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)

Treatment of human serum albumin with a proteolytic enzyme such as pepsin, alpha-chymotrypsin, cathepsin D or trypsin generated histamine releasing peptides. A low-molecular weight peptide (P-1) responsible for releasing histamine was isolated from peptic digests of human serum albumin by affinity chromatography on heparin-Ultrogel and reversed-phase high performance liquid chromatography. The amino acid sequence of the P-1 was estimated to be V-R-Y-T-K-K-V-P-Q-V-S-T-P-T-L by Edman degradation. The sequence determined appears to correspond to residues 409-423 of human serum albumin. Peptide P-1 produced dose-related histamine release from isolated rat mast cells in the concentration range of 1-50 microM. The intradermal injection of the P-1 (0.5 micrograms) increased capillary permeability in rats. This response was blocked by the antihistamine diphenhydramine.
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PMID:Histamine release induced by proteolytic digests of human serum albumin: isolation and structure of an active peptide from pepsin treatment. 247 58

The acid proteases, pepsin, rennin and cathepsin D, were shown to generate mast cell histamine releasing peptides (HRP) when incubated with the albumin fraction of mammalian plasmas. Significant histamine release was observed using less than 1 microliter equivalent of pepsin-treated plasma. Histamine release was rapid, dependent on calcium and energy, and accompanied by degranulation. The major HRP present in pepsin-treated human and canine plasma was identified as H-Ile-Ala-Arg-Arg-His-Pro-Tyr-Phe-OH whereas that from rat plasma had valine substituted for isoleucine. Cathepsin D-treated BSA gave rise to the human octapeptide (above) as well as to an extended decapeptide with H-Tyr-Glu- at the N-terminus. These peptides were apparently derived from one region of serum albumin, residues 139 to 149 of the human, canine, or bovine sequence. We hypothesize that cathepsin D, released from leukocyte lysosomes, might generate HRP during the delayed phase of an inflammatory response.
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PMID:Structures of histamine-releasing peptides formed by the action of acid proteases on mammalian albumin(s). 247 9

CGP 38 560 is a low-molecular-weight (730) inhibitor of human renin that contains only one natural amino acid. In vitro, it is a potent inhibitor of human renin (Ki with tetradecapeptide, 0.4 X 10(-9) M). It has a high enzyme specificity (Ki values against human pepsin, gastricsin, and cathepsin D are 5 X 10(-6), 3 X 10(-6), and 0.6 X 10(-6) M) and is also species specific (IC50 values against human, marmoset, dog, and rat plasma renins are 7 X 10(-10), 7 X 10(-10), 7 X 10(-9), and 1 X 10(-6) M). In vivo, CGP 38 560 inhibits plasma renin activity (PRA) and lowers blood pressure (BP) after oral administration to conscious, normotensive, furosemide-pretreated marmosets. A dose of 10 mg/kg induces complete inhibition of PRA and a decrease in BP of 23 +/- 3 mm Hg (n = 4) after 30 min. These effects persist for up to 2 h. Blockade of the renin-angiotensin system appears to cause the hypotensive response since it is completely prevented by pretreatment with a converting-enzyme inhibitor. These findings demonstrate that the molecular size of renin inhibitors may be reduced to improve their oral activity without loss of potency or specificity.
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PMID:CGP 38 560: orally active, low-molecular-weight renin inhibitor with high potency and specificity. 247 94

Proteinase yscA is an intracellular aspartic proteinase located in the lysosome-like vacuole of the yeast cell. The specificity towards denatured protein substrates was determined by separation and identification of cleavage products after digestions with proteinase yscA, and compared to that obtained with pepsin used under similar conditions. Proteinase yscA is more selective towards the peptide bonds it cleaves than pepsin, but shows the same preference for large hydrophobic residues on both sides of the cleaved bond as pepsin and lysosomal cathepsin D. Phe, Leu and Glu are favoured in substrate subsite P1 and Phe, Ile, Leu and Ala in P'1, whereas Val is unfavoured in P'1. The implications for the role of proteinase yscA as hydrolase maturase are discussed.
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PMID:Substrate specificity of proteinase yscA from saccharomyces cerevisiae. 247 40

