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

1. We have found that 'acid'-activation of inactive human plasma renin is a two-phase process. About 30% of activation occurs during dialysis to pH 3.3; the remaining 70% occurs at alkaline pH. 2. The 'alkaline phase' of activation has a pH optimum between 7.5 and 8.4. It is inhibited by unacidified plasma and by soya-bean or lima-bean trypsin inhibitors. 3. 'Cryoactivation' of inactive plasma renin, which occurs at -4 degrees C and alkaline pH, is also inhibited by soya-bean or lima-bean trypsin inhibitors and by the serine protease inhibitors diisopropylphosphorofluoridate and benzamidine. 4. Thus endogenous neutral serine proteases participate in the activation of inactive plasma renin in vitro. Their action is prevented in the circulation by inhibitors which are inactivated by acid or cold.
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PMID:Activation of inactive plasma renin: evidence that both cryoactivation and acid-activation work by liberating a neutral serine protease from endogenous inhibitors. 3 4

In this paper, we present the amino-terminal sequence of rat tonin, an endopeptidase responsible for the conversion of angiotensinogen, the tetradecapeptide renin substrate, or angiotensin I to angiotensin II. It is shown that isoleucine and proline occupy the amino- and carboxy-terminal residues respectively. The N-terminal sequence analysis permitted the identification of 34 out of the first 40 residues of the single polypeptide chain composed of 272 amino acids. These results showed an extensive homology with the sequence of many serine proteases of the trypsin-chymotrypsin family. This information, coupled with the slow inhibition of tonin by diisopropylfluorophosphate, classified this enzyme as a selective endopeptidase of the active serine protease family.
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PMID:N-Terminal amino acid sequence of rat tonin: homology with serine proteases. 21 93

1. The mechanism of increased renin activity after human plasma had been kept at -5 degrees C for 4 days (cryoactivation) was investigated. 2. The increase in renin activity of human plasma by cryoactivation was closely correlated to the increase obtained by incubation with trypsin (r = 0.88, P less than 0.001, n = 10). 3. An inhibitor of thiol enzyme, N-ethylmaleimide did not inhibit cryoactivation. 4. Soyabean trypsin inhibitor and di-isopropylflurophosphate (DFP) inhibited cryoactivation, suggesting that the cryoactivation may be due to the action of a trypsin-like serine enzyme. 5. In an experiment in the rat haemorrhagic shock caused parallel and cryoactivated plasma, the renin activity being about two times higher in the latter. No significant differences were found in the concentrations of renin and renin substrate between the non-cryoactivated and cryoactivated plasma samples. 6. The results may indicate that a destruction of an inhibitor of the renin-renin substrate reaction is responsible for the increase of renin activity after exposure of rat plasma to low temperature. A trypsin-like enzyme in plasma might have destroyed the inhibitor during this procedure.
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PMID:Cryoactivation of plasma renin. 28 40

The mechanism of the increase in renin activity in human plasma which had been kept -5 degrees C for 4 days (cryoactivation) was investigated. From the results of clinical studies, it is likely that the controling mechanism of inactive renin has something in common with that of active renin. The experimental data showed that the increase in renin activity of human plasma by cryoactivation was closely correlated to the increase obtained by incubation with trypsin (r = 0.88, p less than 0.001, n = 10). Soybean trypsin inhibitor, aprotinin and di-isopropylfluorophosphate (DFP) inhibited cryoactivation, indicating that the cryoactivation is due to the action of a trypsin-like serine enzyme. Trypsin which had no effect on plasma renin activity in the presence of the same amount of soybean trypsin inhibitor at 37 degrees C, activated the renin activity during cold incubation, suggesting that the dissociation of the trypsin-inhibitor complex may have taken place at a low temperature. Endogenous trypsin inhibitor is also likely to lose its affinity to endogenous trypsin-like enzyme at a low temperature.
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PMID:Cryoactivation of inactive renin in human plasma. 31 80

Left renal artery stenosis increased and timolol maleate chronic administration decreased systolic blood pressure, plasma renin activity, and plasma aldosterone concentration, in adult male rats. In the hypertensive animals the volume of the zona glomerulosa, the volume and number of zona glomerulosa cells, as well as the volume of the mitochondrial compartment and the surface area of SER and mitochondrial cristae, were significantly increased. The volume of the lipid compartment was reduced, and several clumps of electron-dense granules appeared at the juxta-sinusoidal pole of the cells. Opposite results were found in the zona glomerulosa of the hypotensive rats, with the exception that the volume of the lipid compartment showed no significant change. These findings suggest that the renin-angiotensin system is involved in the maintenance and stimulation of the growth in the zona glomerulosa. Since in the hypertensive rats the increase in the volume density of electron-dense granules fits well with that in the intracellular concentration of aldosterone, the working hypothesis is that these granules are aldosterone-containing secretory organelles.
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PMID:A stereological study of the trophic effects of the renin-angiotensin system on the rat adrenal zona glomerulosa. 39 87

