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)

The low-molecular-weight peptide protease inhibitors, tosyl-lysine-chloromethyl ketone, antipain and leupeptin, inhibited poly(ADP-ribose) [poly(ADP-Rib)] polymerase in permeable cells. The concentrations required for 50% inhibition were 3.6, 5 and 29 mM, respectively. Two peptides without protease inhibitor activity, fibrinopeptide A and phenylalanine-leucine-(glutamine)2-leucine, also inhibited poly (ADP-Rib) synthesis; doses required for 50% inhibition were 0.37 and 11.2 mM, respectively. These concentrations lie within a range bracketed by the 50% inhibition concentrations of the strong and weak poly(ADP-Rib) synthesis inhibitors, 3-amino-benzamide (0.15 mM) and caffeine (greater than 100 mM), respectively. N-Ethylmaleimide also inhibited poly(ADP-Rib) synthesis, at a 50% inhibitory dose of 0.3 mM, in the absence of exogenous thiol reagents. High-molecular-weight protease inhibitors, such as soybean (including Bowman-Birk reagent) and lima bean trypsin inhibitors and human alpha 1-protease inhibitor, had no effect on poly(ADP-Rib) synthesis up to 2 mg/ml. Interference with transformation and other cellular effects that have been reported in carcinogen-damaged cells treated with low-molecular-weight peptide protease inhibitors may therefore involve common mechanisms with poly(ADP-Rib) inhibitors. Similar effects of high-molecular-weight protease inhibitors presumably involve different mechanisms.
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PMID:Some protease inhibitors are also inhibitors of poly(ADP-ribose) polymerase. 308 Dec 73

This review is concerned with the influence of different classes of chemical agents on cellular repair of DNA damage induced by ionizing radiation. Single-strand break rejoining is little affected by inhibitors of DNA synthesis; however, such inhibitors do lead to a persistence of double-strand breaks in the DNA, and this correlates with an enhancement of chromosome aberrations and cell killing. Experiments with antagonists of topoisomerase II suggest an intriguing role for this DNA unwinding enzyme in double-strand break repair. Interference with poly(ADP-ribose) synthesis, by means of the inhibitor 3-aminobenzamide, does not have a clear-cut effect on recovery from ionizing radiation damage. Various substances (for example, caffeine and trypsin) affect DNA repair via a modulation of the cell cycle, altering the time available to the cell for repairing potentially lethal DNA damage before such damage is 'fixed' by the process of DNA replication. Finally, disturbing cellular energy metabolism, and depressing the level of ATP, can inhibit the repair of radiation damage.
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PMID:Cellular responses to ionizing radiation: effects of interrupting DNA repair with chemical agents. 329 8

The effects of coffee on exocrine pancreatic secretion are unknown but may be important, because a link between chronic stimulation of pancreatic secretion and experimental chemical carcinogenesis and an association between coffee drinking and human pancreatic adenocarcinoma have been reported. We measured exocrine pancreatic trypsin and gastric acid secretions collected through orogastroduodenal tubes and serum gastrin in eight non-coffee drinkers and eight coffee drinkers. During fasting, after one interdigestive cycle control period, one of four 250-ml samples [plain water, water plus caffeine (4.6 mg/kg), decaffeinated coffee (127.9 mg/kg), caffeinated coffee (127.9 mg/kg)] was administered through the orogastric tube. Caffeinated and decaffeinated coffee (p = 0.008), caffeine (p = 0.03), and an unidentified substance(s) in coffee other than caffeine (p = 0.008) were associated with increased interdigestive exocrine pancreatic trypsin secretion. In addition, we also confirmed that coffee and caffeine stimulated gastric acid secretion (p = 0.02) and decaffeinated coffee raised serum gastrin concentrations (p = 0.005). If an association between coffee and pancreatic carcinogenesis exists, chronic stimulation of the exocrine pancreas by secretagogues could result in a gland susceptible to carcinogenesis.
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PMID:The acute effects of coffee and caffeine on human interdigestive exocrine pancreatic secretion. 357

It has been proposed that Ca2+ ions mediate the stimulation by insulin of glucose uptake in muscle (Clausen, T., Cell Calcium 1:311-325, 1980). However, absolute measurements of the concentration of cytosolic free Ca2+, [Ca2+]i, during the course of insulin action have not been made. The stimulation of hexose uptake by insulin was studied in an in vitro model system of muscle cells, the L6 cell line. The following evidence suggests that Ca2+ ions are not likely to fulfill the purported role. 1) Insulin in Ca2+-free media induced stimulation of 2-deoxy-D-glucose uptake. 2) Elevation of [Ca2+]i with the ionophore A23187 did not enhance hexose uptake. 3) Insulin action was not diminished when the hormone was added to Ca2+-depleted cells in Ca2+-free media with A23187. 4) Hexose uptake was not affected by a number of agents thought to modify [Ca2+]i including epinephrine, caffeine, 2,4-dinitrophenol, hyperosmolar mannitol, salicylate, vanadate, veratrine, and trypsin. 5) Direct determinations of [Ca2+]i by fluorescence of the novel indicator Quin-2 did not show differences between basal and insulin-stimulated cells; under identical conditions hexose uptake was stimulated by the hormone. 6) Chelation of [Ca2+]i with Quin-2 in Ca2+-free media did not affect the response to insulin. 7) Low concentrations of trypsin (7.5 micrograms/ml) elevated [Ca2+]i but did not increase the rate of hexose uptake.
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PMID:Role of calcium ions in insulin action on hexose transport in L6 muscle cells. 643 19

