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)

Cerebrospinal fluid contains several proteolytic enzymes that can degrade myelin basic protein (BP) under physiological conditions into peptide fragments of various sizes which still contain antigenic determinants capable of binding antibodies to BP. These enzymes are optimally active in either acid (pH 4) or nuetral (pH 7 to 8) conditions and can be characterized by the nature of the BP peptide fragments produced. Proteinases resembling cathepsin D, thrombin, plasmin (fibrinolysin), or kallikrein are present in variable amounts in CSF. No relationship to any particular disease has yet been established.
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PMID:Degradation of myelin basic protein by cerebrospinal fluid: preservation of antigenic determinants under physiological conditions. 9 75

Tumor cell invasion and metastasis is a multifactorial process, which at each step may require the action of proteolytic enzymes such as collagenases, cathepsins, plasmin, or plasminogen activators. An enzymatically inactive proenzyme form of the urokinase-type plasminogen activator (pro-uPA) is secreted by tumor cells which may be converted to an enzymatically active two-chain uPA-molecule (HMW-uPA) by plasmin-like enzymes. Action of proteases on pro-uPA may generate the enzymatically active or inactive high-molecular-weight form of uPA (HMW-uPA). Some proteases (plasmin, cathepsin B and L, kallikrein, trypsin or thermolysin) activate pro-uPA by cleaving the peptide bond Lys158 and IIe159. Other proteases (elastase, thrombin) cleave pro-uPA at different positions to yield enzymatically inactive HMW-uPA. HMW-uPA may be split into the enzymatically active LMW-uPA and the enzymatically inactive ATF (amino terminal fragment). ATF may be cleaved between peptide sequence 20 and 40 within the receptor binding domain of uPA (GFD). Such impaired ATF does not bind to uPA-receptors. Action of the bacterial endoproteinase Asp-N from Pseudomonas fragi mutant on pro-uPA or HMW-uPA, however, generates intact ATF which efficiently competes for binding of HMW-uPA or pro-uPA to receptors on tumor cells. High uPA-antigen content (pro-uPA, HMW-uPA, or LMW-uPA) in breast cancer tissue (not in plasma) indicates an elevated risk for the patient of recurrences and shorter overall survival. Thus pro-uPA/uPA-antigen content in breast cancer tissue serves as an independent prognostic parameter for the outcome of the disease. Cathepsin D is also an independent prognostic factor for recurrences and overall survival. High content of cathepsin D in breast cancer tumors is, however, not correlated with elevated levels of pro-uPA/uPA indicating that synthesis and release of cathepsin D and pro-uPA/uPA are independent events.
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PMID:Biological and clinical relevance of the urokinase-type plasminogen activator (uPA) in breast cancer. 180 51

Action of purified human cathepsin B on recombinant single-chain urokinase-type plasminogen activator (pro-uPA) generated enzymatically active two-chain uPA (HMW-uPA), which was indistinguishable by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot from plasmin-generated HMW-uPA and from elastase- or thrombin-generated inactive two-chain urokinase-type plasminogen activator. Preincubation of cathepsin B with E-64 (transepoxysuccinyl-L-leucylamino- (4-guanidino)butane, a potent inhibitor for cathepsin B) prior to the addition of pro-uPA prevented the activation of pro-uPA. The cleavage site within the cathepsin B-treated urokinase-type plasminogen activator (uPA) molecule, determined by N-terminal amino acid sequence analysis, is located between Lys158 and Ile159. Pro-uPA is cleaved by cathepsin B at the same peptide bond that is cleaved by plasmin or kallikrein. Binding of cathepsin B-activated pro-uPA to the uPA receptor on U937 cells did not differ from that of enzymatically inactive pro-uPA, indicating an intact receptor-binding region within the growth factor-like domain of the cathepsin B-treated uPA molecule. Not only soluble but also tumor cell receptor-bound pro-uPA could be efficiently cleaved by cathepsin B to generate enzymatically active two-chain uPA. Thus, cathepsin B can substitute for plasmin in the proteolytic activation of pro-uPA to enzymatically active HMW-uPA. In contrast, no significant activation of pro-uPA by cathepsin D was observed. As tumor cells may produce both pro-uPA and cathepsin B, implications for the activation of tumor cell-derived pro-uPA by cellular proteases may be considered.
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PMID:Cathepsin B efficiently activates the soluble and the tumor cell receptor-bound form of the proenzyme urokinase-type plasminogen activator (Pro-uPA). 190 May 15