The availability of pure submaximillary renin, its antibody and pure specific immunoreactive Fab fragments of the antirenin molecule were used in an attempt to detect in which form renin is stored in the submaxillary gland. The proteolytic activity of serine-, metallo- and sulfhydryl enzymes during homogenisation was inhibited, but no inactive or high molecular weight form could be detected enzymatically or antigenically after gelfiltration. Nor were they demonstrable in crossed immuno-electrophoresis by using antibodies elicited against pure renin. Furthermore, pepstatin which additionally inhibits acid proteases, including a possible autoactivation of renin, and renin specific Fab fragments, were added, the latter in order to steric hinder proteolytic attack on a possible renin precursor. The renin-Fab complex was purified by precipitation with anti-Fab antibodies. No high molecular weight renin was demonstrable in SDS polyacrylamide gel electrophoresis. The only form of renin demonstrable in the submaxillary gland of mice was the fully active 40,000 dalton form. Its specific enzymatic activity was identical to that of pure submaxillary renin, being 0.4 . 10(-3) Goldblatt unit . ng-1.
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PMID:Renin in the mouse submaxillary gland has a molecular weight of 40,000. 42 89

Renin (EC 3.4.99.19) has been observed to exist in a high molecular weight (Mr greater than 50,000) and a low molecular weight from (Mr approximately 42,000) in various tissues. Little is known concerning the origin and function of the high molecular weight form of renin and its relationship to low molecular weight renin. We have found that the high molecular weight form of renin in the kidney was converted to the low molecular weight form during the extraction process. The conversion is apparenly catalyzed by an agent(s) which requires free sulfhydryl groups since blockers of sulfhydryl groups completely suppress the conversion. This conversion could not be prevented by various specific inhibitors of serine proteases nor by the metal chelator EDTA. By the use of Na-tetrathionate it was possible to preserve the renin activity of hog kidney exclusively in the high molecular weight form. Similarly, using N-ethylmaleimide it was shown that a similar high molecular weight form of renin is the exclusive form present in rat kidney. These results suggest that the high molecular weight form of renin is the native form stored in the kidney and that it is converted by an enzyme or agent requiring sulfhydryl groups to the circulating (low molecular weight) form when it is secreted into blood. Renin activity was increased to approximately 155% of the original level upon conversion.
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PMID:Native form of renin in the kidney. 91 34

We report the X-ray analysis at 2.0 A resolution for crystals of the aspartic proteinase endothiapepsin (EC 3.4.23.6) complexed with a potent difluorostatone-containing tripeptide renin inhibitor (CP-81,282). The scissile bond surrogate, an electrophilic ketone, is hydrated in the complex. The pro-(R) (statine-like) hydroxyl of the tetrahedral carbonyl hydrate is hydrogen-bonded to both active-site aspartates 32 and 215 in the position occupied by a water in the native enzyme. The second hydroxyl oxygen of the hydrate is hydrogen-bonded only to the outer oxygen of Asp 32. These experimental data provide a basis for a model of the tetrahedral intermediate in aspartic proteinase-mediated cleavage of the amide bond. This indicates a mechanism in which Asp 32 is the proton donor and Asp 215 carboxylate polarizes a bound water for nucleophilic attack. The mechanism involves a carboxylate (Asp 32) that is stabilized by extensive hydrogen bonding, rather than an oxyanion derivative of the peptide as in serine proteinase catalysis.
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PMID:Direct observation by X-ray analysis of the tetrahedral "intermediate" of aspartic proteinases. 130 40

Replacing one amide bond in macrocyclic renin inhibitors of the general structure 1 and 2 with an ester linkage gave glutamate-derived inhibitors 3 and serine-derived inhibitors 4. While this oxygen-for-nitrogen exchange had little effect on potency in the glutamate series, potency was dramatically increased in the serine series. In this series, the 14-membered ring compounds proved to be more potent than the corresponding 13-membered ring derivatives. Substitution of the ring at the position corresponding to P2' generally increased potency. The absolute configuration at this center was shown to be R for the 4-morpholinomethyl derivative (4o), both by asymmetric synthesis and X-ray crystallography. Replacing the "Boc-Phe" moiety of inhibitor 4o with a variety of substituents led to subnanomolar inhibitors, one of which (the "3(S)-quinuclidinyl-Phe" derivative 33) lowered blood pressure 20 mmHg and completely inhibited plasma renin activity for 6 h in sodium-depleted rhesus monkeys. This compound proved to have limited bioavailability (1% in rats) due to cleavage of the serine ester bond and rapid hepatic extraction.
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PMID:Highly potent, orally active diester macrocyclic human renin inhibitors. 143 90

A linear hydrophobic peptide, (Code no. EMD 55068), a synthetic renin-antagonist, competitively inhibits the uptake of taurocholate and of another linear peptide (EMD 51921) but not of oleic acid, serine or thiamin hydrochloride into isolated rat liver cells. EMD 55068 was attached to a gel matrix at a position that is not involved in the protein ligand interaction. The gel matrix used did not interact nonspecifically with solubilized proteins from rat liver. The quantity of bound ligand was determined to be 3.6 mg/ml of gel matrix. In the fraction of EDTA extracted hydrophilic membrane-associated proteins, no binding proteins were detected. Affinity chromatography of integral plasma membrane proteins resulted in four protein bands with molecular masses of 46, 49, 53 and 56 kDa in SDS-PAGE. In contrast, solubilized plasma membrane proteins from AS-30D ascites hepatoma cells, which are unable to transport bile acids and linear peptides, did not bind specifically to the affinity matrix.
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PMID:Binding proteins for linear renin-inhibiting peptides in basolateral plasma membranes of rat liver. 154 6


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