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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

KT5926, (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-14-n-propoxy-2,3 ,9, 10-tetrahydro-8,11-epoxy, 1H,8H, 11H-2,7b,11a-triazadibenzo[a,g]cycloocta[cde] trinden-1-one, was found to be a potent and selective inhibitor of myosin light chain kinase. The compound inhibited both Ca2+/calmodulin-dependent and -independent smooth muscle myosin light chain kinases to a similar extent. The inhibition was not affected by the concentration of calmodulin. Kinetic analyses showed that the mode of inhibition was of the competitive type with respect to ATP (Ki, 18 nM) and of the noncompetitive type with respect to myosin light chain (Ki, 12 nM). These results indicated that KT5926 directly interacted with the enzyme at the catalytic site. KT5926 also inhibited other protein kinases, but with relatively high Ki values; the values for protein kinase C, cAMP-dependent protein kinase, and cGMP-dependent protein kinase were 723, 1200, and 158 nM, respectively. Ca2(+)-ATPase, Na+/K(+)-ATPase, hexokinase, and 5'-nucleotidase were not inhibited by KT5926 at less than 10 microM. The effect of KT5926 on serotonin secretion and protein phosphorylation induced by platelet-activating factor or phorbol ester was examined in rabbit platelets. KT5926 inhibited the phosphorylation of a 20-kDa protein but had no effect on the phosphorylation of a 40-kDa protein, thereby indicating that the compound exerts its selective inhibition of myosin light chain kinase in intact cells. The compound inhibited serotonin secretion induced by platelet-activating factor, but its potency was significantly less than that of K-252a, (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9, 10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b, 11a-triazadibenzo[a,g]cycloocta [cde]trinden-1-one, which inhibited the phosphorylation of both the 20-kDa protein and the 40-kDa protein. Phorbol ester-induced secretion was not suppressed by KT5926. These results provide the evidence that both the 20-kDa protein phosphorylation by myosin light chain kinase and the 40-kDa protein phosphorylation by protein kinase C substantially contribute to the secretion response in platelets.
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PMID:KT5926, a potent and selective inhibitor of myosin light chain kinase. 232 35

Previously, we have shown that okadaic acid (OA), isolated from black sponge (Halichondria okadai) causes contraction even in the absence of Ca++ in the saponin-permealized taenia isolated from guinea pig cecum. In the present study, mechanism of action of OA was examined using native actomyosin extracted from chicken gizzard smooth muscle. In the absence of Ca++, OA (0.1-1 microM) induced superprecipitation and increased the Mg++-adenosine triphosphatase activity. The OA-induced superprecipitation was enhanced by Ca++ at a concentration (greater than 0.1 microM) which did not activate the calmodulin-dependent myosin light chain (MLC) kinase. The effect of OA was not affected by the calmodulin inhibitor, trifluoperazine, at a concentration (100 microM) needed to inhibit the Ca++-induced response, but was inhibited markedly by the nonselective kinase inhibitors, amiloride (1 mM) and K-252a (5 microM). The OA-induced superprecipitation in the absence of Ca++ was accompanied by phosphorylation of the 20 K dalton MLC, which also was enhanced by low concentration of Ca++ (greater than 0.1 microM). OA did not change the phosphatase activity which dephosphorylates the phosphorylated MLC. An activator of Ca++- and phospholipid-dependent protein kinase, 12-O-tetradecanoylphorbol 13-acetate (1 microM), did not modulate superprecipitation or phosphorylation of MLC in the presence and absence of OA. Furthermore, inhibitors of Ca++ and phospholipid-dependent protein kinase, 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine dihydrochloride (400 microM) and polymyxin B (100 micrograms/ml), affected neither superprecipitation nor phosphorylation of MLC induced by OA. With a reconstituted system containing purified myosin and MLC kinase, OA induced only slight phosphorylation of MLC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcium-independent phosphorylation of smooth muscle myosin light chain by okadaic acid isolated from black sponge (Halichondria okadai). 282 58

