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)

A high activity of renin was demonstrated in human pheochromocytoma tissue. This activity was inhibited by specific antibody raised against human renal renin, indicating that it was not due to the nonspecific actions of proteases such as cathepsin D. The specific renin shared some biochemical features with well-known kidney renin, such as molecular weight (47,000 daltons), optimum pH (6.0), the presence of trypsin-activatable inactive renin, and glycoprotein nature. However, the isoelectrofocusing pattern of renin from the pheochromocytoma differed from that of kidney and plasma renins hitherto reported, a discrepancy which could be interpreted as evidence for endogenous synthesis of the enzyme. Furthermore, angiotensin converting enzyme activity was found in the tissue. Since pheochromocytoma is considered to be of neural crest origin, these results provide biochemical and immunological evidence for the presence of the renin-angiotensin cycle within human neuronal cells.
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PMID:Biochemical identification of renin in human pheochromocytoma. 300 87

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

Oleic acid binds in a saturable fashion to human plasma fibronectin (FN). Analysis of the binding indicated the presence of a high affinity binding site with nKa approximately equal to 10 uM-1. Furthermore, it was found that binding of sodium oleate to FN modulated its susceptibility to degradation by various proteinases. FN saturated with sodium oleate was hydrolysed at a higher rate by trypsin, cathepsin D, thermolysin and pancreatic elastase than native FN. In contrast, sodium oleate inhibits the activity of two human granulocyte proteinases, human leucocyte elastase (HLE) and cathepsin G on either FN or on their respective specific synthetic substrates (at concentrations ranging from 10(-6) mM to 10 mM). Cathepsin G inhibition was non-competitive and gave a Ki in the 10 uM range similar to the previously reported inhibitory constant of oleic acid toward HLE.
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PMID:Effect of sodium oleate on the hydrolysis of human plasma fibronectin by proteinases. 329 75

Proteolytic cleavage of bovine fibrinogen with covalently bound methotrexate (MTX) was studied using four different proteolytic enzymes--trypsin, chymotrypsin, pepsin, and cathepsin D and the interaction of the modified fibrinogen (or fibrin) with HeLa cells was investigated. The presence of fibrin-MTX derivative did not induce any significant morphological alternations of cells. The fibrin-MTX derivative in the gel form was solubilized easily by the action of all proteinases investigated, hydrolysis of highly crosslinked denatured fibrin-MTX in suspension proceeded slower. The solubilized fibrin-MTX degradation products had a strong inhibiting effect on the growth of HeLa cells cultured in monolayer indicating the liberation of chemotherapeutically active MTX from its fibrin derivative.
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PMID:The effect of fibrinogen-methotrexate derivatives on HeLa cell growth. 353 94

The activity of chymase was markedly inhibited by phosphoglycerides such as phosphatidic acid, phosphatidylserine, and phosphatidylinositol, but was not affected by acylglycerides, phosphoglyceroserine, serine, inositol, or glycerol. These results suggest that both the nonpolar hydrophobic hydrocarbon tails and the polar hydrophilic head are essential for the inhibitory effects of phosphoglycerides. Binding of a primary amine to an anionic polar head of phosphatidic acid, such as in phosphatidylserine and phosphatidylethanolamine, slightly decreased the inhibitory effect of phosphatidic acid and, conversely, binding of a strong cation to the head, such as in phosphatidylcholine, resulted in its activation of chymase. Phosphatidic acid containing an unsaturated fatty acid, such as dioleoyl phosphatidic acid, caused the same extent of inhibition as natural phosphatidic acid from bovine brain, but was 20 times more inhibitory than phosphatidic acid containing a saturated fatty acid, such as distearoyl phosphatidic acid. The inhibition by phosphatidylserine was noncompetitive and pseudoirreversible, and the Ki value was 0.54 microM. The inhibition of chymase by phosphatidylserine was pH dependent, being strong at pH 8.5 to 9.5 but weak below pH 7.5. Phosphatidylserine specifically inhibited chymase and elastase; it did not inhibit the other chymotrypsin-type serine endopeptidases tested, trypsin, papain, collagenase, carboxypeptidase A, or cathepsin D.
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PMID:Inhibition of chymase activity by phosphoglycerides. 388 53

