Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Based on studies of structure-activity relationship, trans-4-aminomethylcyclohexanecarbonyl-L-phenylalanine-4-carbox ymethylanilide (Tra-Phe-APAA) was designed as a selective plasma kallikrein inhibitor and synthesized. Tra-Phe-APAA inhibited plasma kallikrein with a Ki value of 0.81 microM, while it inhibited glandular kallikrein, plasmin, urokinase, factor Xa and thrombin with Ki values of greater than 500, 390, 200, greater than 500, and greater than 500 microM, respectively. However, its stereoisomer, Tra-D-Phe-APPA did not exhibit any detectable inhibitory activity against the above enzymes.
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PMID:Synthesis of trans-4-aminomethylcyclohexanecarbonyl-L- and -D-phenylalanine-4-carboxymethylanilide and examination of their inhibitory activity against plasma kallikrein. 139 97

The mammalian urinary bladder epithelium accommodates volume changes by the insertion and withdrawal of cytoplasmic vesicles. Both apical membrane (which is entirely composed of fused vesicles) and the cytoplasmic vesicles contain three types of ionic conductances, one amiloride sensitive, another a cation-selective conductance and the third a cation conductance which seems to partition between the apical membrane and the mucosal solution. The transport properties of the apical membrane (which has been exposed to urine in vivo) differ from the cytoplasmic vesicles by possessing a lower density of amiloride-sensitive channels and a variable level of leak conductance. It was previously shown that glandular kallikrein was able to hydrolyze epithelial sodium channels into the leak conductance and that this leak conductance was further degraded into a channel which partitioned between the apical membrane and the mucosal solution. This report investigates whether kallikrein is the only urinary constituent capable of altering the apical membrane ionic permeability or whether other proteases or ionic conditions also irreversible modify apical membrane permeability. Alterations of mucosal pH, urea concentrations, calcium concentrations or osmolarity did not irreversible affect the apical membrane ionic conductances. However, urokinase and plasmin (both serine proteases found in mammalian urine) were found to cause an irreversible loss of amiloride-sensitive current, a variable change in the leak current as well as the appearance of a third conductance which was unstable in the apical membrane and appears to partition between the apical membrane and the mucosal solution. Amiloride protects the amiloride-sensitive conductance from hydrolysis but does not protect the leak pathway. Neither channel is protected by sodium. Fluctuation analysis demonstrated that the loss of amiloride-sensitive current was due to a decrease in the sodium-channel density and not a change in the single-channel current. Assuming a simple model of sequential degradation, estimates of single-channel currents and conductances for both the leak channel and unstable leak channel are determined.
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PMID:Urinary proteases degrade epithelial sodium channels. 165 31

A highly selective inhibitor of plasma-kallikrein (PK), N-(trans-4-aminomethylcyclohexylcarbonyl)-L-phenylalanine 4-carboxymethyl-anilide hydrochloride, was designed and synthesized by the authors' group, called PKSI-527 in our laboratories. (I) PKSI-527 inhibited PK with a Ki value of 0.81 microM. By contrast, the Ki values for glandular kallikrein (GK), plasmin, thrombin, urokinase and factor Xa were greater than 500 microM, 390 microM, greater than 500 microM, 200 microM and greater than 500 microM, respectively. (II) Effects of PKSI-527 on bradykinin (BK) generation, coagulation and fibrinolysis by contact activation were examined using human plasma. (a) BK generation induced by kaolin appeared to be reduced by PKSI-527. Furthermore BK generation induced by lambda-carrageenan, a strong inflammatory agent, was also reduced by PKSI-527. (b) Partial thromboplastin time (PTT) was prolonged by PKSI-527, indicating the suppression of the intrinsic coagulation system. (c) Euglobulin clot lysis time (ECLT) of plasma which was shortened by activation with kaolin, was prolonged by the addition of PKSI-527, confirming the participation of PK in contact-fibrinolysis. These results indicate that PKSI-527 shows great potential in elucidating the significance of PK, and as such deserves further investigation.
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PMID:Effect of a highly selective plasma-kallikrein synthetic inhibitor on contact activation relating to kinin generation, coagulation and fibrinolysis. 238 57

