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:3.4.21.4 (trypsin)
42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cleavage of C3 and kininogen in human plasma following the addition of increasing amounts of human cationic trypsin was studied using an in vitro model. The cleavage was correlated to the degree of saturation of the plasma protease inhibitors alpha 2-macroglobulin and alpha 1-proteinase inhibitor, and also with varying amounts of human pancreatic secretory trypsin inhibitor. When alpha 2-macroglobulin reached about 70% saturation, there was a prompt cleavage of most of the C3 and kininogen in spite of the presence of 90% free alpha 1-proteinase inhibitor. The consumption of alpha 1-proteinase inhibitor decreased with increasing concentrations of the pancreatic secretory trypsin inhibitor. This inhibitor was needed in a concentration of about 10 mumol to block trypsin-induced C3 and kininogen cleavage completely. As trypsin is thought to be the key trigger enzyme of the pathophysiological changes in acute pancreatitis, it seems reasonable to propose that the pancreatic secretory trypsin inhibitor might be of therapeutic interest in severe acute pancreatitis provided large enough amounts can be made available.
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PMID:Influence of the human pancreatic secretory trypsin inhibitor on trypsin-induced C3 and kininogen cleavage: an in vitro study. 243 81

The inhibition of trypsin, human blood plasma kallikrein and porcine pancreatic kallikrein by aprotinin (native and immobilized on carboxymethyl ester of dextran) was investigated. The experimental values of Ki of native and immobilized aprotinin--enzyme complexes are equal to 0.037 and 0.045 nM for trypsin, 0.38 and 112.3 nM for pancreatic kallikrein and 34.4 and 454.5 nM for plasma kallikrein with N alpha-benzoyl-L-arginine ethyl ester as substrate, and to 82.6 and 231.7 nM for plasma kallikrein with a natural substrate--kininogen. These data suggest that covalent binding of aprotinin to the water-soluble polysaccharide carrier does not interfere with its interaction with trypsin, whereas the inhibition of kallikreins decreases, especially that of pancreatic kallikrein. The experimental results indicate the marked differences in the structure of the binding site of the active center (or its environment) of plasma and pancreatic kallikreins, on one hand, and trypsin, on the other, as well as the differences between the plasma and pancreatic kallikreins. A high requirement of kallikreins to the maintenance of the native conformation of aprotinin during immobilization is postulated.
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PMID:[Effect of covalent binding of aprotinin with a polysaccharide carrier on its inhibition of kallikrein from human plasma, porcine pancreatic kallikrein and trypsin]. 243 35

Serine proteases in mast cell granules, such as chymase, atypical chymase, and tryptase, which are major proteins in the granules, may play important roles in the process of immunoglobulin E (IgE)-mediated degranulation and in pathobiological alterations in tissues. Indeed, inhibitors of chymase, substrate analogs, and antichymase F(ab')2, but not inhibitors of tryptase, markedly inhibited histamine release induced by IgE-receptor bridging but not that induced by Ca ionophore. In contrast, inhibitors of metalloprotease inhibited histamine release induced not only by IgE-receptor bridging but also by Ca ionophore. These results suggest that chymase and metalloprotease are involved at different steps in the process of degranulation. The extents of inhibition of histamine release were closely correlated with the amounts of the inhibitors of chymase accumulated in the granules. After degranulation, the released proteases may in part contribute to pathobiological alterations in allergic disorders through generations of C3a anaphylatoxin and thrombin by human and rat tryptase, respectively, and those of angiotensin II and a chemotactic factor of neutrophils by human and rat chymase, respectively. Moreover, chymase and atypical chymase from rat were shown to destroy type IV collagen, and human tryptase was found to hydrolyze various plasma proteins, such as fibrinogen and high-molecular-weight kininogen. The biological activities of tryptase and chymase from rat may be regulated by their dissociation from and association with trypstatin, an endogenous inhibitor of these proteases.
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PMID:Biological functions of serine proteases in mast cells in allergic inflammation. 246 15

