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)

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

A compound containing cyclostatine ES-6864 (N-[(2R)-3-morpholinocarbonyl-2-(1-naphthylmethyl)propionyl]-(4-th iazolyl)- L-alanyl-cyclostatine-(2-morpholinoethyl)amide) was found to be a competitive inhibitor of human renin with an inhibitory constant (Ki) value of 7.3 x 10(-9) M. The compound was also potent against monkey renin but was less effective against renins from pig, goat, dog, rabbit and rat. ES-6864 did not inhibit cathepsin D, pepsin, urinary kallikrein, angiotensin converting enzyme, trypsin and chymotrypsin at a concentration of 10(-5) M. ES-6864 also inhibited the tissue renin-like activity from dog tissues with IC50 values of 10(-7)-10(-8) M in vitro. Oral administration of ES-6864 at 30 mg/kg to conscious, sodium-depleted marmosets produced a significant blood pressure reduction and a significant inhibition of plasma renin activity, which persisted for 6 hours. Plasma concentration of ES-6864 reached a maximum of 1.2 micrograms/ml at 1 hour after an oral administration. Oral administration of ES-6864 to hog renin-infused rats produced dose-related decreases in blood pressure. The results demonstrate that ES-6864 is an orally active renin inhibitor with high potency and specificity for human renin. Thus, ES-6864 is a candidate compound for development of renin inhibitors that can be used clinically.
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PMID:[In vitro and in vivo inhibition of renin by a thiazolylalanyl cyclostatine derivative]. 251 1

The effect of ONO-3307 (4-sulfamoyl phenyl-4-guanidinobenzoate methanesulfonate), a new protease inhibitor, was studied on various proteases in vitro and in an experimental thrombosis model in vivo. ONO-3307 competitively inhibited trypsin, thrombin, plasma kallikrein, plasmin, pancreatic kallikrein and chymotrypsin; and their Ki values were 0.048 microM, 0.18 microM, 0.29 microM, 0.31 microM, 3.6 microM and 47 microM, respectively. In addition, ONO-3307 inhibited both elastase release from N-formyl-Met-Leu-Phe (fMLP)-stimulated leukocytes and tissue thromboplastin release from endotoxin-stimulated leukocytes. To examine the effects of ONO-3307 on disseminated intravascular coagulation (DIC), we developed an experimental thrombosis model. ONO-3307 (10 mg/kg/hr) completely inhibited the deposition of radioactive fibrin in kidney and lung. Gabexate mesilate (50 mg/kg/hr) was also effective in this model, but the effect of nafamostat mesilate was unclear. These results indicate that ONO-3307 exhibits a wide range of inhibitory effects on various proteases, and ONO-3307 may be useful for the treatment of protease-mediated diseases such as thrombosis and DIC.
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PMID:Inhibitory effects of ONO-3307 on various proteases and tissue thromboplastin in vitro and on experimental thrombosis in vivo. 251 29

The effects of insulin on pancreatic kallikrein secretion were studied in streptozotocin diabetic rats and after acute administration of insulin to normal rats. Studies on total protein and amylase secretion were included for comparison. In diabetic rats, the concentration of amylase in pancreatic tissue as well as basal and CCK-stimulated amylase exocrine secretion were significantly reduced. Insulin treatment restored pancreatic tissue concentration and exocrine release of amylase to normal. Insulin deficiency did not induce any change in the concentration of kallikrein or trypsin-like activity in pancreatic tissue. However, basal kallikrein secretion was higher in diabetic rats than in controls. Insulin treatment of diabetics rats did not alter basal kallikrein secretion but potentiated CCK-stimulation of kallikrein release. In normal rats, CCK induced an increase of pancreatic protein, amylase, and kallikrein secretion but not pancreatic juice flow. Additional administration of insulin potentiated the CCK-induced secretory rate of pancreatic juice, protein, and kallikrein but not amylase. A 1.6 times higher concentration of kallikrein was found in the portal vein than in arterial blood, indicating an endocrine release of pancreatic kallikrein. No difference in the concentration of circulating kallikrein was observed between the control and the insulin-treated group.
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PMID:Insulin potentiates cholecystokinin (CCK)-induced secretion of pancreatic kallikrein. 257 23

