Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Four derivatives of pepstatin, each of which contains the unusual amino acid 4-amino-3-hydroxy-6-methylheptanoic acid (statine) have been prepared. All four are porcine pepsin inhibitors. Both N-acetylstatine 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 values 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 Rhizopus chinensis and bovine chymosin, also are inhibited by pepstatin and its derivatives. It is suggested 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:Mode of inhibition of acid proteases by pepstatin. 99 6

1. Five synthetic peptides which together spanned the propart segment of human prorenin were tested for their ability to interact with human renin, pepsin, gastricsin, cathepsin D, cathepsin E, calf chymosin and the aspartic proteinase from Endothia parasitica. 2. While two peptides showed no significant effect with any of the enzymes, a further two were cleaved by several enzymes. 3. Only one (corresponding to the 32P-43P residues in the propart sequence) acted as a weak competitive inhibitor of most of the enzymes.
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PMID:Inhibition of aspartic proteinases by synthetic peptides derived from the propart region of human prorenin. 173 96

The interactions of five human enzymes (renin, pepsin, gastricsin, cathepsin D and cathepsin E) and the aspartic proteinase from Endothia parasitica with several series of synthetic inhibitors were examined. All of the inhibitors contained the dipeptide analogue statine or its phenylalanine or cyclohexylalanine homologues in the P1-P1' positions. The residues occupying the peripheral sub-sites (P4 to P3') were varied systematically and inhibitory constants were determined for the interactions with each of the proteinases. Inhibitors were elucidated that specifically inhibited human renin and did not affect any of the other human enzymes or the fungal proteinase. With suitable selection of residues to occupy individual sub-sites, effective inhibitors of specific human aspartic proteinases may now be designed.
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PMID:The selectivity of statine-based inhibitors against various human aspartic proteinases. 240 37

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

The synthesis of diol-containing renin inhibitors has revealed that a simple vicinal diol functionality corresponding to the scissile Leu-Val bond in human angiotensinogen is capable of imparting inhibitory activity at a comparable or higher level than either the corresponding aldehyde or hydroxymethyl functionality (compare inhibitors 2a-c or 3a-c). This finding has led to the further optimization of a series of small transition-state analogue inhibitors by the inclusion of a second hydroxyl group in the Leu-Val surrogate to give compounds that inhibited human renin in the 200-700-pM range (e.g. 43, 45, 63, 66). The magnitude of effect of the second hydroxyl group on potency is not only dictated by the absolute stereochemistry of the diol but also by the side chain of the P1 residue. Molecular modeling of the diol-containing inhibitors suggests that one of the hydroxyl groups hydrogen bonds to Asp 32 and Asp 215, while the second hydrogen bonds to Asp 215. These diol inhibitors are extremely selective for human renin over the related enzymes cathepsin D, pepsin, and gastricsin. At high concentrations, compounds containing a leucine or phenylalanine rather than a histidine at the P2 position gave only minor amounts of inhibition of the other enzymes. Inhibitor 43 suppressed plasma renin activity completely and lowered mean blood pressure in monkeys after both intravenous and intraduodenal administration, but the blood pressure drop lasted less than 1 h. Monitoring the blood levels of 43 by enzyme inhibition assay after intraduodenal administration to monkeys or oral administration to rats revealed low absorption and rapid clearance. While intratracheal administration to dogs gave approximately 50% bioavailability, rapid clearance was still a problem. After examination of inhibitor 45 in a sensitive primate model in which monkeys were rendered both hypertensive and hyperreninemic, the effects on lowering systolic but not diastolic pressure were apparent even after 22 h postdosing. Details on the synthesis, in vitro structure-activity relationships, molecular modeling, in vivo activity, and metabolism of these inhibitors are described.
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PMID:Renin inhibitors. Dipeptide analogues of angiotensinogen utilizing a dihydroxyethylene transition-state mimic at the scissile bond to impart greater inhibitory potency. 314 9

The amino acid sequence of endothiapepsin, the aspartic protease from Endothia parasitica has been determined. The enzyme consists of 330 residues. The sequence determination was performed exclusively at the protein level. The homology of this fungal milk-clotting enzyme with aspartic proteases is demonstrated by alignment with pepsin, chymosin, gastricsin, renin, and cathepsin D from various vertebrates and proteinase A from Saccharomyces cerevisiae showing 25-30% identity. The identity with mucor rennin from Mucor pucillus was 21% and with penicillopepsin from Penicillium janthinellum 53%, the fungal enzymes thus representing the lowest as well as the highest degree of homology.
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PMID:Amino acid sequence of endothiapepsin. Complete primary structure of the aspartic protease from Endothia parasitica. 330 16