The synthetic inhibitors of plasma kallikrein (PK) were found, which are called PKSI-1007, PKSI-0180 and PKSI-0527 in our laboratories. (1) The inhibitors inhibited PK competitively with D-Pro-Phe-Arg-pNA and the Ki values obtained were considerably small, 10(-6) M-10(-7) M. However, the Ki values for glandular kallikrein (GK), plasmin (PL), thrombin (TH) and factor Xa (FXa) were larger. In particular, a selectivity of PKSI-0527 towards PK was very high and the toxicity was weak (i.v. LD50 for mice is over 100 mg/kg). (2) The inhibitors were effective (a) to prevent the bradykinin formation in the kaolin-activated human plasma and the acid-treated ascites taken from the mice bearing Sarcoma 180, (b) to prolong the coagulation time by contact activation, and (c) to inhibit the enhancement of ADP-platelet aggregation by PK. The results indicated that the some PKSI-inhibitors will be much useful for the basic studies, furthermore they deem to be even promising towards the clinical application.
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PMID:Highly selective synthetic inhibitors with regard to plasma-kallikrein activities. 261 76

The relationship between chemical modifications of arginine derivatives and inhibitory activity to trypsin, plasmin and glandular kallikrein was investigated comparing with that of thrombin and concluded as follows: The hydrophobic binding pocket, which has been reported previously to be stereogeometrically very similar in trypsin and thrombin, corresponded to the length of ethylpiperidine. Concerning the site (termed the P site) next to the hydrophobic binding pocket, there were large differences in stereogeometry between trypsin and thrombin; the binding site of trypsin extended further to allow propyl and phenyl group attached to piperidine, while that of thrombin would be much narrower and unable to allow them. The P sites of plasmin and glandular kallikrein resembled that of trypsin in being able to allow phenyl group. To substantialize the hydrophobic binding pocket and the P site, a (2R, 4R)-MQPA-trypsin complex model was generated using the results of X-ray crystallography of (2R, 4R)-MQPA and BPTI-trypsin complex by calculation to minimize van der Waals contacts, and it was of great use for understanding the geometry of the active sites of trypsin, thrombin, plasmin and glandular kallikrein.
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PMID:Similarity and dissimilarity in the stereogeometry of the active sites of thrombin, trypsin, plasmin and glandular kallikrein. 295 62

A plasminogen activator inhibitor was purified from human cornified cell extract by DEAE-Sepharose, Sephacryl S-200, and high-performance liquid chromatographies on hydroxyapatite HPHT and anion-exchanger Mono Q at pH 7.2 and 8.0. The purified inhibitor showed Mr 43,000 and pI 5.2 50% inhibition of fibrinolytic activity (1.5 IU) of urokinase and tissue-type plasminogen activator was attained by 0.60 ng and 11.0 ng purified inhibitor, respectively. Synthetic substrate assay demonstrated slow tight-binding inhibition to both urokinase and tissue-type plasminogen activator. The inhibitor did not inactivate plasmin, thrombin, glandular kallikrein or trypsin.
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PMID:Purification of epidermal plasminogen activator inhibitor. 309 78

The relationship between chemical modifications of arginine derivatives and inhibitory activity to horse serum cholinesterase (BuChE) was investigated. It provided a new insight into the topography of the active site of BuChE. 1) BuChE has the hydrophobic binding pocket, the depth of which corresponds to the length of ethylpiperidine. 2) In the opposite side to the hydrophobic binding pocket, BuChE has a certain entity which repulses carboxyl group at the 2-position of piperidine of L-arginine piperidine amide. 3) The P site of BuChE can allow 4-propyl and 4-phenyl group attached to piperidine. Comparison of the results with those of thrombin and trypsin clearly revealed similarities and dissimilarities among BuChE, trypsin, and thrombin in the active site topography, and hence, we introduce a new selective inhibitor for BuChE, N alpha-dansyl-L-arginine 4-phenylpiperidine amide. It inhibits BuChE strongly (Ki = 0.016 microM), whereas it inhibits trypsin, thrombin, plasmin, and glandular kallikrein only weakly and shows actually no inhibition on acetylcholinesterase from the human erythrocyte. In addition, the new inhibitor becomes highly fluorescent when bound with BuChE, indicating that the compound is an ideal probe of the interactions of BuChE as well as a titrant of it.
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PMID:N alpha-dansyl-L-arginine 4-phenylpiperidine amide. A potent and selective inhibitor of horse serum cholinesterase. 340 26