The complete amino acid sequence of human urinary kallikrein has been determined. The enzyme was a single polypeptide which comprised 238 amino acid residues. In the case of prokallikrein, a propeptide which was consisted of seven amino acid residues was attached to N-terminal isoleucine of kallikrein. The sequence of Asn-X-Thr(Ser), common to glycosylation site, was identified at positions 78-80, 84-86 and 141-143. It has been shown from the sequence of kallikrein that Arg(-1)-Ile(1) and Arg(87)-Gln(88) bonds are hydrolyzed with trypsin on rapid activation of prokallikrein and the formation of disulfide-linked two chain kallikrein.
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PMID:Human urinary prokallikrein--structural analysis on activation mechanism. 260 16

We studied urinary excretion of active and inactive kallikrein every day for 3 weeks in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) subjected to 5/6 nephrectomy (5/6), 1/2-nephrectomy (1/2) or sham-operation (Sham). We determined urinary active and inactive kallikrein by measuring kallikrein activity using a kininogenase assay before and after treatment with trypsin (200 micrograms/ml). In the SHR group, blood pressure was significantly elevated in 5/6-animals as compared with 1/2 or sham, whereas in the WKY group blood pressure was not changed after either operation. Urinary active and total kallikrein excretion were decreased in 5/6-SHR to 34% and 59%, respectively, as compared with values of sham-SHR, and in 1/2-SHR to 70% and 70%, respectively. Similarly, they were also decreased in 5/6-WKY to 36% and 55%, respectively, as compared with values of sham-WKY. In 1/2-WKY urinary active kallikrein excretion was decreased to 88% as compared with the value of sham-WKY, but urinary total kallikrein excretion was not different from that of sham-WKY. Thus, the suppressed renal kallikrein activity due to reduced renal mass was not associated with any significant change in blood pressure in WKY, although it induced an elevation of blood pressure in SHR. These results indicate that the decreased production of renal active kallikrein may not play a significant role in the regulation of blood pressure in the rat remnant kidney model of chronic renal failure. In addition, it is suggested that the elevation of blood pressure in this model of SHR may be due to other factors than renal kallikrein.
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PMID:Role of renal kallikrein in the regulation of blood pressure in the rat remnant kidney model of chronic renal failure. 261 50

A kallikrein-like kininogenase was identified in the rat adrenal gland. Most of the enzyme was present in an inactive form, since pre-incubation with trypsin markedly increased kininogenase activity from 54.8 +/- 11.8 to 230 +/- 23.0 pg bradykinin/mg protein/min. Adrenal kininogenase was inhibited 90% by phenyl methyl sulfonyl fluoride, 92% by D-Phe-Phe-Arg-chloromethylketone, 91% by aprotinin, and only 15% by soybean trypsin inhibitor. Pre-incubation with antibodies against rat urinary kallikrein resulted in 85% inhibition. The apparent molecular weight of adrenal kininogenase on gel filtration chromatography was 33 Kd. The enzyme was strongly adsorbed to immobilized rat urinary kallikrein antibodies and required drastic conditions for elution. In canine adrenal glands, we found that there was no difference in the cortical and medullary distribution of active and inactive SBTI resistant kininogenase activity. We conclude that an enzyme which closely resembles glandular kallikrein is present in adrenal glands.
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PMID:Glandular kallikrein-like enzyme in adrenal glands. 261 63