Identification of inactive prorenin in the kidney has been difficult due to rapid proteolytic conversion of the inactive zymogen to its active form in the tissue or during homogenization and purification. Immunochemical methods, Western blotting, direct radioimmunoassay, and immunoaffinity chromatography were used to isolate and identify rat kidney renin and prorenin and to determine their molecular weights without complete purification. Antisera to pure rat renin were raised in rabbits. A specific reaction between the antisera and rat renin was demonstrated by double immunodiffusion, inhibition of enzyme activity, and competitive radioimmunoassay. The anti-rat renin IgG did not cross-react with purified human renin or rat spleen or kidney cathepsin D. The IgG showed binding affinity to both inactive renin as well as active enzyme. A combination of affinity chromatographies consisting of pepstatin-Sepharose, IgG-Sepharose, and Affi-Gel Blue permitted rapid and complete separation of inactive renin from active renin in rat kidney extract. Neither inactive nor active renin preparations exhibited aspartyl protease activity on hemoglobin used as substrate. The apparent molecular weight of inactive renin was estimated as 50,000 by gel filtration. Electrophoresis of partially purified inactive renin in sodium dodecyl sulfate (SDS) polyacrylamide gel followed by transblotting of proteins to a nitrocellulose sheet and immunochemical staining with anti-renin IgG showed a single protein band with a molecular weight of 48,000. Activation of inactive renin by trypsin was accompanied by the reduction of the 48,000-dalton native protein to a 39,000-dalton protein as determined by the SDS polyacrylamide gel electrophoresis and the transblotting.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Application of immunochemical methods to the identification and characterization of rat kidney inactive renin. 388 4

The biochemical properties of renin, extracted from human pituitary specimens obtained at autopsy, were studied using a specific antirenin antibody raised against human kidney renin. The following results were obtained. The molecular weight of pituitary renin was estimated to be about 37,000 daltons by gel filtration through Sephadex G-100. The optimum pH of pituitary renin was between 6.0 approximately 7.0, while that of a renin-like substance which did not react with the antirenin antibody had an acidic pH of 4.0, with a pH comparable to that of the cathepsin D-like enzyme in the pituitary tissue. The presence of two different isoelectric-point species of pituitary renin was revealed by isoelectric focusing, one with a point of pH 4.47 and the other with that of pH 5.77. The Km value of pituitary renin was 37.9 microM for synthetic human renin substrate. Affinity chromatography of the pituitary renin on a Concanavalin-Sepharose column showed that most (87.4%) of the pituitary renin did not contain glycoprotein residues. Treatment with either trypsin or glandular kallikrein increased the renin activity, indicating the presence of an inactive form of renin in the pituitary tissue. From these findings, it is concluded that specific renin exists in human pituitary tissue. It seems likely that the pituitary renin is of local origin rather than contamination of the circulating enzyme.
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PMID:[Biochemical properties of renin in human pituitary tissue]. 389 64

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

Proteolytic fragments of fibronectin were used to identify regions of the molecule that support neurite extension and to investigate further the differential behavior of central and peripheral nervous system neurons in response to fibronectin (Rogers, S. L., P. C. Letourneau, S. L. Palm, J. B. McCarthy, and L. T. Furcht (1983) Dev. Biol. 98: 212-220). Fibronectin fragments with differing biological activities were produced by proteolytic digestion with trypsin and cathepsin D and sequential affinity chromatography on gelatin-agarose and heparin-Sepharose. The resulting fragments (described by Smith, D. E., D. F. Mosher, R. B. Johnson, and L. T. Furcht (1982) J. Biol. Chem. 257: 5831-5838; Smith, D. E., and L. T. Furcht (1982) J. Biol. Chem. 257: 6518-6523 included an NH2-terminal 27,000-dalton peptide that weakly binds heparin, a 46,000-dalton gelatin-binding fragment, a series of fragments (80,000 to 125,000 daltons) from the center of the molecule containing previously described cell-binding activity, two major peptides of Mr = 33,000 and 66,000 that bind heparin strongly and are thought to originate from the A and B chains, respectively, of plasma fibronectin, and a 31,000-dalton COOH-terminal peptide containing a free sulfhydryl from the A chain of the molecule. Tissue culture dishes were treated with these proteolytic preparations, and dissociated embryonic chick peripheral (PNS) and central nervous system (CNS) cells were cultured on each experimental substratum in serum-free medium. The fibronectin fragments were evaluated for ability to promote cell attachment, neurite initiation, and maintenance of neurite growth. The 27,000-, 46,000-, and 31,000-dalton preparations did not promote cell attachment or neurite extension. Both PNS and CNS neurons attached to and extended stable neurites upon the COOH-terminal heparin-binding preparation containing the 33,000- and 66,000-dalton peptides. A differential response of the neurons to the 80,000- to 125,000-dalton "cell-binding" peptides was observed: whereas PNS neurons maintained neuritic growth on this preparation for at least 48 hr, CNS neurons extended neurites during the first 24 hr of culture but, by 48 hr, withdrew these neurites and became increasingly clumped. On the basis of (1) the observed neuronal responses to the heparin binding and "cell binding" regions, and (2) the different ligand-binding properties of these regions, we propose that cell attachment and neurite extension can be mediated and/or modulated by two separate regions of fibronectin and that cellular response to the intact molecule may involve multivalent interactions.
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PMID:Neuron-specific interactions with two neurite-promoting fragments of fibronectin. 397 71


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