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)

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 effect of a specific inhibitor of thromboxane (Tx) A2 synthesis, CGS-13080, a new angiotensin converting enzyme inhibitor, CGS-16617, and a combination of both drugs was studied in hemorrhagic shock in rats. Treatment with CGS-16617 (1 microgram/kg) or CGS-13080 (200 micrograms/kg) alone did not alter significantly postoligemic hypotension or the increase in plasma cathepsin D activity in shocked rats, compared with hemorrhaged rats receiving only their vehicle. Combined treatment with both drugs maintained postreinfusion mean arterial blood pressure and attenuated the increase in plasma cathepsin D activity in hemorrhaged rats. Treatment of shocked rats with each drug alone attenuated the accumulation of a myocardial depressant factor activity in the plasma, but the lowest myocardial depressant factor activities were observed in rats treated with the drug combination. Additionally, animals treated with the drug combination exhibited significantly longer postreinfusion survival times than rats receiving either the vehicle (P less than .01), CGS-16617 (P less than .05) or CGS-13080 (P less than .02). CGS-16617 (1 microgram/kg) attenuated significantly the pressor response to angiotensin I throughout the shock period. CGS-13080 attenuated the increase in TxB2 plasma concentrations in shock when compared with hemorrhaged rats receiving the vehicle (P less than .05). Greater attenuation of TxB2 was found after treatment with the drug combination (P less than .01 from vehicle, P less than .05 from CGS-13080 alone). CGS-16617, but not CGS-13080, was also found to have a direct antiproteolytic action in pancreatic homogenates. However, the drug combination (CGS-16617 and CGS-13080) decreased proteolytic activity even further (P less than .001) from CGS-16617 alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potentiation of the protective effects of a converting enzyme inhibitor and a thromboxane synthetase inhibitor in hemorrhagic shock. 303 16

We have designed and synthesized a series of small peptides containing a perfluoroalkyl ketone group at the C-terminal position of the angiotensin I sequence as inhibitors of human renin. From this series of compounds, 8 and 10 showed strong inhibition of human renin (IC50 = 3 X 10(-9), 7 X 10(-9) M, respectively). Compound 10 did not inhibit pepsin and cathepsin D at 10(-4) M. Comparison of the IC50 of compound 8 and compound 11 (8.7 X 10(-7) M) demonstrated the marked effect of the perfluoropropyl group on the potency of inhibition on renin, presumably due to the strong electron-withdrawing effect causing the ketone in 8 to exist predominantly as the hydrate--thus mimicking the tetrahedral transition state during hydrolysis of the scissile Leu10--Val11 amide bond.
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PMID:Highly potent and specific inhibitors of human renin. 311 89

There is increasing evidence which suggests that the adrenal gland contains the renin-angiotensin cycle. The localization of renin has been reported to be mainly in the zona glomerulosa rather than the fasciculata medullary portion. In the present study we have investigated extracts from aldosteronomas (n = 3), which are believed to derive from the zona glomerulosa cells. In addition, we have attempted to characterize the biochemical properties of the adrenal renin. Sizable quantities of renin-like activity (32.0 +/- 7.7 ng of angiotensin I generated h-1 mg-1 of protein, mean +/- SEM) were detected in the extracts. This renin-like activity was inhibited by anti-renin antibody raised against pure renin (mean, 95% of the total renin-like activity), indicating that it was not due to the non-specific action of proteases such as cathepsin D. The optimum pH of the tissue renin-like enzyme was 6.0 for rat plasma substrate. Differences were found, however, in the molecular mass (36,000, 37,000, 44,000 and 48,000), binding to concanavalin A and isoelectric points (4.40, 4.68 and 5.00). These results confirm the existence of specific renin in aldosteronoma. Renin microheterogeneity could be evidence for local production of the enzyme.
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PMID:Multiple forms of immunoreactive renin in human adrenocortical tumour tissue from patients with primary aldosteronism. 329 70

Immunocytochemical and biochemical techniques have been utilized in the present study to characterize renin in brain cell cultures. With the use of renin-specific antibody, positive renin staining was seen in neuronal and in astrocytic glial cells using the peroxidase-antiperoxidase method. Renin concentration was pH-dependent with highest concentrations at 5.5, decreasing from pH 6.0 to 6.5. At pH 7.4 no renin was detectable in either glial or neuronal cells. The contribution of cathepsin D to the measured renin was about 10% at pH 5.5; 7% at pH 6.0 and 3% at pH 6.5. Comparison of glial with neuronal cells from WKY rats revealed significantly elevated renin at pH 5.5 in glial cells. No difference was seen between glial and neuronal renin levels in WKY rats at pH 6.0 and 6.5. At pH 5.5 and 6.0 renin was significantly increased in neuronal cells of SHR compared to WKY, whereas at pH 6.5 no difference was observed. The renin concentration in cells kept for 2 days in serum-free medium did not differ from those measured in cells kept in serum-containing medium. The generated peptide was identified as [Ile5]Angiotensin I on reversed-phase HPLC.
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PMID:Presence of renin in primary neuronal and glial cells from rat brain. 332 28

