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)

The distribution and biochemical properties of the renin activity present in the dog brain were compared with those of the lysosomal enzyme cathepsin D. Renin and cathepsin activity were present in all brain regions studied, in association with high angiotensinase activity. Brain renin activity was partially purified by ammonium sulfate fractionation and Sephadex gel filtration, resulting in the removal of angiotensinase activity. The specific brain renin activity increased approximately one hundred times during this procedure; cathepsin D activity accompanied the brain renin activity throughout the purification and showed a similar increase in specific activity. The renin and cathepsin activity in the partially purified preparation behaved identically during isoelectric focusing. The partially purified renin and cathepsin activity exhibited saturation kinetics with their respective substrates and were without activity above pH 6.0. Both enzyme activities were irreversibly inhibited by the pepsin inhibitor pepstatin, in nanomolar concentrations. These data, in conjunction with the literature concerning brain cathepsin, suggest that the renin activity in brain is due to cathepsin D, and that this renin activity exhibited by cathepsin D may be of limited significance under physiological conditions.
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PMID:Renin activity in dog brain: enzymological similarity to cathepsin D. 18 Dec 41

Pepstatin is a low molecular weight, potent inhibitor specific for acid proteases with a Ki value of about 10(-10)M for pepsin. The chemical structure of pepstatin is essentially a hexapeptide which contains two residues of an unusual amino acid, 4-amino-3-hydroxy-6-methylheptanoic acid (statine). The complete structure of pepstatin is isovaleryl-L-valyl-L-valyl-statyl-L-alanyl-statine. To study its mode of inhibition, we prepared several derivatives and measured their kinetics of inhibition. Both N-acetyl-statine and N-acetyl-alanyl-statine are competitive inhibitors for pepsin with Ki values of 1.2 x 10(-4)M and 5.65 x 10(-6)M, respectively. The Ki value for N-acetyl-valyl-statine is 4.8 x 10(-6)M. These statyl derivatives, therefore, are very strong inhibitors. The Ki value for N-acetyl-statine is 600-fold smaller than that of its structural analog N-acetyl-leucine. The derivative which contains two statyl residues in a tetrapeptide exhibits inhibitory properties which approach those of pepstatin itself. Other acid proteases, human pepsin, human gastricsin, renin, cathepsin D, the acid protease from R. chinensis and bovine chymosin, also are inhibited by pepstatin and its derivatives. We suggest that the statyl residue is responsible for the unusual inhibitory capability of pepstatin and that statine is an analog of the previously proposed transition state for catalysis by pepsin and other acid proteases.
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PMID:Pepstatin inhibition mechanism. 33 90

Inactive human renin is found in amniotic fluid, plasma, and kidney and may be a renin precursor ("prorenin"). The mechanism of activation of inactive renin in vivo is not known. The present study examined the hypothesis that cathepsin D, a lysosomal pepsin-like endopeptidase may be capable of eliciting activation. Cathepsin D was incubated with inactive renin in human amniotic fluid at pH 4.8 and 22 C for 0-5 h. Marked activation occurred and the reaction displayed first order kinetics with respect to the concentration of cathepsin D. The initial velocity of conversion of inactive renin to active renin by cathepsin D was 0.007%/min/microgram cathepsin D. Under identical conditions, the initial velocity of conversion by pepsin was 0.18%/min/microgram pepsin. The 25-fold higher potency of pepsin compared with cathepsin D is in accordance with the recognized relative substrate affinities and catalytic efficiencies of the two enzymes. Inactive renin in human amniotic fluid seems to be similar to that found in human kidney and since cathepsin D is present in juxtaglomerular cells, this activation process may have physiological importance.
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PMID:Activation of human inactive ("pro-") renin by cathepsin D and pepsin. 37 40

Antibodies were raised in rabbit against pure human renin. The antisera obtained are highly specific for human renin versus hog, dog and rat renin. They do not cross-react with acid proteases such as pepsin and human cathepsin D. A direct radioimunoassay is described for human renin in plasma and kidney extracts. 30 to 50 pg of enzyme (2.5 to 4 x 10(-5) Goldblatt units) are detected.
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PMID:Direct radioimmunoassay of human renin. 44 94

The concept of a brain renin-angiotensin system originated with the observation that the components necessary for the formation of angiotensin II are present in the central nervous system. This observation has been confirmed and extended, and it is now frequently assumed that there is a functional brain renin-angiotensin system. However, careful analysis of the available evidence has revealed a number of significant problems. It appears that most of the renin-like activity measured in extracts of brain is due to the acid protease cathepsin D; this is unlikely to function as an angiotensin-forming enzyme in vivo. Experiments involving central administration of renin substrate have not provided convincing evidence for a significant renin-renin substrate interaction in vivo. Attempts to demonstrate the presence of angiotensin in the brain have been plagued with problems of specificity and it is still not clear if the peptide is actually present in the central nervous system. These problems do not rule out the possibility that there is a brain renin-angiotensin system, but more definitive evidence is required before it can be concluded that such a tensin system exists.
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PMID:The brain renin-angiotensin system: a critical analysis. 45 11

