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)

Syntheses and biological activities of 12 N6-substituted adenosine 5'-phosphates and 15 cyclic 3',5'-phosphates are described. Included among these are the cyclic phosphates of the naturally occurring anticodon adjacent modified nucleosides, N6-(delta2-isopentenyl)adenosine and N-(purin-6-ylcarbamoyl)-L-threonine ribonucleoside. Also reported in this paper are the 5'-phosphates and cyclic phosphates of the cytokinins, N6-benzyladenosine, kinetin ribonucleoside, 3-(chloro-trans-2-buten-2-yl)adenosine,6-o-chlorophenylureidopurine ribonucleoside, and 6-allylureidopurine ribonucleoside. The 5'-nucleotides were prepared by direct phosphorylation of the corresponding ribonucleosides with POCl3 and triethyl phosphate. These compounds were converted to the cyclic 3',5'-phosphates by cyclization of the corresponding 5'-nucleotides with dicyclohexylcarbodiimide. Comparison of the cytotoxicity of the ribonucleosides with their 5'-nucleotides and cyclic 3',5'-nucleotides showed that some of the 5'-phosphates and cyclic phosphates were almost as active as the parent nucleosides. The 5'-nucleotides and the cyclic phosphates were more soluble than the parent nucleosides. The cyclic 3',5'-nucleotides were examined as alternate activators of cAMP-dependent protein kinase from beef heart. While all of the analogs studied showed some activity toward this enzyme, several compounds were more effective than cAMP itself. The analogs were also tested as substrates for cyclic 3',5'-nucleotide phosphodiesterase from beef heart. The N6-alkyl-cAMP analogs were poor substrates for the enzyme, while N6-carbamoyl-cAMP derivatives were inert toward this enzyme. These compounds did not inhibit the phosphodiesterase. Some of the cyclic phosphates exhibited marginal effect in the inhibition of glycogen synthesis in skin slices.
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PMID:Synthesis and antitumor activity of 5'-phosphates and cyclic 3',5'-phosphates derived from biologically active nucleosides. 16 81

Adenine requiring mutants of Serratia marcescens SM-6-F'lac+ have been found to grow well in minimal-glucose medium solely supplemented with cAMP. From one of these ade strains double mutants (called ade cpd) were isolated which could no longer utilize cAMP but which still grew on 5'AMP. Dialyzed cell extracts (soluble fraction) of the double mutants, assayed for cAMP phosphodiesterase, were unable to hydrolyze cAMP whereas cell extracts of the parental strains yielded 5'AMP at a rate of 1.6-2.0 mumoles min-1 mg-1 protein. The loss of the phosphodiesterase activity in S. marcescens cpd W 1181 did not cause an accumulation of large amounts of cAMP as was found for the diesterase-negative mutant AB257pc-1 of Escherichia coli. The induced synthesis of beta-galactosidase in mutant cpd W 1181 showed about the same sensitivity to transient and permanent catabolite (glucose) repression as the corresponding cpd+ strain. Starting from S. marcescens cpd W 1182 three independent double mutants (called cpd cya) were isolated which required exogenous cAMP for utilizing various carbohydrates as carbon source, for motility and for the formation of extracellular lipase and the red pigment prodigiosine. The intracellular concentration of cAMP in these mutants, grown in nutrient broth, was 40-60% of that of the parental strain which is about 4 x 10(-4) M. However, the adenylate cyclase in cell extracts of the mutants W 1237 and W 1270 was like that of the corresponding cya+ strain (about 2 x 10(-2) mumoles min-1 mg-1 protein).
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PMID:Mutants of Serratia marcescens lacking cyclic nucleotide phosphodiesterase activity and requiring cyclic 3',5'-AMP for the utilization of various carbohydrates. 16 32