A highly active angiotensin-producing enzyme (enzyme II) was obtained from dog serum by acid treatment and fractionation to remove angiotensinase and converting enzyme, separate an inhibitor, and convert an inactive precursor (proenzyme II) to enzyme II. Proenzyme II was found to be converted to enzyme II by an endogenous activating enzyme identified as plasmin. Conversion was also caused by the interaction of bacterial streptokinase with human proactivator, by trypsin, and by an activator formed from liver tissue extract and dog serum. Neither plasma kallikrein nor the labile, human extrinsic tissue-type plasminogen activator induced activation. The inhibitor, which normally blocks the activation of proenzyme II, was unusually stable against high temperatures and extremes of pH, and it was not identical to any of the six known protease inhibitors of serum. Enzyme II was not identical to other angiotensin-producing enzymes such as enzyme I, renin, cathepsin D, pepsin, plasmin, tonin, or cathepsin G. Enzyme II reacted maximally at pH 4.7 and produced up to 2250 ng of angiotensin I/ml serum/hr from the substrate of dog serum (i.e., amounts 3200-fold higher than that produced by endogenous renin of normal dog serum). Since at pH 7.2, angiotensin I formation is still about 30 times higher than that of renin, enzyme II may be physiologically active under some conditions.
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PMID:Angiotensin-producing serum enzyme II. Formation by inhibitor removal and proenzyme activation. 390 15

The action of three previously isolated electrophoretically homogeneous brain proteinases--cathepsin B (EC 3.4.22.1), cathepsin D (EC 3.4.23.5), and high-molecular-weight aspartic proteinase (Mr = 90K; EC 3.4.23.-)--on human angiotensins I and II has been investigated. The products of enzymatic hydrolysis have been identified by thin-layer chromatography on Silufol plates using authentic standards and by N-terminal amino acid residue analysis using a dansyl chloride method. Cathepsin D and high-molecular-weight aspartic proteinase did not split angiotensin I or angiotensin II. Cathepsin B hydrolyzed angiotensin I via a dipeptidyl carboxypeptidase mechanism removing His-Leu to form angiotensin II, and it degraded angiotensin II as an endopeptidase at the Val3-Tyr4 bond. Cathepsin B did not split off His-Leu from Z-Phe-His-Leu. Brain cathepsin B may have a role in the generation and degradation of angiotensin II in physiological conditions.
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PMID:Action of brain cathepsin B, cathepsin D, and high-molecular-weight aspartic proteinase on angiotensins I and II. 391 Oct 93

A new angiotensin converting enzyme inhibitor, enalaprilic acid (MK-422), was given in a bolus of 0.5 mg/kg i.v., followed by an infusion of 0.25 mg/kg/hr to determine its effects in hemorrhagic shock. MK-422 produced no significant hemodynamic effects in sham shock controls, yet it effectively blocked the pressor effect of exogenously administered angiotensin I throughout the 260-min experimental period and reduced angiotensin converting enzyme activity by 90% as determined by radiochemical assay. In vitro studies on cat papillary muscles and pancreatic homogenates revealed no direct inotropic or antiproteolytic effect of enalaprilic acid. Nevertheless, converting enzyme inhibitor treatment maintained postreinfusion mean arterial blood pressure at a significantly higher value (P less than .01) than that of untreated hemorrhaged animals (66 +/- 5 vs. 27 +/- 10 mm Hg, respectively). Superior mesenteric artery flow for hemorrhaged cats was significantly higher (P less than .05) in the treated group both during the end of the oligemic period (6.1 +/- 0.4 vs. 3.8 +/- 0.8 ml/kg/min) and during the postreinfusion period (6.5 +/- 0.7 vs. 1.9 +/- 1.0 ml/kg/min). Moreover, enalaprilic acid blunted the marked rise in plasma cathepsin D (P less than .01) and myocardial depressant factor activities (P less than .01), and plasma amino-nitrogen concentrations (P less than .05) observed in the untreated hemorrhaged cats. These results indicate that enalaprilic acid improved the hemodynamic and metabolic status of cats in hemorrhagic shock.
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PMID:Anti-shock actions of a new converting enzyme inhibitor, enalaprilic acid, in hemorrhagic shock in cats. 609 95

Immunization with renin from the kidneys of hog, beef, dog, rabbit and man induced the formation of a highly active enzyme (enzyme I) in the serum of dogs, guinea pigs, rabbits and rats. Enzyme I produces angiotensin I maximally at pH 4.7, up to 2900 ng/ml serum/h, i.e. at a rate 2500 times higher than the endogenous renin of normal serum. At pH 7.2 the angiotensin I production by enzyme I is about 16 to 28 times higher than that of plasma renin. Enzyme I is produced by immunization with renin and not by other kidney proteins. Enzymatically-active renin is required and separate mechanisms are involved in the formation of enzyme I and antirenin. Enzyme I is not identical to renin, pepsin, cathepsin D, plasmin, tonin or cathepsin G and it is inhibited by pepstatin, but not by diisopropyl fluorophosphate.
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PMID:Angiotensin-producing enzyme I of serum: formation by immunization with renin. 609 39

Renin is stored in synaptosomes of rat brain, separately from cathepsin D and intraneuronal angiotensin II (ANG II) has been demonstrated with the electron-microscope. Although the subcellular localization of other components of the renin-angiotensin system (RAS) have still to be investigated, these data suggest possible intracellular synthesis of ANG II in the brain. Brain ANG II is biochemically identical to the plasma peptide and corresponds to (IIe) 5-ANG II. The peptide level is unchanged after bilateral nephrectomy, and angiotensin I (ANG I) accumulation is observed in nephrectomized animals following brain angiotensin converting enzyme blockade. The significantly greater accumulation of ANG I and reduction of ANG II in stroke prone spontaneously hypertensive Wistar-Kyoto rats (WKY) indicates a higher synthesis and turnover rate of ANG II in SHR. Most converting enzyme inhibitors (CEI) penetrate the brain after chronic oral treatment. Part of their blood pressure lowering action may therefore be explained by an inhibition of the brain RAS.
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PMID:The brain angiotensin system: subcellular localization and interferences with converting enzyme inhibitors. 610 Jun 13


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