Dipeptide and tripeptide derivatives containing a statine residue were synthesized as human renin inhibitors. ES-305, bis[(1-naphthyl)methyl]acetyl-histidyl-statine-2(S)-methylbutylami de, was found to be a highly potent human renin inhibitor that is species-specific and enzyme-specific. The replacement of the methylbutylamide of ES-305 with the leucyl-lysinol (ES-1005) showed similar high potency against human renin (Ki value of 2.4 x 10(-9) M) and monkey renin (Ki value of 7.9 x 10(-9) M) as ES-305. ES-1005 competitively inhibited human renin. The compound was about one order of magnitude less potent against pig, dog, and rabbit renins. It had moderate inhibitory potencies against cathepsin D and pepsin (IC50 of cathepsin D and pepsin of 1.6 x 10(-5) and 8.0 x 10(-6) M, respectively). ES-1005, a newly synthesized tripeptide derivative containing statine, is a highly potent inhibitor of not only primate renin but also a wide variety of nonprimate renins.
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PMID:In vitro inhibition of human renin by statine-containing tripeptide renin inhibitor (ES-1005). 248 69

Using TEA3A1 rat endocrine thymic epithelial cells, we demonstrated that kallikrein (EC 3.4.21.35) not only stimulated the release of arachidonic acid (AA) and its metabolites from TEA3A1 cells but also enhanced the intracellular synthesis of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) by approx. 2-fold. The stimulatory effect of kallikrein was dose- and time-dependent and could be blocked by aprotinin, a kallikrein inhibitor. It was found that the phospholipase A inhibitors ONO RS082 [2-(p-amylcinnamoyl)amino-4-chlorobenzoic acid], and mepacrine (6-chloro-9-[(4-dimethylamino)-1-methyl)]amino-2-methoxyacridine; quinacrine) also inhibited the kallikrein-stimulated release of AA and its metabolites. It is suggested that the kallikrein-induced stimulatory effect might be mediated through a phospholipase A2 pathway. The effect of bradykinin was studied and no significant stimulation was observed, even at a high dose (10 micrograms/ml). This suggested that the formation of kinin does not have a role in the kallikrein-induced stimulation of AA release from TEA3A1 cells. Furthermore, the effect of kallikrein was also totally abolished by adding pepstatin A, a known inhibitor of renin, pepsin and cathepsin D which does not inhibit kallikrein itself. This indicates that kallikrein did not act on the phospholipase-like enzyme directly. There is at least one more enzyme, a pepstatin A-inhibitable proteinase, that acts as a mediator for kallikrein-induced regulation of AA release.
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PMID:Kallikrein stimulates arachidonic acid release and production of prostaglandins from TEA3A1 endocrine thymic epithelial cells. 249 91

A precursor form of cathepsin B (Mr 45-47 kd) was purified from ascitic fluids of patients with ovarian adenocarcinomas. Following pepsin activation, this precursor produced a 33 kd cathepsin B-like proteinase closely related to lysosomal cathepsin B. A similar activation was found using the 52 kd pro-cathepsin D secreted by the MCF7 human breast cancer cells. This activation was a time, dose and pH dependent process. These results suggest that the 52 kd pro-cathepsin D may be involved in the early steps of the "metastatic cascade", activating pro-cathepsin B in an acidic environment.
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PMID:[Pro-cathepsin D can activate in vitro pro-cathepsin B secreted by ovarian cancers]. 250 Feb 29