We studied the characteristics of two monoclonal antibodies (mAbs), F1 and F3, against human coagulation factor XII (Hageman factor). Experiments with trypsin-digested 125I-factor XII revealed that the epitope for mAb F1 is located in the NH2-terminal Mr 40,100 portion of factor XII, whereas that for mAb F3 resides in the COOH-terminal Mr 30,000 portion of this protein. Factor XII in fresh plasma (single-chain factor XII) bound approximately 190 times less to mAb F1 than factor XII in dextran sulfate-activated plasma (cleaved factor XII). However, no difference in accessibility of the epitope for mAb F1 was observed between cleaved and single-chain factor XII when bound to glass. mAb F3 appeared to bind to both single-chain and cleaved factor XII in plasma as well as when bound to glass. Neither mAb F1, nor F3 affected the amidolytic activity of factor XIIa, whereas both mAb F1 and F3 inhibited factor XII-coagulant activity to about 15 and 70%, respectively, at a molar ratio of mAb to factor XII of 20 to 1. mAb F1, as well as F(ab')2 and F(ab') fragments of this antibody induced activation of the contact system in plasma, as reflected by the generation of factor XIIa. C1 inhibitor and kallikrein. C1 inhibitor complexes. Activation was induced neither upon incubation with mAb F3, nor with that of control mAbs. mAb F1-induced contact activation required the presence of factor XII, prekallikrein, and high molecular weight kininogen and, in contrast to activation by negatively charged surfaces, was not inhibited by the presence of Polybrene. Based on these results we propose that a conformational change in factor XII is a key event in the activation process of this molecule. This conformational change can be induced by binding of factor XII to a surface as well as by proteolytic cleavage. As mAb F1 can also induce this conformational change, this antibody may provide a unique tool in studies of the activation of factor XII.
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PMID:Activation of the contact system of coagulation by a monoclonal antibody directed against a neodeterminant in the heavy chain region of human coagulation factor XII (Hageman factor). 247 84

Kininogen sequence analogs containing amino acid residues around the Arg-Ser cleavage site of bovine kininogens were prepared with bulky aliphatic residues in P3 position. KKI-7 (containing a cyclohexylacetyl group) and KKI-8 (containing an adamantaneacetyl group) both inhibited human urinary kallikrein (HUK) with Ki of 4 microM. These inhibitors were 40 times more potent than the corresponding peptide containing the naturally occurring Pro at P3 and were one-seventh as susceptible to hydrolysis by HUK. Rat submaxillary kallikrein (RSK) and porcine pancreatic kallikrein (PPK) were also inhibited by these analogs. Both analogs were poor inhibitors of human plasma kallikrein, while their capacity to inhibit bovine trypsin was 1/3 and 1/17, respectively, that to inhibit HUK. In a rat blood flow study, KKI-7 infusion depressed the response to injected RSK. The response gradually returned toward normal 30 to 60 min after the infusion was terminated. Blood flow increase of dog jejunal artery in response to infused PPK was blunted by the simultaneous local infusion of Trasylol, KKI-7, or KKI-8, whereas these infusions did not alter the response to infused bradykinin. The vehicle infusion did not attenuate the response either to PPK or bradykinin. These analogs appear to have greater specificity and stability than those previously developed and to be appropriate for the in vivo inhibition of glandular kallikreins.
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PMID:In vivo inhibition of tissue kallikreins by kininogen sequence analogue peptides. 248 44

Various factors in the kallikrein-kinin system were evaluated in acute and chronic pancreatitis. It was noted in particular that plasma trypsin and glandular kallikrein increased markedly in acute phase of pancreatitis and its correlation with amylase was observed. Plasma prekallikrein (PPK) decreased in acute pancreatitis, but increased in chronic pancreatitis. A negative correlation was noted between PPK and kallikrein like activity. Both HMW and LMW kininogen decreased in acute pancreatitis. It was presumed from these findings that the increase in kinin and its activation at the acute phase of pancreatitis might be due to kallikrein or trypsin originating from the pancreas.
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PMID:Role of the kallikrein-kinin system in human pancreatitis. 248 54

Pancreatic pseudocyst fluid from eight patients was examined biochemically. The fluid was found to be a mixture of plasma proteins and pancreatic juice, possessing a high proteolytic activity against high- as well as low-molecular-weight proteins. The proteolytic activity was found to be trypsin-, kallikrein- and plasmin-like. Gel filtration studies showed proteolytic activity to be present corresponding to alpha-2-macroglobulin-bound proteases and also to free proteases. Quantitative immunochemical levels were about 30-100% of normal plasma levels for alpha-2-macroglobulin, C1 inhibitor, antithrombin III and alpha-2-antiplasmin. However, there was practically no functional inhibitory capacity left in the pseudocyst fluid, except for alpha-1-protease inhibitor, which retained its inhibitory capacity. Neither native kininogen nor complement factor C3 was found: this was probably a result of the proteolytic activity. It is concluded, that a continuing proteolytic activity within the pseudocyst, although decreasing with aging of the cyst, could explain symptoms and complications caused by the pseudocyst.
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PMID:Pancreatic pseudocyst fluid--a mixture of plasma proteins and pancreatic juice possessing a high proteolytic activity. 253 13