A new method to determine plasmaprokallikrein independently of its inhibitors is described. By ion exchange chromatography with DEAE-A-50 Sephadex plasmaprokallikrein can be separated from its inhibitors Cl-esterase inhibitor, alpha 2-macroglobulin, alpha 1-antitrypsin (protease inhibitor) and antithrombin III as well as from other enzymes like plasmin, Hagemann factor and glandular kallikrein, which can interfere with the chromogenic substrate of the amidolytic assay (S 2302) used to determine plasmakallikrein activity. Furthermore, this method also allows the measurement of plasmaprokallikrein in heparinized plasma, since heparin was separated by this chromatography technique from plasmaprokallikrein too. The enzymatic activity of activated plasmakallikrein was not changed by the ion exchange chromatography. Normal values of the plasmaprokallikrein content in plasma were in the range of 2.57 +/- 0.12 U/ml of plasma (n:42; X +/- SEM). No influence on plasmaprokallikrein activity of age and sex was found.
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PMID:Measurement of plasma prokallikrein independent of inhibitors and interfering enzymes. 364 44

Two different plasma membrane enriched fractions were isolated from the homogenized rat kidney by differential centrifugation in dextran or sucrose. Marker enzymes and morphological studies indicated that one fraction (BLM) was enriched in membrane particles originating from the basolateral membrane of tubular cells, while the other, the PM fraction, contained membrane from the luminal side. Membrane-bound kallikrein and renin were found in both fractions. Kallikrein activity was enhanced by phospholipase A2, melittin and detergents. Renin activity was greatly increased after solubilization by the same agents. In addition to bound kallikrein and renin BLM contained a prekallikrein which was activated by trypsin or plasmin. BLM prekallikrein has a slower electrophoretic mobility and a higher molecular weight than urinary or glandular kallikrein. The basal membrane of tubular cells appears to contain all of the essential enzyme components of the kallikrein and renin systems. Kallikrein of the PM fraction is probably released into the urine, while prekallikrein and kallikrein from basal membrane may be the source of kallikrein in lymph and renal venous effluent. Membrane-bound renin could be a form of renin retained by the kidney.
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PMID:Prekallikrein, kallikrein and renin in membrane fractions of rat kidney. 675 83

The spicule venoms of Euproctis chrysorrhoea and Euproctis subflava were investigated for their capacity to hydrolyze chromogenic tripeptide substrates with selective affinities for various serine proteases. Seven substrates were assayed with affinities for trypsin and thrombin, trypsin and urokinase, serine proteases, chymotrypsin, glandular kallikrein, plasma kallikrein and plasmin. Venom material has a broad spectrum of affinities for the substrates with relative high plasma kallikrein activities. In E. chrysorrhoea venom, trypsin-like activities predominated, whereas E. subflava venom hydrolyzed, in preference, substrates with an affinity for chymotrypsin. The venoms were fractionated on Sephadex G-100, leading to three fractions, all having serine protease activity. The ratios of substrate specificities were markedly different, indicating that in both caterpillar venom preparations at least two separate serine proteases are present. In addition, in human plasma, inhibitor activity could be detected to the kallikrein activity of E. chrysorrhoea, but not of E. subflava. The trypsin-like activity was not inhibited by human plasma. These and earlier studies warrant the assumption that serine proteases, particularly kallikrein, are major factors in the elicitation of clinical symptoms observed after contact with caterpillar spicules.
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PMID:Protease activities in the spicule venom of Euproctis caterpillars. 704 29


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