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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

beta-Adrenergic receptors and the activities of adenylate cyclase, phosphodiesterase and protein kinase were examined in two human glioma cell lines, U 251 and LM, as well as in rat C6 glioma. [3H]Dihydroalprenolol binding to beta-adrenergic receptors was specific, saturable and of high affinity in each cell line. The dissociation constant (Kd) and maximal binding (Bmax) extrapolated from Scatchard curves were Kd = 17.4 +/- 3.2 nM and Bmax = 1110 +/- 197 fmol/mg protein for the U-251 cells; Kd = 14.4 +/- 2.2 nM and Bmax = 655 +/- 105 fmol/mg protein for the LM cells; and Kd = 5.6 +/- 1.1 nM and Bmax = 454 +/- 80 fmol/mg protein for the C6 glioma cells. L-Isoproterenol stimulated cyclic AMP formation in all 3 cell lines. beta-Adrenergic agonists also increased calcium-dependent and calcium non-dependent phosphodiesterase activity in these tumor cells. Cytosolic protein kinase in the 3 cell lines phosphorylated exogenous histone as a substrate. The phosphorylation was enhanced by cyclic AMP. Cytosolic protein kinase also phosphorylated endogenous cytosolic macromolecules. The phosphorylated proteins had molecular weights of 30,000, 51,000 and 90,000 in the two human glioma cell lines. The present results indicate that human glioma cell lines have functional beta-adrenergic receptors linked to adenylate cyclase. These beta-receptors can also regulate phosphodiesterase activity and cyclic AMP in human glioma cells can activate protein kinase and induce the phosphorylation of specific proteins.
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PMID:The beta-adrenergic receptor system in human glioma-derived cell lines: the mode of phosphodiesterase induction and the macromolecules phosphorylated by cyclic AMP-dependent protein kinase. 632 58

Poly(ADP-ribose) glycohydrolase has been purified about 12 300-fold from pig thymus with a recovery of 8.5%. The specific activity of the purified enzyme is 13.8 mumol min -1 mg protein -1. The molecular weight was estimated to be 59 000 by gel filtration through Sephadex G-100 in a non-denaturing solvent. Analysis of the final preparation by sodium dodecyl sulphate gel electrophoresis reveals two protein bands of molecular weight, 61 500 and 67 500. The Km value for poly(ADP-ribose) is estimated to be 1.8 microM monomer units. The enzyme preparation is free from phosphodiesterase, NADase and ADP-ribosyltransferase activities. The purified enzyme is inhibited by cyclic AMP, ADP-ribose, naphthylamine, histones H1, H2A, H2B, H3, polylysine, polyarginine, polyornithine and protamine. The inhibition by histone is relieved by an equal mass of DNA. Single-stranded DNA, poly(A), poly(I) and polyvinyl sulphate were inhibitory, but double-stranded DNA was not inhibitory.
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PMID:Isolation and purification of poly(ADP-ribose) glycohydrolase from pig thymus. 661 43

Two SH-dependent proteinases (I and II) active in neutral media were isolated from bovine spleen and purified to apparent homogeneity. The histone-hydrolyzing activity of proteinase I was increased 3500-fold as compared to that of the original extract. Proteinase I hydrolyzed a variety of proteins (histones, azocasein, hemoglobin, collagen) but did not hydrolyze low molecular weight synthetic substrates, such as BAPA, BANA, BAEE, ATEE, Leu-beta-NA, Arg-beta-Na and Ala-beta-NA. The molecular weight of the enzyme as determined by SDS electrophoresis was found to be about 23,000. Isoelectrofocusing of the enzyme resulted in one major component with pI of 6.05 and in two minor components with pI of 6.2 and 6.4. Proteinase II hydrolyzed Leu-beta-NA, Arg-beta-NA and Ala-beta-NA but did not hydrolyze beta-naphthylamides of dicarboxylic acids and Gly-Phe-beta-Na. This proteinase split BANA and histone and very slowly split azocasein and collagen. Proteinase II was found to have a molecular weight of 30 000 and a pI of 6.8-6.9. Proteinase I inactivated fructose-1.6-diphosphate aldolase, partly inactivated glucose-6-phosphatase dehydrogenase and caused activation of phosphodiesterase of cyclic nucleotides. Proteinase II had no effect on the activity of the above enzymes. A comparison of proteinase I and II with enzymes described in literature demonstrated that the former was cathepsin L, while the latter was cathepsin H from spleen.
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PMID:[Characteristics of two thiol proteinases from spleen active in neutral media]. 675 12