The significance of Ca++ for glucose stimulation of insulin release was studied in an in vitro system with beta-cell-rich pancreatic islets microdissected from oh/ob-mice. There was only a slight depression of cAMP in islets exposed to the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine after withdrawal of Ca++ from the incubation medium. The lack of a stimulatory effect of glucose noted in the absence of extracellular Ca++ is therefore probably accounted for by factors other than impaired adenylate cyclase activity. A rise of extracellular Ca++ above the concentration necessary for obtaining the optimal secretagogic effect of glucose resulted in inhibition of the glucose-stimulated insulin release, leaving basal secretions and islet contents of cAMP unaffected. Evidence was provided in support of the idea that H+ completes for Ca++ in glucose stimulation of insulin release. Both the rate of basal insulin release and that seen after stimulation with glucose were diminished by about 50% after introducing 0.2 mM La+++ in the incubation medium. These observations emphasize the significant role of Ca++ in the regulation of insulin secretion, suggesting that not only a decrease but also an increase of the functionally important intracellular pool(s) of Ca++ can result in a diminished response to glucose.
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PMID:The significance of calcium for glucose stimulation of insulin release. 16 23

The prostaglandin endoperoxide PGH2 (15-hydroxy-9alpha, 11alpha-peroxidoprosta-5,13-dienoic acid), at a concentration of 2.8 x 10(-5) M inhibited basal adenylate cyclase activity 11% and epinephrine-stimulated activity 30 to 35%. PGH2 inhibited epinephrine-stimulated enzyme activity in the presence of 10 mM theophylline, 2.5 mM adenosine 3':5'-monophosphate (cAMP), or in the absence of inhibitors or substrates of the cAMP phosphodiesterase. When the cAMP phosphodiesterase was assayed directly using 62 nM and 1.1 muM cAMP, PGH2 did not affect the 100,000 x g particulate cAMP phosphodiesterase from fat cells. The inhibition of adenylate cyclase by PGH2 was readily reversible. A 6-min preincubation of ghost membranes with PGH2, followed by washing, did not alter subsequent epinephrine-stimulated adenylate cyclase activity. During epinephrine stimulation, the PGH2 inhibition was apparent on initial rates of cAMP synthesis, and the addition of PGH2 to the enzyme system at any point during an assay markedly reduced the rate of cAMP synthesis. Between 2.8 x 10(-7) M and 2.8 x 10(-5) M, PGH2 inhibited epinephrine-stimulated enzyme activity in a concentration-dependent manner. The stimulation of adenylate cyclase by thyroid-stimulating hormone, glucagon, and adrenocorticotropic hormone as well as by epinephrine was antagonized by PGH2, suggesting that PGH2 may be an endogenous feedback regulator of hormone-stimulated lipolysis in adipose tissue.
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PMID:Inhibition of basal and hormone-stimulated adenylate cyclase in adipocyte ghosts by the prostaglandin endoperoxide prostaglandin H2. 16 45

Intact human platelets loaded with 32PO4 contain multiple phosphorylated proteins. Thrombin treatment of intact 32PO4-loaded platelets results in a 2-6-fold increase in phosphorylation of a platelet protein (designated "peak 7" protein) of approximately 40,000 mol wt as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis and by gel filtration on Sephadex G-150. A similar increase in phosphorylation was observed in a platelet protein (designated "peak 9" protein) of approximately 20,000 mol wt. The time for half-maximal phosphorylation of peak 7 and peak 9 protein was 10-14 s. The concentration of thrombin at half-maximal phosphorylation was 0.25 U/ml for both proteins. Prior incubation of platelets with dibutyryl cyclic adenosine 3',5'-monophosphate or prostaglandin E1 inhibited thrombin-induced peak 7 and peak 9 protein phosphorylation. The erythroagglutinating phytohemagglutinin of Phaseolus vulgaris, a non-proteolytic release-inducing agent, induced peak 7 and peak 9 protein phosphorylation. Thus, the characteristics of peak 7 and peak 9 protein phosphorylation are similar to those of the platelet release reaction, suggesting that the phosphorylation of these proteins may play a role in the platelet release reaction. When platelet sonicates or the supernatant fraction from platelet sonicates were incubated with [gamma-32P]ATP there was phosphorylation of both peak 7 and peak 9 proteins. This phosphorylation was unaffected by either added thrombin or adenosine 3',5'-cyclic monophosphate (cAMP) despite the presence of the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine. Thus, the thrombin-dependent phosphorylation depends upon intact platelets. When the supernatant fraction from platelet sonicates was fractionated by histone-Sepharose affinity chromatography, two distinct protein kinase enzymes were resolved, one a cAMP-dependent holoenzyme and the other a cAMP-independent enzyme. The isolated cAMP-dependent enzyme fraction catalyzed the cAMP-(but not thrombin-) stimulated phosphorylation of a protein that co-electrophoresed with peak 7 protein.
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PMID:Thrombin-induced protein phosphorylation in human platelets. 16 98