Rabbit myelin basic protein (BP) was subjected to partial cleavage with plasmin, and 15 cleavage products were isolated by a combination of gel filtration and ion-exchange chromatography. Their identification was achieved by amino acid analysis and tryptic peptide mapping, supplemented in some instances by carboxy-terminal analyses with carboxypeptidases A, B, and Y and amino-terminal analyses with dipeptidyl aminopeptidase I. The results showed that major plasmic cleavage sites included the Lys89-Asn90, Lys133-Ser134, and Lys153-Leu154 bonds. Cleavages also occurred at the Arg31-His32, Lys53-Arg54, and Arg25-His26 bonds, but these appeared to be less extensive. A large number of additional peptides were produced in relatively low yield. The smaller of these were isolated from heterogeneous fractions by high-voltage electrophoresis-TLC. Amino acid analysis of these peptides showed that minor cleavage sites included the Arg9-His10, Lys13-Tyr14, Lys103-Gly104, Lys137-Gly138, Lys140-Gly141, and Arg160-Ser161 bonds. In spite of a lower selectivity toward peptide bonds in BP as compared with pepsin, cathepsin D, and thrombin, plasmin has the advantage over the former proteinases in that it does not cleave at or near the Phe44-Phe45 bond. Instead it cleaves at the Arg31-His32 and Lys53-Arg54 bonds, thus preserving the entire hydrophobic sequence Ile-Leu-Asp-Ser-Ile-Gly-Arg-Phe-Phe as well as short sequences to either side.
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PMID:Cleavage of rabbit myelin basic protein by plasmin: isolation and identification of the major products. 241 69

Both bovine and human myelin basic protein (MBP) have been shown to have electrophysiological activity. As MBP is susceptible to proteolytic degradation, our aim was to discover whether the resulting peptides retained this activity. Bovine MBP was completely cleaved by plasmin into at least nine peptides. The electrophysiological activities of this peptide mixture and of bovine MBP were directly compared on the hemisected frog spinal cord. The peptide mixture and intact bovine MBP had quantitatively and qualitatively similar effects (dose-dependent long-lasting depolarization, about 100 times more active than glutamate). Four peptides (molecular weights 14,000, 10,500, 8,000, 4,500) from thrombin or cathepsin D cleavage of bovine MBP also showed electrophysiological activity, positively correlated to their molecular weights. As MBP-like material occurs in increased concentrations in the cerebrospinal fluid during demyelinating diseases, peptides resulting from proteolytic degradation of MBP, e.g. in demyelinating foci of multiple sclerosis, might cause neuronal disturbances.
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PMID:Effects of peptides from bovine myelin basic protein on the bioelectrical activity of the frog spinal cord. 245 64

Hydrolysis of histones by proteinases from rat liver, skin and other sources was studied by using a rat thymus histone preparation as the substrate and polyacrylamide-gel electrophoresis and densitometric analysis as the methods to detect histone subtypes and their hydrolysis. The rat mast-cell proteinase I effectively hydrolysed histones except type H4. Thrombin hydrolysed effectively histones H1 and H2A, whereas plasmin hydrolysed all types of histones. Cathepsin D hydrolysed especially histone H2A. Cathepsins B and L hydrolysed all histones more slowly, and cathepsin H hydrolysed them extremely slowly. Epidermal aminoendopeptidase did not hydrolyse histones. Trypsin and chymotrypsin were used as reference enzymes, which hydrolysed all types of histones in very low concentrations. This study suggests that a variety of proteinases could play a role in histone hydrolysis. Hydrolysis of a specific subtype of histones, such as histone H2A at pH 6 by cathepsin D, may be directly involved in regulation of epidermal-cell differentiation.
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PMID:Hydrolysis of histones by proteinases. 296 88

In a continuing study of proteolysis of CNS proteins by CNS enzymes, neurofilament proteins (210 K, 155 K, 70 K) and desmin were separated, and the breakdown of individual proteins by purified brain cathepsin D was measured and compared to breakdown by plasma thrombin. With both cathepsin D and thrombin, the rate of breakdown of the 70 K protein was the highest, followed by the 155 K, and that of the 210 K was the lowest. With each substrate cathepsin D breakdown was the highest at pH 3; small but significant breakdown could be seen at pH 6. The pattern of intermediate breakdown products depended on pH, with greater amounts of fragments detected at higher pH, and the patterns with the two enzymes were different. We showed that differences exist in cleavage sites and breakdown rates of the neurofilament proteins. The capacity of the cathepsin D present in the tissue to hydrolyze these substrates was high, even at pH close to neutral, and was greatly in excess of that needed for physiological neurofilament turnover.
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PMID:The breakdown of the individual neurofilament proteins by cathepsin D. 360 Sep 62