K-252a, an indole carbazol compound of microbial origin, inhibited activation of bovine brain phosphodiesterase induced by calmodulin (CaM), sodium oleate, or limited proteolysis with almost equal potency. Kinetic analysis revealed that the CaM-activated phosphodiesterase (CaM-PDE) was competitively inhibited by K-252a with respect to CaM. On the other hand, inhibition of the trypsin-activated phosphodiesterase was competitive with respect to cyclic AMP. Addition of a lower amount of phosphatidylserine or sodium oleate to the reaction medium was efficacious in attenuating the inhibition of the CaM-PDE by W-7, compound 48/80, or calmidazolium but, in contrast, had no effect on the inhibition by K-252a. Furthermore, CaM-independent systems such as [3H]nitrendipine receptor binding or Na+ + K+-ATPase were influenced less by K-252a compared with W-7, compound 48/80 and calmidazolium. In conclusion, K-252a is an inhibitor of CaM-dependent cyclic nucleotide phosphodiesterase and it appears that it inhibits the enzyme not only via CaM antagonism but possibly also by interfering with the enzyme.
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PMID:The effect of K-252a, a potent microbial inhibitor of protein kinase, on activated cyclic nucleotide phosphodiesterase. 285 86

Effects of K-252a, (8R*, 9S*, 11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8, 11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta [cde]trinden-1-one, purified from the culture broth of Nocardiopsis sp., on the activity of myosin light chain kinase were investigated. 1) K-252a (1 x 10(-5) M) affected three characteristic properties of chicken gizzard myosin-B, natural actomyosin, to a similar degree: the Ca2+-dependent activity of ATPase, superprecipitation, and the phosphorylation of the myosin light chain. 2) K-252a inhibited the activities of the purified myosin light chain kinase and a Ca2+-independent form of the enzyme which was constructed by cross-linking of myosin light chain kinase and calmodulin using glutaraldehyde. The degrees of inhibition by 3 x 10(-6) M K-252a were 69 and 48% of the control activities with the purified enzyme and the cross-linked complex, respectively. Chlorpromazine (3 x 10(-4) M), a calmodulin antagonist, inhibited the native enzyme, but not the cross-linked one. These results suggested that K-252a inhibited myosin light chain kinase by direct interaction with the enzyme, whereas chlorpromazine suppressed the enzyme activation by interacting with calmodulin. 3) The inhibition by K-252a of the cross-linked kinase was affected by the concentration of ATP, a phosphate donor. The concentration causing 50% inhibition was two orders magnitude lower in the presence of 100 microM ATP than in the presence of 2 mM ATP. 4) Kinetic analyses using [gama-32P]ATP indicated that the inhibitory mode of K-252a was competitive with respect to ATP (Ki = 20 nM). These results suggest that K-252a interacts at the ATP-binding domain of myosin light chain kinase. The direct action of the compound on the enzyme would explain the multivarious inhibition of myosin ATPase, of superprecipitation, and of the contractile response of smooth muscle.
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PMID:K-252a, a novel microbial product, inhibits smooth muscle myosin light chain kinase. 296 51

Bafilomycin A1, a selective inhibitor of vacuolar H+-ATPase, time- and dose-dependently induced the differentiation of M1 cells, a murine myeloid leukemic cell line, into macrophage-like cells as revealed by the phagocytosis of polystyrene latex particles. This differentiation was inhibited not only by actinomycin D and cycloheximide but also by ST-638 (an inhibitor of tyrosine kinase). However, it was affected neither by K-252a (an inhibitor of C-kinase) nor by H-89 (an inhibitor of A-kinase), in contrast to the M1 cell differentiation induced by leukemia inhibitory factor (LIF). Okadaic acid inhibited both the bafilomycin A1-induced and LIF-induced differentiation of M1 cells.
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PMID:Induction of phagocytic activity of M1 cells by an inhibitor of vacuolar H+-ATPase, bafilomycin A1. 750 42