A compound containing cyclostatine ES-6864 (N-[(2R)-3-morpholinocarbonyl-2-(1-naphthylmethyl)propionyl]-(4-th iazolyl)- L-alanyl-cyclostatine-(2-morpholinoethyl)amide) was found to be a competitive inhibitor of human renin with an inhibitory constant (Ki) value of 7.3 x 10(-9) M. The compound was also potent against monkey renin but was less effective against renins from pig, goat, dog, rabbit and rat. ES-6864 did not inhibit cathepsin D, pepsin, urinary kallikrein, angiotensin converting enzyme, trypsin and chymotrypsin at a concentration of 10(-5) M. ES-6864 also inhibited the tissue renin-like activity from dog tissues with IC50 values of 10(-7)-10(-8) M in vitro. Oral administration of ES-6864 at 30 mg/kg to conscious, sodium-depleted marmosets produced a significant blood pressure reduction and a significant inhibition of plasma renin activity, which persisted for 6 hours. Plasma concentration of ES-6864 reached a maximum of 1.2 micrograms/ml at 1 hour after an oral administration. Oral administration of ES-6864 to hog renin-infused rats produced dose-related decreases in blood pressure. The results demonstrate that ES-6864 is an orally active renin inhibitor with high potency and specificity for human renin. Thus, ES-6864 is a candidate compound for development of renin inhibitors that can be used clinically.
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PMID:[In vitro and in vivo inhibition of renin by a thiazolylalanyl cyclostatine derivative]. 251 1

Small peptide analogues representing the C-terminal portion of angiotensin I sequence were designed as inhibitors of human renin. Among synthesized compounds, benzyloxycarbonyl (-"Z")-(1-naphthyl)Ala-His-leucinal (ES-188), Z-(1-naphthyl)Ala-His-statine ethyl ester (ES-226), and Z-(1-naphthyl)Ala-His-statine 2-methylbutylamide (ES-254) markedly inhibited human and primate renins (inhibitory concentration, 50% [IC50], near 10(-7) M). These peptide analogues inhibited rabbit renin with one or two orders of magnitude less potency. They were very weak inhibitors of renins from pig, goat, dog, and rat. ES-188 had no discernible effect on cathepsin D, pepsin, or human angiotensin-converting enzyme at the concentration of 10(-4)M. ES-226 had little effect on the three enzymes at the concentration of 10(-5)M; however, ES-254 had a considerable inhibitory effect on cathepsin D (IC50 of 1.4 X 10(-5)M), pepsin (IC50 of 4.2 X 10(-5)M), and human angiotensin-converting enzyme (IC50 of 7.1 X 10(-6)M). Our results indicate that 1-naphthylalanine-containing tripeptide analogues are highly potent human renin inhibitors.
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PMID:Highly potent and specific inhibitors of human renin. 298 28

The proteinase A structural gene of Saccharomyces cerevisiae was cloned by using an immunological screening procedure that allows detection of yeast cells which are aberrantly secreting vacuolar proteins (J. H. Rothman, C. P. Hunter, L. A. Valls, and T. H. Stevens, Proc. Natl. Acad. Sci. USA, 83:3248-3252, 1986). A second cloned gene was obtained on a multicopy plasmid by complementation of a pep4-3 mutation. The nucleotide sequences of these two genes were determined independently and were found to be identical. The predicted amino acid sequence of the cloned gene suggests that proteinase A is synthesized as a 405-amino-acid precursor which is proteolytically converted to the 329-amino-acid mature enzyme. Proteinase A shows substantial homology to mammalian aspartyl proteases, such as pepsin, renin, and cathepsin D. The similarities may reflect not only analogous functions but also similar processing and intracellular targeting mechanisms for the two proteins. The cloned proteinase A structural gene, even when it is carried on a single-copy plasmid, complements the deficiency in several vacuolar hydrolase activities that is observed in a pep4 mutant. A strain carrying a deletion in the genomic copy of the gene fails to complement a pep4 mutant of the opposite mating type. Genetic linkage data demonstrate that integrated copies of the cloned proteinase A structural gene map to the PEP4 locus. Thus, the PEP4 gene encodes a vacuolar aspartyl protease, proteinase A, that is required for the in vivo processing of a number of vacuolar zymogens.
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PMID:PEP4 gene of Saccharomyces cerevisiae encodes proteinase A, a vacuolar enzyme required for processing of vacuolar precursors. 302 36


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