To define the role of activated platelets we have attempted to prepare monoclonal antibodies specific for activated platelets. The IgG2b antibody of one of the clones, designated 2.28, was studied in more detail. Native platelets from normal individuals bound 650 125I-2.28 molecules/platelet, whereas thrombin-activated platelets bound 12,600 molecules/platelet with high affinity (4.6 nmol/L). Immunoelectrophoretic analysis revealed that 2.28 reacted with a 53,000-mol wt protein. Immunocytochemistry showed that the antigen is located in a special subclass of platelet granules in unstimulated platelets and is exposed on the surface of thrombin-activated platelets. Double-labeling studies with immunogold labels disclosed simultaneous localization of 2.28 binding sites and cathepsin D in the same granules both in megakaryocytes and endothelial cells, thereby indicating that the antigen may be localized in lysosomes. By using flow cytofluorometry, in vivo platelet activation was studied in patients undergoing cardiac surgery with cardiopulmonary bypass. Increased numbers of platelets that expressed the 2.28 antigen on their surface were observed after extracorporeal perfusion. The percentage of 2.28-positive platelets in the circulation was 3.9% +/- 2.7% (SD) in controls (n = 20), 5.5% +/- 3.0% in patients (n = 10) before cardiopulmonary bypass surgery, 24.6% +/- 13.5% after the bypass, and 8.5% in two patients with acute deep venous thrombosis. These data indicate that 2.28 may serve as a useful probe of in vitro and in vivo platelet activation.
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PMID:Studies with a monoclonal antibody against activated platelets: evidence that a secreted 53,000-molecular weight lysosome-like granule protein is exposed on the surface of activated platelets in the circulation. 362 Jul 3

Experiments were performed on isolated human cerebral arteries to evaluate the role desensitization and tachyphylaxis might play in preventing certain agonists from producing prolonged vasoconstriction after subarachnoid hemorrhage. In addition, the antiproteases leupeptin and pepstatin were studied to ascertain whether these peptides might inhibit contraction as does antithrombin III. The maximal contraction to KCl was used as a standard for comparing the responses elicited by the agonists, the decay of the responses to the agonists over 15 minutes was used as an index of desensitization, and the percentage of decrease in response to a second application of the agonist over the first was a measure of tachyphylaxis. The results showed that desensitization and tachyphylaxis greatly reduced or abolished the contractile responses to norepinephrine, serotonin, angiotensin II, arginine vasopressin, substance P, neuropeptide Y, neurotensin, thrombin, uridine triphosphate, linoleic acid, melittin, and cathepsin D. Moreover, some arteries failed to respond to some of these agonists, and no contractile response was elicited by acetylcholine or bradykinin. In contrast, prostaglandins E2, D2, and F2 alpha, as well as plasmin, produced sustained contractions, without tachyphylaxis, but only prostaglandin E2 and plasmin produced contractions at concentrations of 10(-7) M or less that were comparable to those of KCl. None of the antiprotease peptides inhibited the responses to KCl whereas small concentrations (6 X 10(-8) M) of antithrombin III did. The results support the hypotheses that the phenomenon of desensitization and tachyphylaxis would prevent many diverse agents from acting as spasmogens and that substances like antithrombin III present in the cerebrospinal fluid after hemorrhage could immediately protect patients from cerebral vasospasm.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacodynamic evaluation of human cerebral arteries in the genesis of vasospasm. 368 86

Immunocytochemistry with affinity-purified anti-human cathepsin D was applied to ultrathin frozen sections of human bone marrow megakaryocytes and of blood platelets from peripheral blood. The fixative used was paraformaldehyde (concentration gradient 2----8%). Protein A/colloidal gold (5 and 8) particles were used as second label. Cathepsin D was localized in primary and secondary lysosomes in blood platelets and in primary and secondary lysosomes in megakaryocytes. Primary lysosomes in megakaryocytes were identified by their localization on the trans-side of the Golgi complex and secondary lysosomes by the presence of inclusions. The lysosomes in platelets differed from alpha-granules by being smaller, lacking an electron dense core, and by the presence of a transparent submembrane halo. Platelets undergoing a release reaction after stimulation with thrombin showed cathepsin-D staining in the surface-connecting tubules.
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PMID:Immuno-electron microscopical demonstration of lysosomes in human blood platelets and megakaryocytes using anti-cathepsin D. 399 73


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