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)

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

Human renin is synthesized as an inactive zymogen (prorenin) which is processed to the active form. We synthesized an 11-amino acid peptide which spans the human prorenin processing site in order to develop a simple assay to study human prorenin activation. Six enzymes which are capable of activating recombinant prorenin in vitro were studied. Four of these enzymes digested the synthetic peptide in a specific fashion, as analyzed by reverse-phase high-performance liquid chromatography. Amino acid analysis of the purified digestion products revealed that trypsin cleaves between Arg-Leu, the authentic processing site, while kallikrein, plasmin and elastase all cleaved at alternate sites. On the other hand, pepsin and cathepsin D did not cleave this substrate, suggesting that the activation of prorenin by these proteases might occur at a site distinct from the authentic processing site. Our data suggest that this synthetic peptide may be used as a simple and specific assay for prorenin activation.
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PMID:Characterization of prorenin activation using a synthetic peptide substrate. 165 85

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

A newly synthesized orally active renin inhibitor, N-morpholinoacetyl-(1-naphthyl)-L-alanyl-(4-thiazolyl)-L-alanyl (3S,4S)-4-amino-3-hydroxy-5-cyclohexylpentanoyl-n-hexylamide (ES-8891), was found to be a highly potent competitive inhibitor of human renin with an inhibition constant of 1.1 nM. This inhibitor was also active against monkey renin, although there was less inhibition of renin in pig, rabbit, and rat. ES-8891 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10(-5) M. A single oral administration of ES-8891 (10 or 30 mg/kg) to conscious, sodium-depleted marmosets caused a dose-related decrease in plasma renin activity and blood pressure. ES-8891 (30 mg/kg) produced an 80% inhibition of plasma renin activity, which lasted for more than 6 hours. Kidney renin messenger RNA was not significantly changed 6 hours after oral administration of ES-8891 (30 mg/kg). A single oral administration of 240 mg ES-8891 to healthy human volunteers (n = 6) produced a significant inhibition of plasma renin activity (75% inhibition at 0.5 and 1 hour, 50% inhibition at 2 hours) with a good correlation of plasma levels of ES-8891. There were no significant changes in blood pressure or heart rate, and no adverse effects were observed. These results suggest that ES-8891 is an orally active human renin inhibitor that may be clinically useful.
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PMID:ES-8891, an orally active inhibitor of human renin. 211 12

1. An in vitro experiment was carried out to compare the inhibitory effect of SQ29,852 on human renal angiotensin converting enzyme (ACE) with those of captopril, enalapril and enalaprilat. 2. SQ29,852 strongly inhibited human renal ACE; its IC50 value was 1.5 x 10(-8) M. In terms of the IC50, SQ29,852's efficacy was about 1/10 of that of captopril and 1/28 of that of enalaprilat, but it was about 14 times more potent than enalapril. 3. SQ29,852 showed no inhibitory effects on cathepsin D, urinary kallikrein, renal renin, pepsin, trypsin and chymotrypsin. Its ACE-specificity was higher than that of captopril. 4. ACE inhibition by SQ29,852 was shown to be competitive, as revealed by Lineweaver-Burk plots. The affinity of SQ29,852 to ACE was shown to be high by a Ki value of 1.2 x 10(-8) M.
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PMID:Effect of SQ29,852, a new angiotensin converting enzyme (ACE) inhibitor with a phosphonic acid group, on the activity of angiotensin converting enzyme from human kidney. 216 61

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 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

Dipeptide and tripeptide derivatives containing a statine residue were synthesized as inhibitors of human renin. ES-305, bis[(1-naphthyl)methyl]acetyl(BNMA)-histidyl-statine 2(S)-methylbutylamide was found to be a highly potent inhibitor of human renin with a Ki value of 1.7 X 10(-9) M. Dipeptide derivatives with the BNMA group at the N-terminal (BNMA-Val-Sta-isoleucinol [ES-313], BNMA-Leu-Sta-isoleucinol [ES-316], and BNMA-Nle-Sta-isoleucinol [ES-317]) had potencies against human renin that were similar to the potency of ES-305. All these dipeptide derivatives competitively inhibited human renin. The inhibitors were also potent against monkey renin but were less effective against renins from pig, goat, dog, rabbit, and rat. ES-305 had little effect on cathepsin D and pepsin at the concentration of 10(-5) M. The other derivatives showed detectable inhibition of cathepsin D (IC50, 10(-6) - 10(-7) M) and pepsin (10(-5) - 10(-6) M). All the compounds had little or no effect on trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at the concentration of 10(-5) M. Our results indicate that ES-305 is a highly potent and specific inhibitor of human renin. This compound is superior to other, previously described statine-containing renin inhibitors with respect to molecular size and enzyme specificity.
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PMID:Statine-containing dipeptide and tripeptide inhibitors of human renin. 308 74

An orally active renin inhibitor, ES 6864 (N-[(2R)-3-morpholinocarbonyl-2-(1-naphthylmethyl)propionyl]-(4- thiazolyl)-L-alanyl-cyclostatine-(2-morpholinoethyl)amide), was synthesized. ES 6864 was found to be a highly potent inhibitor of human renin with a Ki value of 7.3 x 10(-9) M. The compound competitively inhibited human renin. The inhibitor 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, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10(-5) M. ES 6864 was resistant to proteolytic actions of the enzymes in rat tissue homogenates (liver, kidney, pancreas, and small intestine). Oral administration of ES 6864 at 30 mg/kg to conscious, sodium-depleted marmosets produced a significant blood pressure reduction and almost complete inhibition of plasma renin activity, which persisted for 5 hours. Oral administration of ES 6864 also produced dose-related decreases of blood pressure in hog renin-infused rats, but the duration of action was much shorter than that in conscious marmosets. The parent compound in the blood following oral administration of ES 6864 to marmosets was confirmed directly by measuring the plasma concentration of ES 6864. These results enhance the possibility of developing renin inhibitors that can be used clinically.
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PMID:A highly potent and long-acting oral inhibitor of human renin. 313 6


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