N-alpha-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline (MK-0521) is a new non-sulfhydryl-containing angiotensin converting enzyme (ACE) inhibitor. The present investigation describes its ACE and other enzymes inhibitory properties and compares it to those of captopril, MK-421 and MK-422 in vitro. MK-0521 inhibited rat pulmonary ACE by 50% (IC50) at a concentration of 3 nM and was 6.13 times more potent than captopril. The IC50 values of MK-421 and MK-422 against ACE were 2,000 nM and 3.5 nM, respectively. MK-0521 had practically no inhibitory activities against carboxypeptidase A, carboxypeptidase B, leucine aminopeptidase, papain, pepsin and trypsin. The kinetic study on the inhibitory activity of M-0521 against ACE using Lineweaver-Burk plots indicated that MK-0521 exerted competitive ACE inhibition. The dialysis study conducted on the ACE-MK-0521 complex revealed that the inhibitory effect of MK-0521 against ACE was reversible. In the guinea pig ileum, MK-0521 potentiated the contractile effect of bradykinin and depressed the contractile effect of angiotensin I. These effects on bradykinin and angiotensin I were 33.11 and 2.63 times more potent than that of captopril, respectively. The present results suggest that MK-0521 may show a potent hypotensive effect in vivo.
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PMID:[Inhibitory effect of N-alpha-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline (MK-0521) on angiotensin converting enzyme in vitro]. 254 78

The present study was aimed to examine whether BANA-degrading enzyme activities could be enhanced by bradykinin(BK) in dental pulp of the rat in vitro. The results showed that BK(0.1-10 microM) dose-dependently enhanced BANA-degrading enzyme activity at pH 7.4. The effects of BK(1 microM) were found to be most effective at both pH 7 and 8, with enhancement of the enzyme activities at a wide range of pH. The BK effects at both the pH were not inhibited by FOY-305(0.1 microM), an inhibitor of trypsin-like enzymes, differing from that at pH 6 in adrenal medulla of the rat. On the other hand, the effects of BK at both the pH were remarkably inhibited by EGTA (2 mM), followed by reversal with calcium ion (2.42 mM). These results suggested as follows: 1) there might be two kinds of BANA-degrading enzymes activated by BK in the pulp. 2) it was conceivable that BANA-degrading enzymes activated by BK were quite different from serine proteinases and were interfered with them in the pulp. 3) calcium ion might play a role in BK-induced enhancement of BANA-degrading enzyme activities which were regarded as met-enkephalin (ME) processing enzyme activities in the pulp.
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PMID:Activation of calcium ion-dependent proteinases by bradykinin in dental pulp of the rat. 255 23

Two dynorphin-degrading cysteine proteases, I and II, were extracted with Triton X-100 from neuroblastoma cell membrane, isolated from accompanying dynorphin-degrading trypsin-like enzyme by affinity chromatography on columns of soybean trypsin inhibitor-immobilized Sepharose and p-mercuribenzoate-Sepharose, and separated by ion-exchange chromatography on diethylaminoethyl (DEAE)-cellulose and TSK gel DEAE-5PW columns. Cysteine protease II was purified further by hydroxyapatite chromatography and gel filtration. The molecular weights of cysteine proteases I and II were estimated to be 100,000 and 70,000, respectively, by gel filtration. Both of the enzymes, were inhibited by p-chloromercuribenzoate, N-ethylmaleimide, and high-molecular-weight kininogen, but not or only slightly inhibited by diisopropylphosphorofluoridate, antipain, leupeptin, E-64, calpain inhibitor, and phosphoramidon. Cysteine protease I cleaved dynorphin(1-17) at the Arg6-Arg7 bond with the optimum pH of 8.0, whereas II cleaved dynorphin(1-17) at the Lys11-Leu12 bond and the Leu12-Lys13 bond with the optimum pH values of 8.0 and 6.0, respectively. These bonds corresponded to those that had been proposed as the initial sites of degradation by neuroblastoma cell membrane. Cysteine protease I was further found to show strict specificity toward the Arg-Arg doublet, when susceptibilities of various peptides containing paired basic residues were examined as substrates for the enzyme.
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PMID:Characterization of cysteine proteases functioning in degradation of dynorphin in neuroblastoma cells: evidence for the presence of a novel enzyme with strict specificity toward paired basic residues. 256 12


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