in 3 mol/l urea at pH 5.0. Several organs from rat, pigeon, frog and carp have been investigated using these methods. Especially kidneys from rat, frog and carp contain a high Z-Phe-Phe-CHN2 inhibited activity. Investigating the different liver cell types we could confirm earlier findings that Kupffer cells and endothelial cells contain more pepstatin inhibited activity than parenchymal cells.
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PMID:Inhibition of cysteine proteinase activity by Z-Phe-Phe-diazomethane and of aspartic proteinase activity by pepstatin in different organs from some animals and isolated cells from rat liver. 705 5

In vivo proteolytic modification of liver aldolase on administration of leupeptin, a thiol proteinase inhibitor of microbial origin, is reported. When leupeptin was injected into rats, the activity of aldolase in the liver decreased to 40% of that in control rats. Molecular properties of aldolase isolated from the livers of control rats and leupeptin-treated rats indicated that a decrease of aldolase activity is attributable to hydrolysis of a peptide linkage(s) near the carboxyterminal of the enzyme. Injection of leupeptin also caused marked increase in the activities of free lysosomal proteinases, such as cathepsin A and cathepsin D and moderate increase of cathepsin B and cathepsin L. Increase in free activity of cathepsin A returned to the level of control rats by 12 hr after injection of leupeptin, whereas 36 hr was required for recovery of decreased aldolase activity. When insulin was coinjected with leupeptin, increase in the activity of free cathepsin A and decrease of activity of aldolase produced by the injection of leupeptin was prevented. These findings indicate that modification of aldolase may be due to action of a lysosomal protease(s). Incubation of the purified aldolase with the lysosomal fraction produced the same changes in properties of aldolase as those observed in vivo on injection of leupeptin. The aldolase inactivating proteinase in the lysosomal fraction was inhibited by PMSF and leupeptin and not by pepstatin. Purified cathepsin A (a serine proteinase), cathepsin B and cathepsin L (thiol proteinase) are potent inactivators of aldolase but cathepsin H and cathepsin D are not. Cathepsin A, B and L are involved in inactivation of aldolase in lysosomes. Endogenous thiol proteinase inhibitor which inhibits lysosomal thiol proteinases (cathepsin B, L and H) is found in the cytosol fraction of liver. The level of thiol proteinase inhibitor actually decreased to 60% of that in control rats in leupeptin-treated rats, suggesting that non-thiol proteinase cathepsin A is a major factor in inactivation of aldolase in lysosomes. Not only leupeptin but also other proteinase inhibitors (antipain, E-64-D, chloroquine) caused increase of labilization of the lysosomes and decrease in aldolase activity. Physiological stimuli which are known to induce the labilization of the lysosomal membrane, such as starvation and glucagon, caused slight or no significant increase of activities of free cathepsin A and D and resulted in no apparent change in aldolase activity.
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PMID:Modification of rat liver fructose biphosphate aldolase by lysosomal proteinases. 705 71