To determine the presence of cone or rod cyclic GMP phosphodiesterase (EC 3.1.4.17) in the mammalian pineal, extracts from adult rat and bovine pineals were injected onto a Mono Q anion-exchange HPLC column and eluted with an NaCl linear gradient. Fractions were immunoadsorbed with monoclonal antibodies specific to rod and cone phosphodiesterases (ROS-1) and to calmodulin-phosphodiesterase complexes (ACC). Profiles were assayed with 10 mumol/L [3H]cyclic GMP in the presence of calcium-calmodulin, histone, or trypsin. Rat and bovine pineals displayed a single peak of activity recognized by ROS-1, which corresponded to the activity of the cone but not to the rod in bovine retina. ROS-1 immunoadsorbed approximately 80% of the activity in the 60-day-old rat pineal but only 26% of the activity in bovine pineal. ACC immunoadsorbed the remaining activity in both species. Western blot analysis of rat pineal extracts revealed three polypeptides of approximately 87, 15, and 10 kDa when probed with a rod/cone phosphodiesterase-specific antiserum. The specific activity of the cone-like phosphodiesterase in 10-day-old rat pineals was twice that of this isozyme in the bovine retina and 150 times that in the bovine pineal. The specific activity of phosphodiesterase in rat pineals decreased with age. We conclude that an enzyme with biochemical and antigenic characteristics similar to cone, but distinct from rod phosphodiesterase, is present in bovine and rat pineals.
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PMID:The mammalian pineal expresses the cone but not the rod cyclic GMP phosphodiesterase. 764 86

Recently the cDNA for two different forms of TNF receptor, with gene products of molecular masses of 60 and 80 kDa, have been cloned. In the present report, we investigated the effects of phorbol ester and dibutyryl cAMP on the regulation of the transcript for each type of TNF receptor in U-937 cells. Our results indicate that exposure of these cells to either phorbol ester or dibutyryl cAMP increases the steady state mRNA levels of the 80 kDa form. This effect is dose- and time-dependent. The induction of the p80 receptor transcript by PMA and dibutyryl cAMP was additive suggesting independent mechanisms of induction. Under identical conditions, both agents failed to induce the transcript for the p60 form of the TNF receptor. As demonstrated by actinomycin D pulse-chase experiment, the mRNA for the p80 receptor was found to be highly stable with an approximate half-life of 16 h. No significant change in the half-life was observed when cells were treated with phorbol ester. The mechanisms by which phorbol ester and dibutyryl cAMP induce the upregulation of p80 receptor mRNA appear to be different. Induction of receptor transcript by cycloheximide suggests the presence of a labile repressor protein. Interestingly, the effect of cycloheximide on the induction of the p80 mRNA was found to be additive with that of dibutyryl cAMP but not with phorbol ester. 1-(5-Isoquinolinylsufonyl)-2-methylpiperazine (H7) and N[2-(methylamino) ethyl]-5-isoquinolinesulfonamide (H-8), inhibitors of protein kinase C and protein kinase A, respectively, both inhibited the phorbol ester-mediated induction of the p80-transcript but not that mediated through dibutyryl cAMP. Since dibutyryl cAMP undergoes intracellular dissociation into cAMP and butyric acid, we found that exposure of cells to sodium butyrate alone could induce p80 mRNA in a dose-dependent manner, thus suggesting the role of histone hyperacetylation. Furthermore forskolin treatment, an intracellular inducer of cAMP, increased the receptor transcript level whereas isobutylmethylxanthine, an inhibitor of phosphodiesterase, had no effect. Interestingly, while the p80 form of the TNF receptor mRNA levels was elevated by both phorbol ester and dibutyryl cAMP, only dibutyryl cAMP increased the TNF binding; phorbol ester treatment decreased the binding activity. Thus, our results demonstrate that the genes for the two forms of TNF receptors are differentially regulated. Furthermore, the mechanism of regulation by PMA differs from that by dibutyryl cAMP.
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PMID:Regulation of two forms of the TNF receptors by phorbol ester and dibutyryl cyclic adenosine 3',5'-monophosphate in human histiocytic lymphoma cell line U-937. 768 79

Cyclic AMP-dependent protein kinase is conventionally assayed by measuring the incorporation of radiolabeled phosphate into a histone substrate. Here the assay of the protein kinase is carried out by the positive-ion fast atom bombardment mass spectrometric analysis of the enzyme incubation mixture after the reaction has been terminated. The data obtained are in good agreement with those obtained from the conventional radiometric assay of the same kinase preparation. The inherent advantage of this mass spectrometric assay is the capacity for multiple component monitoring; in addition to the kinase activity, the ability of the enzyme to bind cyclic nucleotides, together with integral ATPase and phosphodiesterase activity, can also be estimated from the same spectra.
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PMID:Assay of adenosine 3',5'-cyclic monophosphate-dependent protein kinase activity by quantitative fast atom bombardment mass spectrometry. 771 89

