Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.1 (chymotrypsin)
 10,938 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By treating human plasma with trypsin (1 mg/ml), 3 different peaks of renin activity were detected by a gel filtration on Ultrogel AcA 44. The molecular weights of these activated renins were estimated to be 47,000, 45,000 and 43,000 daltons, respectively. 2) The molecular weight of human plasma active renin partially purified was 43,000 daltons. After treatment with neuraminidase, the molecular weight decreased to 38,000 daltons. 3) When the partially purified plasma inactive renin, which was completely separated from active renin, was activated by trypsin, chymotrypsin, plasmin, pepsin and renin, the activated renins had different molecular weights. The highest molecular weight form (47,000-48,000) was trypsin-activated or plasmin-activated renin and the lowest molecular weight form (38,000) was renin-activated renin. 4) These results suggest that cleavage of the specific site in peptide bond of plasma inactive renin by various proteolytic enzymes results in different molecular weights of activated renins. Plasma active renin free from sialic acid is very similar to kidney renin.
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PMID:Activation and molecular weight changes of human plasma inactive renin by proteolytic enzymes. 635 47

Venom of the puff adder (Bitis arietans) contains a potent, basic, Mr 24,000 metalloproteinase activity that can destroy all detectable trypsin and chymotrypsin inhibitory activity, when venom is incubated with human plasma. We have found that during such incubation, concomitant activation of inactive renin occurs. In an examination of the mechanism involved we now report the activation, in addition, of plasma prekallikrein and serine proteinase activity, but not plasminogen, when human plasma is incubated with venom. Furthermore, venom was not able to release active trypsin from its complex with alpha 1-proteinase inhibitor and human renin was not inhibited by alpha 1-proteinase inhibitor. The activities in venom and venom/plasma mixtures were analysed using Sephacryl S-200 gel filtration and the effect of 10 mM EDTA and 5 mM phenylmethanesulphonyl fluoride on activities in column fractions was tested. The inactive-renin-activating, plasma prekallikrein-activating and serine proteinase-activating activities could be accounted for to a large extent by a venom metalloproteinase which was estimated to have a Mr of 24,000 by sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis. This enzyme activity appeared to complex with alpha 2-macroglobulin when venom was mixed with plasma. Since both EDTA and phenylmethanesulphonyl fluoride could inhibit the activation of inactive renin by this metalloproteinase, it is suggested that the enzyme activates serine proteinase(s), which then activate inactive renin. Plasma kallikrein may have a role in this process. Additional peaks of inactive-renin-activating activity eluted from Sephacryl S-200 at Mr 30,000 and 80,000 (minor) and an additional, minor peak of caseinolytic activity eluted at Mr 60,000. The Mr 24,000 metalloproteinase in venom may have considerable utility in activating inactive renin at physiological pH owing to its ability to destroy plasma proteinase inhibitors at the same time.
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PMID:Mechanism of activation of inactive renin in human plasma by puff adder venom. 645 70

This study was undertaken to confirm our previous preliminary observation that hog pancreas kallikrein (EC 3.4.21.35) directly liberated an angiotensin-like substance from human plasma protein Cohn fraction IV-4 at an acidic pH of 4.0-5.0. First, the possibility of proangiotensin or des-Asp1-angiotensin being the pressor substance was ruled out by t.l.c. Secondly, the pressor substance was purified by Sephadex G-25 and Bio-Gel P-2 gel filtration, and finally by high-performance liquid chromatography. The amino acid composition of the isolated pressor substance (residues/mol) was: Asp, 1.03; Val, 1.03; Ile, 1.00; Tyr, 0.69; Phe, 1.04; His, 0.91; Arg, 0.86; Pro, 0.86. This composition was identical with that of angiotensin. Since the reaction mixture was not contaminated with common proteolytic enzymes, such as trypsin, chymotrypsin, renin, cathepsin D and proangiotensin-converting enzyme, and other enzymes activated by kallikrein, it is clear that hog kallikrein directly produces angiotensin in vitro.
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PMID:Confirmation of direct angiotensin formation by kallikrein. 655 43

