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 in vitro induction of lysosomal enzymes by phagocytosis was demonstrated in cultivated mouse peritoneal macrophages. The contribution of each of several steps in the endocytic process to enzyme induction was examined. The enzymatic response after the uptake of equal numbers of erythrocytes (RBC) and nondigestible particles were compared. Phagocytosis of RBC produced a marked increase in the levels of acid phosphatase, beta-glucuronidase, and cathepsin D. Puromycin (1 microg/ml) inhibited the enzyme response. In contrast, phagocytosis of polyvinyl toluene, polystyrene, and insoluble starch particles produced no increase in macrophage lysosomal enzymes, although fusion of phagosomes with preexisting lysosomes occurred normally. The endocytic stimulus to synthesis of inducible lysosomal enzymes, therefore, occurred at or beyond the stage of digestion. Purified protein (bovine gamma globulin) aggregates and homopolymer coacervates of poly-l-glutamic acid: poly-l-lysine were effective inducers of lysosomal acid phosphatase, beta-glucuronidase, and cathepsin D, whereas homopolymers of the same D-amino acids were ineffective as inducers. Both the quantity of phagocytized substrate and its rate of enzymatic hydrolysis appear to control the level and persistance of lysosomal hydrolases.
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PMID:In vitro induction of lysosomal enzymes by phagocytosis. 491 52

Brain cathepsin D, purified by affinity chromatography on Sepharose pepstatin columns, was incubated with synthetic peptides corresponding to the susceptible regions of the myelin basic protein encompassing the two Phe-Phe bonds. One peptide, Leu-Gly-Arg-Phe-Phe-Gly-Gly, was cleaved by cathepsin D at the Phe-Phe bond while another, Val-His-Phe-Phe-Lys-Asn-Gly, was resistant to cleavage. To determine if this was a result of His flanking the Phe-Phe bond, or chain length on the N-terminal side, two decapeptides were synthesized differing only in the presence or absence of His adjacent to Phe. The results show that both of the decapapetides were cleaved by cathepsin D at the Phe-Phe linkages. In addition, prolonged incubation led to release of N-terminal Lys, indicating an additional cleavage at the Phe-Lys bond. In contrast to the limited cleavage by cathepsin D, pepsin split all four peptides. These results support earlier work on the limited proteolysis of basic protein at the Phe-Phe bond and suggest additional sites upon prolonged exposure. Such peptides may have utility as alternative substrates for basic protein or as models for subsequent synthesis of possible inhibitors of the enzyme.
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PMID:Specificity of brain cathepsin D: cleavage of model peptides containing the susceptible Phe-Phe regions of myelin basic protein. 615 30

The desirable fixation conditions for the histochemical demonstration of cathepsin D using mercury-labeled pepstatin as an enzyme inhibitor were examined biochemically and histochemically. Four well known fixatives, namely, glutaraldehyde (GA), paraformaldehyde (PFA), glutaraldehyde with paraformaldehyde (GA-PFA) and periodate-lysine-paraformaldehyde (PLP), were applied to the prefixation of tissues prior to the reaction of the labeled inhibitor to the enzyme-active site. The effects of fixatives on cathepsin D were biochemically examined using subcellular fractionated lysosomes. Cathepsin D from rat liver lysosomes was rapidly inactivated by the fixatives containing glutaraldehyde, i.e., GA and GA-PFA, whereas the activity of cathepsin D was sufficiently maintained after fixing the enzyme in the PFA or PLP preparations. Effects of the PLP fixative on lysosomal cathepsin D in liver tissues using the mercury-labeled pepstatin method were also studied histochemically. The best result for the visualization of lysosomal cathepsin D in liver tissues was obtained using the PLP fixative with the prefixation time of three hours or more.
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PMID:An improved procedure for the histochemical demonstration of cathepsin D by the mercury-labeled pepstatin method. 620 30