To assess the potential role of renal kallikrein-kinin system in enhancing sodium excretion per nephron in chronic renal failure, we studied urinary excretion of active and inactive kallikrein for 3 weeks in Wistar-Kyoto rats subjected to 5/6 nephrectomy (5/6), 1/2 nephrectomy (1/2) or sham operation (Sham). We determined urinary active and inactive kallikrein by measuring kallikrein activity using a kininogenase assay before and after treatment with trypsin (200 micrograms/ml). Fractional sodium excretion was significantly increased in 5/6-rats as compared with 1/2- or sham-rats. On the contrary, urinary active kallikrein excretion per nephron was not different in the three models whereas a significant rise in urinary inactive kallikrein excretion per nephron was found in 5/6-rats as compared with 1/2- or sham-rats. Urinary total kallikrein excretion per nephron was significantly increased in 5/6-rats as compared with sham-rats. In addition, no correlation was found between fractional sodium excretion and urinary active kallikrein excretion corrected for creatinine clearance (Ccr) in 5/6-rats. These results indicate that decreased excretion of renal active kallikrein may not play a significant role in the increased sodium excretion per nephron in the rat remnant kidney model of chronic renal failure. Furthermore, it is suggested that in this model of rat there might be impaired production of renal active kallikrein although its exact mechanism remains to be determined.
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PMID:Role of renal kallikrein in the increased fractional sodium excretion in the rat remnant kidney model of chronic renal failure. 261 88

The kinetic constants for the hydrolysis of a series of tripeptide p-nitroanilide substrates by mouse epidermal growth factor binding protein (EGF-BP), the gamma-subunit of mouse nerve growth factor (gamma-NGF), bovine pancreatic trypsin (BPT), and porcine pancreatic kallikrein (PPK) have been evaluated. These substrates correspond to the carboxyl-terminal three amino acids of the mature forms of epidermal growth factor (EGF) and beta-nerve growth factor (beta-NGF), as well as various substitutions in the penultimate and antepenultimate positions, and, as such, represent potential recognition sites for precursor processing. The mouse kallikreins (EGF-BP and gamma-NGF) preferentially hydrolyze the substrates with the sequences of their specifically associated growth factors; however, the constants derived from these reactions do not account for the association constants observed with the mature growth factors, and additional significant binding interactions between EGF-BP and EGF and between gamma-NGF and beta-NGF are predicted to exist outside of the catalytic binding site, i.e., the P3 to P1 positions. A comparison of the kinetic constants of BPT, PPK, and the mouse kallikreins indicates that EGF-BP and gamma-NGF display a hybrid catalytic character. A favorable substrate P1 arginine guanidinium group interaction exists for the mouse kallikreins, similar to that of BPT, but a preference for a hydrophobic side chain in the substrate P2 position makes the mouse kallikreins, especially EGF-BP, more closely resemble PPK than BPT. These findings have significant implications with regard to molecular modeling of the mouse kallikreins.
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PMID:Substrate specificities of growth factor associated kallikreins of the mouse submandibular gland. 261 Dec 15

Two thrombin-like isoenzymes, termed catroxobins, were purified by gel filtration and ion exchange chromatography to electrophoretic homogeneity from the venom of the Western diamondback rattlesnake, Crotalus atrox. By SDS-polyacrylamide gel electrophoresis their molecular weights were estimated to be 25,000 and 26,200. A 43-residue NH2-terminal sequence, containing the active histidine residue, was the same for the two isoenzymes. In addition, a 33-residue internal peptide from catroxobin I contained a normal active serine sequence. These sequences were highly homologous to other thrombin-like venom enzymes, and to pancreatic kallikrein and trypsin, but less so to the B chain of thrombin. Catroxobin, possessing 89 TAME esterase units/mg of protein, clotted human fibrinogen very slowly, releasing fibrinopeptide A and a small amount of fibrinopeptide B. No other evidence of cleavage of the fibrinogen molecule was revealed by polyacrylamide gel electrophoresis or HPLC.
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PMID:Catroxobin, a weakly thrombin-like enzyme from the venom of Crotalus atrox. NH2-terminal and active site amino acid sequences. 261 66


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