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

The legume-derived Bowman-Birk trypsin and chymotrypsin protease inhibitors (BBI) are effective anticarcinogens in vivo and in vitro. The chymotrypsin-inhibitory domain has been shown to be responsible for this anticarcinogenic action. In this study we identify hydrolytic enzymes by their ability to hydrolyze the relatively specific chymotrypsin substrate succinyl-Ala-Ala-Pro-Phe-aminomethyl coumarin. Results presented in this study show: there is an approximately 2-fold increase in the activity of these enzyme(s) between normal and transformed C3H/10T1/2 cells; there are five such enzymes associated with transformed cells (separated by diethylaminoethyl-cellulose chromatography); only two of these enzymes are inhibited by BBI; the BBI-inhibitable enzymes are membrane associated; the BBI-inhibitable enzymes are similar to each other but different from pancreatic chymotrypsin. BBI has thus distinguished a subpopulation of enzymes capable of hydrolyzing succinyl-Ala-Ala-Pro-Phe-aminomethyl coumarin which may mediate the transformation of C3H/10T1/2 cells.
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PMID:Proteases occurring in the cell membrane: a possible cell receptor for the Bowman-Birk type of protease inhibitors. 354 48

The objective of this study was to characterize the plasmin-induced stimulation of leukotriene (LT) B4 biosynthesis in human peripheral monocytes (PM). Plasmin up to 175 x 10(-3) CTA U/ml triggers a concentration-dependent release of 5-lipoxygenase-derived LTB4 while release of the cyclooxygenase products thromboxane (TX) B2 and prostaglandin (PG) E2 remained unaffected. The stimulatory effect appeared to be specific in as much as 1) it was found in PM, but not in polymorphonuclear neutrophils (PMN), 2) it requires the lysine binding sites of plasmin molecule since it was inhibited by the lysine analogues 6-aminohexanoic acid (6-AHA) and trans-4(aminomethyl)cyclohexane-1-carboxylic acid (t-AMCA), 3) the intact catalytic center of plasmin is required since neither plasminogen nor catalytic center-blocked plasmin share the stimulatory effect of active plasmin, 4) other serine proteases such as alpha-chymotrypsin, human neutrophil elastase and cathepsin G did not stimulate release of detectable amounts of LTB4 from PM. In addition, catalytic center-blocked plasmin antagonized the stimulatory effect of active plasmin. Plasmin-mediated monocyte activation apparently proceeds via a pertussis toxin-sensitive G protein. Plasmin did not increase inositol (1,4,5) trisphosphate levels, but a time- and concentration-dependent stimulation of cyclic GMP formation was observed. The data show that plasmin is a specific stimulus for human peripheral monocytes. Plasmin may be an important link between the coagulation cascade and inflammatory reactions.
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PMID:Plasmin is a specific stimulus of the 5-lipoxygenase pathway of human peripheral monocytes. 890 97

DPC423, 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide, is a synthetic, orally bioavailable, competitive, and selective inhibitor of human coagulation factor Xa (K(i) [nM]: factor Xa, 0.15; trypsin, 60; thrombin, 6000; plasma kallikrein, 61; activated protein C, 1800; factor IXa, 2200; factor VIIa, >15,000; chymotrypsin, >17,000; urokinase, >19,000; plasmin, >35,000; tissue plasminogen activator, >45,000; complement factor I, 44,000 [IC(50)]). In vitro, DPC423 produced anticoagulant effects in human plasma in which it doubled prothrombin time, activated partial thromboplastin time, and Heptest clotting time at 3.1 +/- 0.4, 3.1 +/- 0.4, and 1.1 +/- 0.5 microM, respectively. In dogs, DPC423 had a good pharmacokinetic profile with an oral bioavailability of 57%, a plasma clearance of 0.24 L/kg/h, and a plasma half-life of 7.5 h. In rabbit and rat models of arteriovenous shunt thrombosis, DPC423 was an effective antithrombotic agent with an IC(50) of 150 and 470 nM, respectively. The antithrombotic effect of DPC423 is likely to be related to the inhibition of factor Xa but not to the inhibition of thrombin or due to direct inhibition of platelet aggregation. Therefore, based on potency, selectivity, efficacy, and oral bioavailability, DPC423 was selected for clinical development as an oral anticoagulant for the potential treatment of thrombotic disorders. Preliminary human data suggest that DPC423 is orally bioavailable in humans and has a long plasma half-life.
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PMID:Nonpeptide factor Xa inhibitors: DPC423, a highly potent and orally bioavailable pyrazole antithrombotic agent. 1217 91