The effect of staurosporine on the Ca2+ signalling induced by the muscarinic receptor agonist carbachol (CCh) was studied in Fura-2-loaded rat parotid acinar cells. At concentrations > 1 nM, staurosporine dose-dependently enhanced the sustained increase in cytosolic free Ca2+ concentration ([Ca2+]i), but did not affect the peak [Ca2+]i seen just after stimulation. The enhancement of the sustained increase in [Ca2+]i was not attenuated by the protein kinase C activator, 4 beta-phorbol 12-myristate 13-acetate, and not mimicked by another inhibitor of protein kinase C, K-252a, suggesting that the effect of staurosporine on the CCh-induced Ca2+ signalling may be due to a mechanism independent of the inhibitory action on protein kinase C. Staurosporine also enhanced the increases in [Ca2+]i induced by the microsomal Ca(2+)-ATPase inhibitor thapsigargin (TG) and the Ca2+ ionophore ionomycin (Iono). When the cells were stimulated by CCh, TG, or Iono in the absence of extracellular Ca2+, a transient increase in [Ca2+]i due to Ca2+ release from intracellular stores was observed. This increase in [Ca2+]i was unaffected by preincubation with staurosporine. However, when Ca2+ was added to the extracellular medium after [Ca2+]i had returned to the resting level, the increase in [Ca2+]i was significantly enhanced by staurosporine. In addition, staurosporine accelerated the Mn2+ influx following the addition of CCh, TG, or Iono. These results suggest that staurosporine modulates the Ca2+ entry system activated by depletion of intracellular Ca2+ stores in rat parotid acinar cells.
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PMID:Staurosporine enhances Ca2+ entry induced by depletion of intracellular Ca2+ stores in rat parotid acinar cells. 755 79

Hypoosmotic shock treatment increased cytosolic Ca2+ ion concentration ([Ca2+]cyt) in tobacco (Nicotiana tabacum) suspension-culture cells. [Ca2+]cyt measurements were made by genetically transforming these cells to express apoaequorin and by reconstituting the Ca2+-dependent photoprotein, aequorin, in the cytosol by incubation with chemically synthesized coelenterazine. Measurement of Ca2+-dependent luminescence output thus allowed the direct monitoring of [Ca2+]cyt changes. When cells were added to a hypoosmotic medium, a biphasic increase in [Ca2+]cyt was observed; an immediate small elevation (phase 1) was observed first, followed by a rapid, large elevation (phase 2). Phase 1 [Ca2+]cyt was stimulated by the V-type ATPase inhibitor bafilomycin A1. Phase 2 was inhibited by the protein kinase inhibitor K-252a and required the continued presence of the hypoosmotic stimulus to maintain it. Although Ca2+ in the medium was needed to produce phase 2, it was not needed to render the cells competent to the hypoosmotic stimulus. If cells were subject to hypoosmotic shock in Ca2+- depleted medium, increases in luminescence could be induced up to 20 min after the shock by adding Ca2+ to the medium. These data suggest that hypoosmotic shock-induced [Ca2+]cyt elevation results from the activity of a Ca2+ channel in the plasma membrane or associated hypoosmotic sensing components that require Ca2+- independent phosphorylation and a continued stimulus to maintain full activity.
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PMID:Hypoosmotic Shock Induces Increases in Cytosolic Ca2+ in Tobacco Suspension-Culture Cells. 1222 27