The 1-methyladenine-induced oocyte maturation in starfish is reversibly inhibited by the anticalmodulin drug, trifluoperazine (TFP). However, when oocytes are exposed for 10 min to trypsin, they lose their sensitivity to TFP. Trypsin does not alter the length of the hormone-dependent period (1-methyladenine minimal contact time) or the 1-methyladenine concentration requirements. Trypsin-treated oocytes remain sensitive to other maturation inhibitors such as procaine, theophylline, caffeine, and D-600. Trypsin exposure modifies the protein pattern composition of the oocyte cortex (breakdown of a 140-kDa protein). TFP binding site localization was studied using fluorescence microscopy: in addition to a general diffuse fluorescence, staining is localized to probably acidic granules located in the cortex. Results are discussed in relation to calmodulin and plasma membrane calmodulin-dependent enzyme involvement in the stimulation of starfish oocyte maturation.
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PMID:Calmodulin in starfish oocytes. II. Trypsin treatment suppresses the trifluoperazine-sensitive step. 653 28

At least three distinct ryanodine receptor genes appear to be expressed in mammalian brain. We have used biochemical and immunological methods to characterize the major form of ryanodine binding protein purified from brain. [3H]Ryanodine binding to the purified brain receptor is stimulated by Ca2+, ATP, KCl, and phosphorylation and is inhibited by calmodulin, Mg2+, and ruthenium red. Immunoblot and immunoprecipitation analysis using a panel of monoclonal and polyclonal antibodies against skeletal and cardiac muscle ryanodine receptors, and two novel polyclonal antibodies against the brain ryanodine receptor, reveals that the major form of ryanodine receptor expressed in brain is immunologically similar to the cardiac ryanodine receptor, but is distinct from the skeletal muscle receptor. Digestion of cardiac and brain ryanodine receptors with trypsin or alpha-chymotrypsin generates similar proteolytic patterns as detected by immunoblot analysis or by autoradiography after labeling with a hydrophobic probe, suggesting that the two proteins are similar in both their large cytoplasmic and hydrophobic transmembrane domains. Taken together, these data indicate that the cardiac ryanodine receptor/Ca2+ release channel is the major form of ryanodine receptor expressed in brain, and that it likely functions in releasing Ca2+ from caffeine-sensitive intracellular Ca2+ stores in neurons by a mechanism of regulated Ca(2+)-induced Ca2+ release.
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PMID:Characterization of the major brain form of the ryanodine receptor/Ca2+ release channel. 769 41

Triphenyltin induces a contracture of the mouse phrenic nerve-diaphragm preparation. This contracture was not inhibited by (+)-tubocurarine, high magnesium or the absence of electrical stimulation. Triphenyltin (0.1 mM) reduced the muscle membrane potential, the amplitude of the muscle action potential and the muscle membrane input resistance. Pretreatment with high K+ (25 mM) or veratridine (1.5 microM; a Na+ channel activator) briefly shortened the onset of the contracture and increased the peak tension of the contracture. Pretreatment with tetrodotoxin (0.3 microM; a Na+ channel blocker) or glycerol (a T tubule uncoupler) however, significantly reduced the triphenyltin-induced contracture. Removing Ca2+ from external solution and prolonged treatment with either caffeine (20 mM) or ryanodine (2 microM) inhibited the triphenyltin-induced contracture. However, a brief treatment with a lower concentration of caffeine (10 mM) potentiated the contracture. 45Ca2+ uptake studies showed that triphenyltin caused the muscle to accumulate Ca2+ which entered from external solution. Pretreatment with trypsin and dithiothreitol (a sulfhydryl-containing reducing agent) blocked the contracture induced by triphenyltin. These results suggest that triphenyltin initially interacts with the sulfhydryl groups of membrane bound proteins (possibly the Na+ channel) to cause depolarization of the muscle fibres. This depolarization triggers the release of Ca2+ from sarcoplasmic reticulum through the mechanism of Ca2+ inducing Ca2+ release, activates the contractile filaments and causes the muscle to contract.
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PMID:Studies on the contracture inducing action of triphenyltin in the mouse diaphragm. 786 95