The effects of starvation, feeding and pentagastrin on gastric mucosal adenylate cyclase (AC) and phosphodiesterase (PDE) activity were studied in the rat. 1. Starvation for 24 hrs and 48 hrs reduced both NaF stimulated and basal AC activities. 2. Feeding of starved rats slowly raised the AC activity up to 430% within 4 hrs after feeding. This effect was more pronounced under basal conditions than with NaF stimulation. 3. A single i.p. injection of pentagastrin (125 mug/kg) caused a stimulation of basal AC lasting 45 min, which was followed by a subsequent decrease in the basal and NaF stimulated enzyme activity. 4. PDE activity was not influenced by starvation and feeding but underwent a transient inhibition by pentagastrin. Accordingly gastric mucosal cAMP levels after starvation, feeding and pentagastrin are regulated by changes in AC and not in PDE activity. The rise in AC activity after feeding appears to be related to functions other than H+ and pepsin secretion.
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PMID:Adenylate cyclase and phosphodiesterase in the rat gastric mucosa after starvation, feeding and pentagastrin. 16 82

Although cyclic adenosine 3':5'-monophosphate (cyclic AMP, cAMP) is known to suppress DNA synthesis is cultured cells and experimental tumors, its role in normal intact tissue has been little explored. This study helps to define the influence of modifiers of cyclic AMP levels on DNA synthesis in rabbit colonic mucosa maintained in short term organ culture system. Base line studies showed that incorporation of [3H]thymidine into DNA was linear for 24 hr and predominantly in mucosal cells, as shown by autoradiography. Colon from a normal fed rabbit showed a gradient of DNA synthesis, lowest in the cecum and increasing to a maximum, 3-fold greater, at the splenic flexure. This pattern was obliterated by fasting, at which time no formed stool remained in the colon, and all colon mucosa incorporated thymidine at the lower level of the right colon. Known modifiers of intracellular cAMP were found to depress colonic DNA synthesis. Theophylline inhibited DNA synthesis by 35% at 0.5 mM concentration and increased intracellular cAMP levels. This inhibition took 10 hr to be manifest and was at least partly reversible. It was by far the most active of the methylxanthines, consistent with its potency as a phosphodiesterase inhibitor. N6,02-dibutyryl cyclic AMP inhibited DNA synthesis at concentrations as low as 0.025 mM, whereas adenosine and sodium butyrate were ineffective up to 1.0 mM. 5'-AMP did inhibit DNA synthesis, but only at 0.1 mM or higher and did not elevate intracellular cAMP levels. Other modifiers of cAMP which were effective included prostaglandins E1, E2, and F2alpha (2 times 10(-6) M) and papaverine (1 muM). Thymidine uptake was not affected by any of these drugs. The intrinsic thymidine pool was estimated at 20 muM by isotope dilution, and was not altered by theophylline. DNA synthesis in rabbit colon can be suppressed by increased cAMP levels within the time period allowed by organ culture. Thus, these drugs that elevated cAMP levels did not seem to suppress DNA synthesis by decreasing intracellular thymidine concentrations.
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PMID:Control of deoxyribonucleic acid synthesis in normal rabbit colonic mucosa. 17 Jan 58