gamma-Endorphin is a naturally occurring biologically active peptide that is produced by an endopeptidase activity cleaving its precursor beta-endorphin. This enzyme was termed gamma-endorphin generating enzyme (gamma-EGE). In order to quantitate gamma-EGE activity by means of a simple and sensitive assay two synthetic peptides derived from the sequence surrounding the gamma-EGE cleavage site in beta-endorphin were tested as substrates. One of these peptides Ac-Val-Thr-Leu-Phe-Lys-NHCH3 fulfilled all criteria for a suitable gamma-EGE substrate. The peptide was exclusively cleaved at the correct bond for gamma-EGE upon incubation with brain synaptic membranes, and this cleavage was inhibited by the naturally occurring substrate beta-endorphin. The peptide was insensitive to cleavage by exopeptidases and cathepsin D. Addition of a 14C-labeled methyl group at the lysine residue of this peptide by reductive methylation did not alter its properties as a substrate for gamma-EGE activity. The use of the 14C-labeled peptide allowed sensitive quantitation of its radioactive products after simple separation by hydrophobic chromatography on minicolumns containing polystyrene beads. gamma-EGE activity increased linearly with a protein concentration and incubation time. This assay can be used for reliable quantitation of gamma-EGE activity and permits investigations on the regulation of gamma-endorphin production.
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PMID:Quantitation of the endopeptidase activity generating gamma-endorphin from beta-endorphin in rat brain synaptic membranes by a radiometric assay. 620 8

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

During pulse-chase experiments in cultured porcine kidney cells, an early 75-kilodalton (kDa) form of beta-glucuronidase is converted to a late 72-kDa form. The relative molecular weight difference between the two forms is maintained on removal of high-mannose carbohydrate with endoglycosidase H. Both forms have the same partial NH2-terminal sequence, and both migrate as single polypeptide chains following reduction, alkylation, and electrophoresis under denaturing conditions. On treatment with carboxypeptidase Y, the early form released [35S]Met faster than the late form. Thus, the late form of beta-glucuronidase is generated by COOH-terminal proteolytic processing of the early form. During similar experiments, the mass of the 30-kDa heavy chain of porcine cathepsin D decreased by about 1 kDa. The heavy chain of the two-chain enzyme is derived from the COOH terminus of a 44-kDa single-chain enzyme. On treatment with carboxypeptidase Y, the early single-chain enzyme released COOH-terminal [35S]Met and [3H]Lys faster than the later 29-kDa heavy chain. Like beta-glucuronidase, cathepsin D evidently undergoes COOH-terminal proteolytic processing during biosynthesis.
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PMID:Carboxyl-terminal proteolytic processing during biosynthesis of the lysosomal enzymes beta-glucuronidase and cathepsin D. 636 Feb 5

The activities of an acid proteinase, of an alkaline proteinase, of a lysine aminopeptidase and of a proteinase B inhibitor were measured in benign and malignant tumors of the human uterus. In carcinomas of the corpus uteri the activity of the acid proteinase (cathepsin D) was increased compared to normal endometrium. This could probably be the result of cell destruction within the tumor. In leiomyomas of the uterus the activities of the alkaline proteinase, of the lysine aminopeptidase, and of the proteinase inhibitor were decreased compared to the normal myometrium. These results suggest that a decrease in the rate of degradation of myofibrillar proteins relative to the rate of protein synthesis may be responsible for the growth of myomas.
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PMID:Activities of proteinases and of a proteinase B inhibitor in tumors of the human uterus. 637 84