1. Renin was purified 30 000-fold from rat kidneys by chromatography on DEAE-cellulose and SP-Sephadex, and by affinity chromatography on pepstatinyl-Sepharose. 2. The enzymatic properties of isorenin from rat brain, pseudorenin from hog spleen, cathepsin D from bovine spleen, and renin from rat kidneys were compared: Isorenin, pseudorenin and cathepsin D generate angiotensin from tetradecapeptide renin substrate with pH optima around 4.9, renin at 6.0. With sheep angiotensinogen as substrate, isorenin, pseudorenin and cathepsin D have similar pH profiles (pH optima at 3.9 and 5.5), in contrast to renin (pH optimum at 6.8). 3. The angiotensin-formation from tetradecapeptide by isorenin, pseudorenin and cathepsin D was inhibited by albumin, alpha-and beta-globulins. These 3 enzymes have acid protease activity at pH 3.2 with hemoglobin as the substrate. Renin is not inhibited by proteins and has no acid protease activity. 4. Renin generates angiotensin I from various angiotensinogens at least 100 000 times faster than isorenin, pseudorenin or cathepsin D, and 3000 000 times faster than isorenin when compared at pH 7.2 with rat angiotensinogen as substrate. 5. The 3 'non-renin' enzymes exhibit a high sensitivity to inhibition by pepstatin (Ki less than 5.10(-10) M), in contrast to renin (Ki approximately 6-10(-7) M), at pH 5.5. 6. It is concluded from the data that isorenin from rat brain and pseudorenin from hog spleen are closely related to, or identical with cathepsin D.
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PMID:Isorenin, pseudorenin, cathepsin D and renin. A comparative enzymatic study of angiotensin-forming enzymes. 62 74

Cathepsin D, purified from hog spleen, releases angiotensin I from tetradecapeptide renin substrate and from protein renin substrates purified from hog and human plasma. However, the enzyme does not act on the naturally occurring renin substrate as it exists in plasma nor on purified substrate in the presence of plasma. Cathepsin D releases angiotensin I quantitatively from tetradecapeptide renin substrate and does not further degrade the angiotensin I on prolonged incubation. The pH optimum for cathepsin D prolonged incubation. The pH optimum for cathepsin D acting on tetradecapeptide renin substrate is 4.5, and there is very low activity above pH 7. These properties are very similar to those of pseudorenin, an angiotensin-forming enzyme originally isolated from human kidney, indicating that cathepsin D and pseudorenin may be identical.
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PMID:A comparison of the substrate specificities of cathepsin D and pseudorenin. 64 Oct 59

Human renal renin (EC 3.4.99.19) and pseudorenin were easily separated in a single step by affinity chromatography on hemoglobin-Sepharose-2B. Renin and pseudorenin were monitored by their actions on crude and partially purified hog protein renin substrates at neutral and acidic pH and on synthetic labelled polymeric renin substrate. Under the conditions employed (0.1 M sodium acetate (pH 3.5)/1 M sodium chloride at 4 degrees C) renin does not bind to the affinity adsorbent while pseudorenin is effectively bound and can be eluted only after raising the pH to 6.5. Pseudorenin-free renin prepared by this method is devoid of proteolytic activity toward hemoglobin. The chromatographic behaviour of renal pseudorenin on hemoglobin-Sepharose-2B is similar to that of cathepsin D.
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PMID:Separation of human renal renin and pseudorenin by affinity chromatography on hemoglobin-Sepharose-2B. 65 43

1. A renin-like enzyme in aortic tissue of the spontaneously hypertensive rat was found to be a freely dissociable enzyme (saline homogenization) with an affinity for the renin inhibitor pepstatin. At neutral pH values, the enzyme was active in homologous plasma to produce angiotensin I, and therefore distinct from pseudorenin and cathepsin D. The arterial enzyme and semi-purified renal renin could not be distinguished on the basis of Km values by using homologous renin substrate 2. An inverse relationship between the aortic renin content of the spontaneously hypertensive rat and the progressive increase of systolic blood pressure was observed with age. In contrast to this strain of rat, aortic renin of the normotensive WKY strain did not decline with age. 3. Plasma renin concentration and the aortic renin content of the spontaneously hypertensive rat showed divergent changes in response to a blood pressure fall associated with acute diuretic therapy, chronic administration of hydrallazine and in some animals in response to chronic administration of propranolol. 4. A low sodium diet elevated both plasma and aortic renin and retarded the progressive increase of blood pressure in the spontaneously hypertensive rat. A high sodium diet accelerated the progress of hypertension with no effect on aortic or plasma renin. 5. Antihypertensive therapy (1--6 weeks), resulting in a lowering of conscious systolic blood pressure of the spontaneously hypertensive rat, consistently led to a decrease in aortic renin content.
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PMID:Partial characterization of aortic renin in the spontaneously hypertensive rat and its interrelationship with plasma renin, blood pressure and sodium balance. 69 2

Cerebrospinal fluid (CSF) of rats contains high angiotensinogen concentrations. When 3500-fold purified renin from human brain was injected into the brain ventricles of rats, angiotensin I concentrations increased from undetectable levels to 147.9 +/- 18.8 fMol per ml CSF. In parallel, mean arterial blood pressure increased from 93 +/- 2.4 mm Hg to 107 +/- 3.7 mm Hg. The increase in blood pressure could be abolished by intraventricular administration of saralasin, a blocker of angiotensin II receptors. Intraventricular injection of cathepsin D had no effect on arterial blood pressure and the agiotensin I concentration in CSF remained below detection limits of the radioimmunoassay. We conclude that brain renin acts on endogenous brain angiotensinogen under physioloical in vivo conditions to form angiotensin I. The latter is converted to angiotensin II and leads to biological effects, i.e. increase of blood pressure.
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PMID:In vivo enzyme activity of purified human brain renin. 73 51


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