Inactive renin (prorenin) can be activated by certain proteases in human blood, of which a possible source in vivo is polymorphonuclear leukocytes (PMNs). We extracted enzyme from PMNs using methods established for the recovery of neutral and acid protease fractions, and tested their effectiveness on plasma prorenin in vitro. Neutral protease preparations, possessing mainly chymotrypsin and elastase activity, produce no activation of prorenin. Exogenous pancreatic alpha-chymotrypsin does activate plasma prorenin, but less effectively than trypsin. From the quantity of PMNs extracted for neutral protease, and its failure to activate protenin, we deduce that this enzyme preparation, like exogenous chymotrypsin, is qualitatively unimportant. In contrast, the extracted PMN acid protease fraction, believed to be rich in cathepsin D, exhibited high prorenin activating ability, suggesting both quantitative and qualitative importance. The low pH requirement of this acid protease (near pH 4.0), together with its inactivity at neutral pH, argues against an important systemic role in the conversion of prorenin. However, it may contribute to systemic activation in partnership with other enzymes, or else play a specialized local role in situations where PMN concentration and activity increase, and the pH is on the acid side.
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PMID:Activation of prorenin by proteases from polymorphonuclear leukocytes. 699 62

1. A completely inactive renin was isolated from hog kidney extract by affinity chromatography on pepstatin-aminohexyl-Sepharose and on an Affi-Gel Blue column. 2. This inactive renin had a molecular weight of 43 000 +/- 1500 as determined by gel filtration on Ultrogel AcA 44. Upon activation with trypsin, its molecular weight fell to 41 000 +/- 1400. 3. The inactive renin lacked the ability to bind renin-binding substance whereas trypsin-activated renin was able to bind the renin-binding protein and to form high-molecular-weight renin. 4. Chymotrypsin as well as trypsin could activate the inactive renin although less effectively. 5. The active renins generated from the inactive renin by the action of different proteolytic enzymes differed in their net charge, reflecting the specificities of the proteases used; the isoelectric points of the native, the trypsin-activated and the chymotrypsin-activated forms of renin occurred at pH 5.3, 5.1 and 4.8 respectively.
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PMID:Renin precursor and its activation mechanism in hog kidney. 700 24

A diglyceride derivative of a pentapeptide renin inhibitor, the 1,3-dipalmitoyl-[Iva-Phe-Nle-Sta-Ala-Sta-acetyl]-glycerol was synthesized and tested in vitro as a potential prodrug for oral administration. The ability of the diglyceride analog to inhibit the renin activity was equivalent to that of the parent peptide after predigestion with pancreatic lipase. Furthermore, the presence of the palmitoyl groups was found to induce, in vitro, an efficient protection of the peptide from gastric and intestinal hydrolysis. During incubation with intestinal and gastric fluids, and with alpha-chymotrypsin and pancreatic lipase, the glycerolipidic derivative was more stable than the peptide alone. These results support the use of glycerolipidic prodrug for oral administration of peptides.
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PMID:Synthesis and in vitro study of a diglyceride prodrug of a peptide. 797 5

DMP 323 is a potent inhibitor of the protease of human immunodeficiency virus (HIV), with antiviral activity against both HIV type 1 and HIV type 2. This compound is representative of a class of small, novel, nonpeptide cyclic urea inhibitors of HIV protease that were designed on the basis of three-dimensional structural information and three-dimensional database searching. We report here studies of the kinetics of DMP 323 inhibition of the cleavage of peptide and HIV-1 gag polyprotein substrates. DMP 323 acts as a rapidly binding, competitive inhibitor of HIV protease. DMP 323 is as potent against both peptide and viral polyprotein substrates as A-80987, Q8024, and Ro-31-8959, which are among the most potent inhibitors of HIV protease described in the literature to date. Incubation with human plasma or serum did not decrease the effective potency of DMP 323 for HIV protease, suggesting that plasma protein binding is of a low affinity relative to that of HIV protease. DMP 323 was also assessed for its ability to inhibit the mammalian proteases renin, pepsin, cathepsin D, cathepsin G, and chymotrypsin. No inhibition of greater than 12% was observed for any of these enzymes at concentrations of DMP 323 that were 350 to 40,000 times higher than that required to inhibit the viral protease 50%.
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PMID:Potency and selectivity of inhibition of human immunodeficiency virus protease by a small nonpeptide cyclic urea, DMP 323. 797 96