Procathepsin D-II (Mr = 37 500) was purified from Japanese monkey lung at pH 7.0, and was shown to be converted to the active form, cathepsin D-II (Mr = 33 000) via an intermediate (Mr = 35 500) upon treatment at pH 3.0 and 14 degrees C. Procathepsin D-II was shown to be the inactive precursor of cathepsin D-II based on the following results: the former was inactive toward heat-denaturated casein at pH 5.4 whereas the latter was active; the former was not inactivated by diazoacetyl-DL-norleucine methyl ester in the presence of Cu2+ ion at pH 6.0 whereas the latter was inactivated rapidly under the same conditions; and the former had no affinity to pepstatin-Sepharose between pH 5 and 7 whereas the latter was adsorbed to it. With a rabbit antiserum against procathepsin D-II, cathepsin D-II, pepsinogen C and pepsin C of Japanese monkey were each found to give a single precipitin line which fused completely with each other on agarose plate. On the other hand, cathepsin D-I purified from the monkey lung, and pepsinogens A (I, II, III-1, III-2 and III-3) obtained from the monkey gastric mucosa failed to precipitate with the antiserum. With the antiserum against the monkey pepsinogen C, the same results were obtained. Further, procathepsin D-II and pepsinogen C were shown to have the same amino-terminal amino acid sequence, Ala-Val-Val-Lys-Val-Pro-Leu-Lys-Lys-Phe-Lys-. All these results indicate a strong similarity of procathepsin D-II and cathepsin D-II to pepsinogen C and pepsin C, respectively.
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PMID:Identification of monkey lung procathepsin D-II as a pepsinogen-C-like acid protease zymogen. 640 25

The amino acid sequence of porcine spleen cathepsin D heavy chain has been determined and, hence, the complete structure of this enzyme is now known. The sequence of heavy chain was constructed by aligning the structures of peptides generated by cyanogen bromide, trypsin, and endo-proteinase Lys C cleavages. The structure of the light chain has been published previously. The cathepsin D molecule contains 339 amino acid residues in two polypeptide chains: a 97-residue light chain and a 242-residue heavy chain, with a combined Mr of 36,779 (without carbohydrate). There are two carbohydrate units linked to asparagine residues 70 and 192. The disulfide bond arrangement in cathepsin D is probably similar to that of pepsin, because the positions of six half-cystine residues are conserved. The active site aspartyl residues, corresponding to aspartic acid-32 and -215 of pepsin, are located at residues 33 and 224 in the cathepsin D molecule. The amino acid sequence around these aspartyl residues is strongly conserved. Cathepsin D shows a strong homology with other acid proteases. When the sequence of cathepsin D, renin, and pepsin are aligned, 32.7% of the residues are identical. The homology is observed throughout the length of the molecules, indicating that three-dimensional structures of all three molecules are similar.
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PMID:Amino acid sequence of porcine spleen cathepsin D. 658 85

The kinin-forming enzyme of rat brain was studied by bioassaying kinin using a rat uterus. The enzyme released a kinin from the partially purified kininogen of rat plasma. The activity is exclusively distributed in the mitochondrial fraction and was detected in the pH range of 2.5-4.0 (optimally at pH 3.0). The enzyme was potently inhibited by pepstatin, but not by aprotinin. Released kinin was extracted by n-butanol and it was purified using Amberlite CG-50 absorption and CM-cellulose column chromatography. The elution profile of kinin from the CM-cellulose column did not coincide with that of bradykinin, Lys-bradykinin or Met-Lys-bradykinin. Isolated kinin was inactivated by treatment with chymotrypsin, but not with trypsin. In addition to the contractile activity on rat uterus, the kinin caused contraction of guinea pig ileum, with the response being potentiated by the presence of bradykinin-potentiator B. It also relaxed a rat duodenum, decreased rat blood pressure, and increased the vascular permeability in guinea pigs. Relative potencies of kinin on these pharmacological activities did not coincide with those of bradykinin. From these results, it is concluded that a kinin-forming enzyme is present in the rat brain. It is a cathepsin D-like enzyme, and furthermore, the enzyme releases a kinin-like peptide from the plasma kininogen fraction.
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PMID:Kinin-forming enzyme in rat brain mitochondria fraction and biological activity of a kinin released from rat plasma kininogen by this enzyme. 674 70


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