Procathepsin L, the precursor to a powerful lysosomal cysteine proteinase, has been purified to apparent homogeneity from guinea pig spermatozoa, a novel and previously unrecognized source of this catalytically active zymogen. In the range of pH 5.0, procathepsin L (39,000 M(r)) readily self-processed yielding a mature, single-chain proteinase (29,000 M(r)) and an intact propeptide (10,000 M(r)) by what appeared kinetically to be an intramolecular reaction mechanism. These characteristics resembled those reported for the "major excreted protein" (MEP) of malignantly transformed mouse fibroblasts-a protein that has been characterized as the precursor to the mouse analog of human cathepsin L (B. R. Troen, S. Gal, and M. M. Gottesman (1987) Biochem. J. 246, 731-735). Other characteristics shared by the guinea pig and mouse zymogens included proteolytic activity at pH 5.0, homologous N-terminal amino acid sequences, and immunological relatedness. It was thus concluded that acrosomal procathepsin L is the guinea pig analog of MEP. Acrosomal procathepsin L had a specific activity on benzyloxy-carbonyl-Phe-Arg-7-(4-methyl)coumarylamide (Z-Phe-Arg-NMec) of 30 mumol min-1 mg-1 enzyme at pH 3.2 and 37 degrees C. Relative to the assay substrate, rates on other fluorogenic substrates were 90% for Z-Phe-Cit-NMec, 63% for Z-Leu-Leu-Arg-NMec, 43% for D-Phe-Ser(Bzl)-Phe-Phe-Ala-Ala-p-aminobenzoate (a "specific" cathepsin D assay substrate), and 32% for Z-Val-Val-Arg-NMec. No action was detected on Z-Arg-Arg-NMec or Arg-NMec. Mature cathepsin L showed the same relative order of substrate specificity as its proenzyme form, but the absolute rates were about 5-fold greater. Additionally, the mature (single-chain) form of cathepsin L displayed Km and kcat values on Z-Phe-Arg-NMec that yielded an exceptionally high catalytic coefficient (11,600 s-1 mM-1) compared to values reported for two-chain forms of cathepsin L. Self-processing by acrosomal procathepsin L at pH 5.5 was totally inhibited by leupeptin, cystatin C, Ep-475, and Z-Phe-Phe-CHN2 at 1 microM levels. Gossypol (0.1 mM) gave 94% inhibition. Interestingly, dextran sulfate (100 micrograms ml-1) gave a 3.6-fold increase in the rate of self-processing seen at pH 5.5--a phenomenon of potential physiological relevance in view of the high-negative-charge density present within the hyaluronic acid-rich outer layer (cumulus oophorus) of the ovum.
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PMID:Purification and characterization of procathepsin L, a self-processing zymogen of guinea pig spermatozoa that acts on a cathepsin D assay substrate. 748 6

In cytosols of tumour and normal tissue of 53 patients suffering from head and neck carcinoma cathepsins D, B, H and L were measured using quantitative immunoreactive assays (ELISA). The values of cathepsins D, B and L were significantly higher in tumour tissue, whereas cathepsin H concentration was lower in tumour than in normal tissue. Median cathepsin D values were 27 pmol (tumour tissue) vs. 12 pmol (normal tissue) per mg of total protein, median cathepsin B values were 1.25 micrograms/mg (tumour tissue) vs. 0.23 micrograms/mg (normal tissue) and median cathepsin L values were 39.8 ng/mg (tumour tissue) vs. 20.0 ng/mg (normal tissue). Median cathepsin H values were 1.05 micrograms/mg and 2.20 micrograms/mg for tumour and normal tissue, respectively. Additionally, stefin A and stefin B were measured in tumour and normal tissue samples. In contrast to the cathepsins, the concentrations of these inhibitors of cysteine proteinases was not significantly different between tumour and normal samples. The concentrations of cathepsins D, B, H and L and stefins A and B measured in head and neck tumours, were independent of standard clinical and histological prognostic factors. Significant correlation of tumour tissue values was observed between cathepsins B and L and between both stefins.
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PMID:Lysosomal proteases cathepsins D, B, H, L and their inhibitors stefins A and B in head and neck cancer. 757 36

Most native antigens require digestion by acidic proteases in order to be recognized in the context of major histocompatibility complex class II by T helper cells (Th). We have studied the roles of three different acidic proteases, cathepsin D, cathepsin B and cathepsin L, in the processing of ovalbumin (OVA) for presentation in the context of I-Ad. We report that digestion of OVA in vitro with the aspartyl protease cathepsin D generates the epitope OVA322-336, which is recognized by I-Ad-restricted OVA-specific Th in the presence of paraformaldehyde-fixed antigen-presenting cells (APC). In contrast, digestion of OVA with the cysteine proteases cathepsin B and L not only failed to generate an epitope, but also destroyed OVA322-336. In the presence of fixed APC expressing I-Ad. OVA322-336 was protected from destructive proteolysis by cathepsin L. These results illustrate the dependence of epitope selection on the intracellular proteolytic environment in APC, and suggest that mechanisms must exist for protection of epitopes from destructive proteolysis in the processing compartments.
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PMID:Destructive proteolysis by cysteine proteases in antigen presentation of ovalbumin. 762 59


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