Eight new peptide renin inhibitors: Boc-Phe/4-OMe/His-Sta-epsilonAhx-Iaa(13), Boc-Phe/4-OMe/-His-Sta-episilonAhx-OMe,(21),Boc-Phe/4-OMe/-MePhe-S ta-epsilonAhx-Iaa(27),Boc-Phe/4-OMe/-MePhe-Sta-epsilonAhx-++ +epsilonAhx-Iaa(32),Boc-Phe/4-OMe/-MePhe-Sta-Val-epsilonAhx- OMe (38),Boc-Phe/4-OMe/-MeVal-Sta-Val-Iaa(48),Boc-Phe/4-OMe/-Me Val-Sta-Iaa(51), Boc-Phe/4-OMe/-MeLeu-Sta-epsilonAhx-Iaa (57) have been synthesized in search after compounds of improved biological properties. All peptides were obtained by carbodimide method in solution by stepwise elongation of the peptide chain or by fragment condensation. Their potency was assayed in vitro by a spectrofluorometric method/assay of Leu-Val-Tyr-Ser released from N-acetyltetradecapeptide substrate by renin in the presence of an inhibitor/. Their resistance to enzymatic degradation was assayed by determination of stability to chymotrypsin activity. The most potent inhibitor was (13):IC50 = 7 x 10(-8)M/1. All inhibitors were stable to chymotrypsin.
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PMID:Enzymatically stable renin inhibitors containing statine and 6 aminohexanoic acid. Part IV. 806 37

Five peptide renin inhibitors containing the sequence: Phe-His-Sta-epsilon Ahx (Sta = 4(S)-amino-3(S)-hydroxy-6-methylheptanoic acid, epsilon Ahx = 6-aminohexanoic acid) were synthesized and their potency was assayed in vitro by a spectrofluorometric method (assay of Leu-Val-Tyr-Ser released from N-acetyltetradecapeptide substrate by renin in the presence of an inhibitor). Their stability was tested by assay of Phe and Pro-Phe released after incubation with chymotrypsin. The most potent inhibitor was Boc-Phe-His-Sta-epsilon Ahx-OMe (IC50 = 5 x 10(-9) M/l), the most stable--Boc-Pro-Phe-His-Sta-epsilon Ahx-OMe (resistant to incubation with chymotrypsin for 4 h).
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PMID:Renin inhibitors containing statine and 6-aminohexanoic acid. Part III. 840 62

Four new compounds: Nic-Phe/4-OMe/-MePhe-Sta-epsilonAhx-OMe/23/,Nic-Phe/4-OMe/-MePhe- Sta-epsilonAhx-Iaa/24/,iNic-Phe/4-OMe/-MeLeu-Sta-ep silonAhx-OMe/29/ and iNic-Phe/4-OMe/-MeLeu-Sta-epsilonAhx-Iaa/30/ have been synthesized in search after renin inhibitors of improved biological properties. Their stability against chymotrypsin activity, solubility in water at pH 7.4, 6.9 and 2.0, partition coefficient and activity in vitro were determined. All synthesized inhibitors are resistant to enzymatic degradation, all are very good soluble in water at pH 2.0, poorly soluble at pH 6.9 and insoluble at pH 7.4. Partition coefficients go up together with increase of pH worth of buffer. IC50 of obtained inhibitors 23,24,29 and 30 is 3 x 10(-4),7.5 x 10(-4),4 x 10(5) and 4 x 10(-3)M/1 respectively.
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PMID:Renin inhibitors containing nicotinic or isonicotinic acid at the N-terminus. Part V. 856 14


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