The in vitro binding of [3H]SR42128 (Iva-Phe-Nle-Sta-Ala-Sta-Arg), a potent inhibitor of human renin activity, to purified human renin and a number of other aspartic proteases was examined. SR42128 was found to be a competitive inhibitor of human renin, with a Ki of 0.35 nM at pH 5.7 and 2.0 nM at pH 7.4; it was thus more effective at pH 5.7 than at pH 7.4. Scatchard analysis of the interaction binding of [3H]SR42128 to human renin indicated that binding was reversible and saturable at both pH 5.7 and pH 7.4. There was a single class of binding sites, and the KD was 0.9 nM at pH 5.7 and 1 nM at pH 7.4. The association rate was 10 times more rapid at pH 5.7 than at pH 7.4, but there was no difference between the rates of dissociation of the enzyme-inhibitor complex at the two pHs. The effect of pH on the binding of [3H]SR42128 to human renin, cathepsin D, pepsin, and gastricsin was also examined over the pH range 3-8. All the aspartic proteases had a high affinity for the inhibitor at low pH. However, at pH 7.4, [3H]SR42128 was bound only to human renin and to none of the other aspartic proteases. Competitive binding studies with [3H]SR42128 and a number of other inhibitors on human renin or cathepsin D were used to examine the relationships between structure and activity in these systems.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A potent radiolabeled human renin inhibitor, [3H]SR42128: enzymatic, kinetic, and binding studies to renin and other aspartic proteases. 332 2

The aspartic proteinase cathepsin D was purified from human spleen and localised in various formalin fixed paraffin embedded human tissues using the peroxidase-antiperoxidase (PAP) technique. Cathepsin D was shown not only in macrophages but also in other connective tissue cells, and in epithelium. It was present in spleen (littoral cells and cells within Malpighian bodies), liver (hepatocytes and Kupffer cells), lung (alveolar macrophages and bronchial epithelium), brain (neurones), lymph nodes (histiocytes in germinal centres, sinusoid lining cells) and stomach (parietal and mucous neck cells). Cathepsin D was also found in carcinomas of bronchus, stomach, colon, kidney, breast, ovary, bladder and pancreas, both in neoplastic epithelium and in stromal cells, but was seldom present in connective tissue neoplasms. A group of malignant lymphomas also contained the enzyme within scattered cells. The distribution of cathepsin D seems to be much wider than that of the structurally related aspartic proteinases pepsin, gastricsin, and renin.
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PMID:Immunolocalization of cathepsin D in normal and neoplastic human tissues. 354 65

Aspartic proteases (EC3.4.23) are a group of proteolytic enzymes of the pepsin family that share the same catalytic apparatus and usually function in acid solutions. This latter aspect limits the function of aspartic proteases to some specific locations in different organisms; thus the occurrence of aspartic proteases is less abundant than other groups of proteases, such as serine proteases. The best known sources of aspartic proteases are stomach (for pepsin, gastricsin, and chymosin), lysosomes (for cathepsins D and E), kidney (for renin), yeast granules, and fungi (for secreted proteases such as rhizopuspepsin, penicillopepsin, and endothiapepsin). These aspartic proteases have been extensively studied for their structure and function relationships and have been the topics of several reviews or monographs (Tang: Acid Proteases, Structure, Function and Biology. New York: Plenum Press, 1977; Tang: J Mol Cell Biochem 26:93-109, 1979; Kostka: Aspartic Proteinases and Their Inhibitors. Berlin: Walter de Gruyter, 1985). All mammalian aspartic proteases are synthesized as zymogens and are subsequently activated to active proteases. Although a zymogen for a fungal aspartic protease has not been found, the cDNA structure of rhizopuspepsin suggests the presence of a "pro" enzyme (Wong et al: Fed Proc 44:2725, 1985). It is probable that other fungal aspartic proteases are also synthesized as zymogens. It is the aim of this article to summarize the major models of structure-function relationships of aspartic proteases and their zymogens with emphasis on more recent findings. Attempts will also be made to relate these models to other aspartic proteases.
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PMID:Evolution in the structure and function of aspartic proteases. 354 46


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