Cyclic AMP (c-AMP) content and turnover were measured in pure preparations of lymphocytes obtained from thymus, spleen and lymph nodes in the Rat. The c-AMP content was determined by combining the methods of Krishna and of Thomson and Appleman, and its turnover was estimated from the activities of adenylcyclase and phosphodiesterase using 3H-adenine. The values, espressed per 10(8) cells, were the lowest for the thymus and the highest for the lymph nodes, while they were intermediary for the spleen. The differences in the c-AMP turnover between the three organs may be correlated with the extent of the mitotic activity of the corresponding lymphocytes, this activity being related inversely to the turnover of c-AMP.
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PMID:[Comparative studies of the cyclic AMP content and renewal of this nucleotide in thymic, splenic and lymph-node lymphocytes in adult rats]. 17 Apr 1

In order to study the metabolism of extracellular 3',5'-adenosine monophosphate (cAMP), rat hearts were perfused and prepubertal rat ovaries incubated with 3H- and 32P-labelled cAMP (0.025-1 muM). The rate of disappearance of cAMP from the medium was determined by "Ba-Zn-precipitation" and degradation products of 3H- and 32P-CAMP by paper chromatography. Both tissues degraded cAMP to 5'-adenosine monophosphate (AMP), but the enzyme kinetic for this phosphodiesterase activity was different (apparent Km value for the heart 3.95 muM and for the ovary 0.2 muM). AMP was further degraded, since also other labelled substances were found in the medium. An uptake of both 3H- and 32P-labelled substance(s) into the heart and the ovary was noticed. Tissue extracts contained several labelled purines, but the amounts of labelled cAMP did not exceed expected amounts in the extracellular space. In the ovary the uptake of cAMP and AMP seemed to be low, since the uptake of labelled substances was inhibited by high concentrations of unlabelled AMP or adenosine. The degradation of 32P-cAMP was unchanged when AMP was present, strongly suggesting that the phosphodiesterase enzyme was acting extracellularly. In the heart added AMP was very rapidly degraded making it impossible to elucidate whether cAMP was degraded extracellularly or not. It is concluded that elimination of extracellular cAMP under physiological conditions can be due to degradation of cAMP by various tissues. At least for the ovary this phosphodiesterase enzyme is extracellularly active.
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PMID:Characterization of the metabolism of exogenous cyclic AMP by perfused rat heart and incubated prepubertal rat ovary. 17 Jul 93

Bencyclane (N-[3-(1-benzyl-cycloheptyloxy)-propyl]-N,N-dimethyl-amine-hydrogenfumarate, Fludilat), inhibits phosphodiesterase(PDE)-activity in vitro similarly to several other smooth muscle relaxants. Compared with papaverine this inhibitory effect of bencyclane on PDE is weak despite of its strong relaxant effect on smooth muscle, which is about equal to that of papaverine. 14C-Bencyclane is accumulated 8-fold in the smooth muscle tissue of bovine coronary arteries, indicating that relaxation is caused by 8-fold higher concentrations in the tissue than in the organ bath. A comparison of (corrected) ED50-values for relaxation with Ki-values for PDE-inhibition obtained with several PDE-inhibitors, including bencyclane, yields a significant correlation between both parameters. Since in subsequent studies in isolated tracheal muscle strips bencyclane at maximum relaxing concentrations did not increase cAMP, which was in contrast to the actions of papaverine or aminophylline, it is likely that bencyclane-induced smooth muscle relaxation is unrelated to inhibition of PDE or cAMP. In the same dose range in which bencyclane relaxes smooth muscles it exerts a non-specific antiadrenergic inhibitory effect, possibly due to its local anesthetic action at the cell membrane. It is also possible that the myocardial inhibitory effect of bencyclane is caused by a direct Ca++-antagonistic mechanism (Fleckenstein et al. 1971).
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PMID:[The mechanism of action of bencyclane on smooth musculature]. 17 Sep 43


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