Cyclic GMP-dependent protein kinase (cGPK) activity was determined in rat pulmonary microvascular endothelial cells (RPMVEC) using cGMP-stimulated phosphorylation of BPDEtide and histone F2B substrates in the presence of PKI [peptide inhibitor of cAMP-dependent protein kinase (cAPK)]. RPMVEC cGPK activity was localized to the 100,000 x g cytosolic fraction. The EC50 for cGMP activation in the presence of PKI was 0.16 microM and H-89 inhibition under similar conditions showed an IC50 value of 0.16 microM. Anion-exchange chromatography of RPMVEC and rat lung cytosolic fractions showed separation of the cGMP-dependent from the cGMP-independent protein kinase activity and similar elution conductivities. Further, Western blots of RPMVEC active DEAE-Trisacryl fractions showed immunoreactivity using bovine Type I cGPK antiserum. Preliminary studies reveal six potential substrates phosphorylated by cGPK in RPMVEC. These studies describe an endothelial cell (EC) cGMP-receptor, cGPK, in addition to cGMP-activated (Type II) phosphodiesterase (PDE).
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PMID:Cyclic GMP-dependent protein kinase activity in rat pulmonary microvascular endothelial cells. 804 44

Sea urchin CS histone variants are electrophoretically heterogeneous when analyzed in two dimensional polyacrylamide gels (2D-PAGE). Previous results suggested that this heterogeneity is due to the poly (ADP-ribosylation) of these proteins. Consequently, native CS histone variants were subjected to different treatments to remove the ADP-ribose moiety. The incubation in 1 M hydroxylamine was not effective in eliminating the polymers of ADP-ribose from CS variants, and the treatment with sodium hydroxide was deleterious to the proteins. In contrast, the ADP-ribose moiety was successfully removed from the CS variants by incubation with phosphodiesterase (PDE). To eliminate contamination of CS histone variants with PDE extract, the enzyme was covalently bound to Sepharose 4B prior to its utilization. Treatment of native CS histone variants with this immobilized phosphodiesterase removed around 85% of the total ADP-ribose moiety from these proteins. After S-PDE treatment the complex electrophoretic pattern of CS histone variants in 2-D PAGE decreases to five major fractions. From these results we conclude that the electrophoretic heterogeneity of native CS histone variants is mainly due to the extent to which five main CS histone variants are poly(ADP)-ribosylated).
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PMID:Decreased heterogeneity of CS histone variants after hydrolysis of the ADP-ribose moiety. 872 60

Autotaxin (ATX) is an extracellular enzyme and an autocrine motility factor that stimulates pertussis toxin-sensitive chemotaxis in human melanoma cells at picomolar to nanomolar concentrations. This 125-kDa glycoprotein contains a peptide sequence identified as the catalytic site in type I alkaline phosphodiesterases (PDEs), and it possesses 5'-nucleotide PDE (EC 3.1.4.1) activity (Stracke, M. L., Krutzsch, H. C., Unsworth, E. J., Arestad, A., Cioce, V., Schiffmann, E., and Liotta, L. (1992) J. Biol. Chem. 267, 2524-2529; Murata, J., Lee, H. Y., Clair, T., Krutsch, H. C., Arestad, A. A., Sobel, M. E., Liotta, L. A., and Stracke, M. L. (1994) J. Biol. Chem. 269, 30479-30484). ATX binds ATP and is phosphorylated only on threonine. Thr210 at the PDE active site of ATX is required for phosphorylation, 5'-nucleotide PDE, and motility-stimulating activities (Lee, H. Y., Clair, T., Mulvaney, P. T., Woodhouse, E. C., Aznavoorian, S., Liotta, L. A., and Stracke, M. L. (1996) J. Biol. Chem. 271, 24408-24412). In this article we report that the phosphorylation of ATX is a transient event, being stable at 0 degrees C but unstable at 37 degrees C, and that ATX has adenosine-5'-triphosphatase (ATPase; EC 3.6.1.3) and ATP pyrophosphatase (EC 3.6.1.8) activities. Thus ATX catalyzes the hydrolysis of the phosphodiester bond on either side of the beta-phosphate of ATP. ATX also catalyzes the hydrolysis of GTP to GDP and GMP, of either AMP or PPi to Pi, and the hydrolysis of NAD to AMP, and each of these substrates can serve as a phosphate donor in the phosphorylation of ATX. ATX possesses no detectable protein kinase activity toward histone, myelin basic protein, or casein. These results lead to the proposal that ATX is capable of at least two alternative reaction mechanisms, threonine (T-type) ATPase and 5'-nucleotide PDE/ATP pyrophosphatase, with a common site (Thr210) for the formation of covalently bound reaction intermediates threonine phosphate and threonine adenylate, respectively.
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PMID:Autotaxin is an exoenzyme possessing 5'-nucleotide phosphodiesterase/ATP pyrophosphatase and ATPase activities. 899 94

The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose theophylline enhances HDAC activity in epithelial cells and macrophages. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes.
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PMID:A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. 1207 Mar 53


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