Local chemical events underlying chemotaxis were characterized in a new model cell, the newt eosinophil. These cells exhibit a chemotactic response to a trypsin-sensitive component of newt serum. Ca2+ plays a role in this process, since treatments expected to diminish Ca2+ availability from the medium [ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, Co2+, and verapamil], to break down transmembrane Ca2+ gradients (ionomycin), or to interfere with the function of intracellular Ca2+ stores (caffeine and neomycin) inhibited cell polarization and movement. Using imaging techniques we found that cytosolic Ca2+ concentration ([Ca2+]i) increased in response to newt serum. Migrating newt eosinophils exhibited a dynamic heterogeneous distribution of [Ca2+]i. [Ca2+]i was elevated in cells undergoing a change of direction relative to cells migrating persistently in one direction. Migrating cells contained gradients of [Ca2+]i along their long axis, with the front of the cell having consistently lower [Ca2+]i than the rear. When cells were loaded with the cell-permeant form of fura 2, fura 2 acetoxymethyl ester, a caffeine-sensitive membrane-delimited region of elevated [Ca2+]i was seen associated with the microtubule organizing center. A model is proposed relating the distribution of [Ca2+]i and the location of the external stimulus to the generation and interaction of substances within the cell that both simulate and inhibit increases in [Ca2+]i.
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PMID:Chemotaxis of newt eosinophils: calcium regulation of chemotactic response. 827 15

A new Golgi resident, p54, has been demonstrated in several eukaryotic species and in multiple organs. Based on Triton X-114 partition, carbonate extraction and trypsin protection assays, p54 behaved as an extrinsic membrane protein, facing the luminal compartment. p54 was purified by two-dimensional electrophoresis and identified by matrix-assisted laser desorption ionization/time-of-flight (MALDI-TOF) mass spectrometry as NEFA, a calcium-binding protein (Barnikol-Watanabe et al., 1994, Biol. Chem. Hoppe Seyler, 375, 497-512). By immunofluorescence, p54/NEFA essentially colocalized with the medial Golgi marker mannosidase II, and did not overlap with the cis-Golgi marker p58, nor with the trans-Golgi network (TGN) marker TGN38. By immuno-electron microscopy, p54/NEFA localized in the medial cisternae and in Golgi-associated vesicles. p54/NEFA remained associated with mannosidase II despite Golgi disruption by nocodazole, caffeine, or, to some extent, potassium depletion (a new procedure to induce Golgi disassembly), but the two markers rapidly dissociated upon brefeldin A treatment and at metaphase, and reassociated upon drug removal and at the end of anaphase. Since p54/NEFA is a peripheral luminal membrane constituent, its distinct trafficking from the transmembrane marker mannosidase II suggests a novel Golgi retention mechanism, by strong association of this soluble protein with another integral transmembrane resident.
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PMID:The calcium-binding protein p54/NEFA is a novel luminal resident of medial Golgi cisternae that traffics independently of mannosidase II. 1189 86

The role of the sequence surrounding M4 in ryanodine receptors (RyR) in membrane association and function was investigated. This sequence contains a basic, 19-amino acid M3/M4 loop, a hydrophobic 44-49 amino acid sequence designated M4 (or M4a/M4b), and a hydrophilic M4/M5 loop. Enhanced green fluorescent protein (EGFP) was inserted into RyR1 and truncated just after the basic sequence, just after M4, within the M4/M5 loop, just before M5 and just after M5. The A52 epitope was inserted into RyR2 and truncated just after M4a. Analysis of these constructs ruled out a M3/M4 transmembrane hairpin and narrowed the region of membrane association to M4a/M4b. EGFP inserted between M4a and M4b in full-length RyR2 was altered conformationally, losing fluorescence and gaining trypsin sensitivity. Although it was accessible to an antibody from the cytosolic side, tryptic fragments were membrane-bound. The expressed protein containing EGFP retained caffeine-induced Ca(2+) release channel function. These results suggest that M4a/M4b either forms a transmembrane hairpin or associates in an unorthodox fashion with the cytosolic leaflet of the membrane, possibly involving the basic M3/M4 loop. The expression of a mutant RyR1, Delta4274-4535, deleted in the sequence surrounding both M3 and M4, restored robust, voltage-gated L-type Ca(2+) currents and Ca(2+) transients in dyspedic myotubes, demonstrating that this sequence is not required for either orthograde (DHPR activation of sarcoplasmic reticulum Ca(2+) release) or retrograde (RyR1 increase in DHPR Ca(2+) channel activity) signals of excitation-contraction coupling. Maximal amplitudes of L-currents and Ca(2+) transients with Delta4274-4535 were larger than with wild-type RyR1, and voltage-gated sarcoplasmic reticulum Ca(2+) release was more sensitive to activation by sarcolemmal voltage sensors. Thus, this region may act as a negative regulatory module that increases the energy barrier for Ca(2+) release channel opening.
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PMID:Role of the sequence surrounding predicted transmembrane helix M4 in membrane association and function of the Ca(2+) release channel of skeletal muscle sarcoplasmic reticulum (ryanodine receptor isoform 1). 1522 93


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