Kazinol B, a natural isoprenylated flavan, stimulated the [Ca(2+)](i) elevation in the presence or absence of Ca(2+) in the medium. Treatment with chymotrypsin or phorbol 12-myristate 13-acetate to shedding of L: -selectin had no effect on subsequent kazinol B-induced Ca(2+) response. Upon initial cyclopiazonic acid (CPA) treatment in the absence of external Ca(2+), the subsequent [Ca(2+)](i) rise followed by challenge with kazinol B was greatly diminished. The ryanodine receptor blockers, 8-bromo-cyclic ADP-ribose and ruthenium red did not affect kazinol B-evoked Ca(2+) release from internal stores. However, the inhibitors of sphingosine kinase, dimethylsphingosine, but not dihydrosphingosine, inhibited kazinol B-induced Ca(2+) release. Kazinol B-induced [Ca(2+)](i) rise was not affected by two nitric oxidase inhibitors, N-(3-aminomethyl)benzylacetamidine (1400W) and 7-nitroindazole, cytochalasin B and Na(+)-deprivation. This response was slightly attenuated by 2-aminoethyldiphenyl borate (2-APB), a D: -myo-inositol 1,4,5-trisphosphate (IP(3)) receptor blocker, and by genistein, a general tyrosine kinase inhibitor. However, the Ca(2+) response was greatly diminished by two actin filament reorganizers, calyculin A and jasplakinolide, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY 294002), an inhibitor of phosphoinositide 3-kinase, N-(3-aminomethyl)benzylacetamidine (SB 203580), the p38 mitogen-activated protein kinase inhibitor, 1-[6-[17beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U-73122), the inhibitor of phospholipase C-coupled processes, and by 0.3 mM La(3+) or Ni(2+). Kazinol B did not evoke any appreciable Ba(2+) and Sr(2+) entry into cells. The Ca(2+) entry blockers, 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole (SKF-96365), but not cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL-12,330A), inhibited a kazinol B-induced [Ca(2+)](i) rise. Kazinol B had no effect on the pharmacologically isolated plasma membrane Ca(2+)-ATPase activity. In a Ca(2+)-free medium, kazinol B inhibited the subsequent Ca(2+) addition, resulting in robust entry in CPA- and formyl peptide-activated cells. Kazinol B produced a concentration-dependent reduction in the mitochondrial membrane potential. These results indicate that kazinol B stimulates Ca(2+) release from internal Ca(2+) store, probably through the sphingosine 1-phosphate and IP(3) signaling, and activates external Ca(2+) influx mainly through a non-store-operated Ca(2+) entry (non-SOCE) pathway. Inhibition of SOCE by kazinol B is probably attributable to a break in the Ca(2+) driven force of mitochondria.
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PMID:Stimulation of cellular free Ca2+ elevation and inhibition of store-operated Ca2+ entry by kazinol B in neutrophils. 1555 42

The capability of binding enzymes adsorptively to unmodified and silanized silica and glass as well as modified polystyrene carriers was studied for alpha-amylase, beta-amylase, and alpha-chymotrypsin. In most cases a high percentage of protein was bound very firmly under considerable loss of activity. The leakage of protein from the carriers was studied by measuring the intrinsic protein fluorescence on beta-amylase adsorptively bound to aminopropyl silica, aminomethyl, and hexadecylaminomethyl polystyrene. It was compared with the leakage of beta-amylase covalently bound to the same carriers via glutaraldehyde, trichloro-triazine, or benzoquinone. In the absence and in the presence of substrate, at 25 and at 60 degrees C, the leakage rates of the adsorptively bound enzymes were not higher than in the covalently bound systems. The poorest binding stability was found in benzoquinone-coupled beta-amylase derivatives. It is even reduced at higher temperatures, whereas the temperature did not show any remarkable influence on the leakage of the other derivatives. In adsorptively as well as in all the covalently bound systems, the presence of substrate did not promote the protein leakage.
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PMID:Protein adsorption and leakage in carrier-enzyme systems. 1859 66