The roles of diphosphoinositol polyphosphates (DIPs) in mammalian cell biology have been difficult to determine because of the lack of tools known to regulate their levels. I have determined a series of protocols that regulate these DIPs, and these can be used to further our understanding of these molecules. Sorbitol and sucrose significantly raised levels of bis-diphosphoinositol tetrakisphosphate ([PP]2-InsP4) but slightly lowered levels of diphosphoinositol pentakisphosphate (PP-InsP5) in DDT1 MF-2 cells. These effects correlate with the ability of hyperosmotic stress to interfere with protein trafficking described previously and suggest that [PP]2-InsP4 specifically impedes protein trafficking. The effects on [PP]2-InsP4 were not regulated by extracellular signal-regulated kinase or phospholipase D, as exemplified by the lack of effect of U0126 and butan-1-ol. I have also found that genistein potently and rapidly lowers levels of [PP]2-InsP4, whereas a similar inhibitor, herbimycin, was without effect. Thapsigargin, a sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase pump inhibitor previously shown to selectively lower PP-InsP5 after short-term treatment, also selectively raises PP-InsP5 after a longer treatment. The calmodulin inhibitors N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and chlorpromazine significantly lowered all higher inositol phosphates, as well as DIPs, whereas the calmodulin-dependent kinase inhibitors methyl 9-(S)-12-(R)-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-2,3,9,10,11,12-hexahydro-10-(R)hydroxy-9-methyl-1-oxo-10-carboxylate (K-252a) and 2-[N-(2-hydroxyethyl)-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine (KN-93) were without effect. W-7 and chlorpromazine also lowered levels of phosphatidylinositol 4,5-bisphosphate and ATP but greatly increased levels of phosphatidylinositol 4-phosphate. Trypan blue exclusion deemed that these doses were not cytotoxic. These results identify an increasing number of reagents that regulate DIP levels. Using these tools, and those described previously, we can further understand the roles of the DIPs in cell biology.
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PMID:Protocols for regulation and study of diphosphoinositol polyphosphates. 1534 93

The leaf of kidney bean (Phaseolus vulgaris) moves in response to blue light. The movement is induced by a decrease in the turgor pressure of pulvinar motor cells on the irradiated side. In this study, we investigated the initial event of the movement with respect to function of phototropin and the plasma membrane H+-ATPase in the motor cells. The results indicated that, in dark conditions, phototropin existed in a dephosphorylated state and the H+-ATPase existed in a phosphorylated state. A pulse of blue light (30 s) induced the phosphorylation of phototropin and the dephosphorylation of the H+-ATPase as determined by the binding behavior of 14-3-3 protein. Phototropin phosphorylation occurred rapidly, followed by the transient gradual dephosphorylation of the H+-ATPase. When the specific flavoprotein inhibitor diphenyleneiodonium and the protein kinase inhibitors K-252a and staurosporine were administered to pulvinar cells, both phototropin phosphorylation and H+-ATPase dephosphorylation were inhibited. The phosphorylation and dephosphorylation exhibited similar fluence rate dependencies to blue light. These results indicated that phototropin may function upstream of the plasma membrane H+-ATPase and decrease the activity of H+-ATPase by dephosphorylation. We provide evidence for the existence of three kinds of phototropins in pulvinar motor cells.
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PMID:Possible involvement of phototropins in leaf movement of kidney bean in response to blue light. 1604 Jun 56

Ganglioside GM1 was shown to increase the viability of PC12 cells exposed to hydrogen peroxide or amyloid beta-peptide (Abeta(25-35)). The PC12 cells transfected with mutant gene (expressing APP(SW)) were found to be more sensitive to oxidative stress than the cells transfected with wild type gene (expressing APP(WT)) or vector-transfected cells, GM1 being effective in enhancing the viability of the cells transfected with mutant gene. The exposure to hydrogen peroxide or Abeta(25-35) results in a partial inactivation of Na(+),K(+)-ATPase in PC12 cells, H(2)O(2) increases MDA accumulation in these cells. But these effects could be partially prevented or practically abolished by GM1 ganglioside. In the presence of the inhibitor of tyrosine kinase of Trk receptors (K-252a) the protective and metabolic effects of GM1 on PC12 cells in conditions of oxidative stress caused by hydrogen peroxide are not observed or are markedly diminished.
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PMID:Neuroprotective effect of ganglioside GM1 on the cytotoxic action of hydrogen peroxide and amyloid beta-peptide in PC12 cells. 1740 55


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