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)

The effects of the alpha-adrenergic agonist phenylephrine on the levels of adenosine 3':5'-monophosphate (cAMP) and the activity of the cAMP-dependent protein kinase in isolated rat liver parenchymal cells were studied. Cyclic AMP was very slightly (5 to 13%) increased in cells incubated with phenylephrine at a concentration (10(-5) M) which was maximally effective on glycogenolysis and gluconeogenesis. However, the increase was significant only at 5 min. Cyclic AMP levels with 10(-5) M phenylephrine measured at this time were reduced by the beta-adrenergic antagonist propranolol, but were unaffected by the alpha-blocker phenoxybenzamine, indicating that the elevation was due to weak beta activity of the agonist. When doses of glucagon, epinephrine, and phenylephrine which produced the same stimulation of glycogenolysis or gluconeogenesis were added to the same batches of cells, there were marked rises in cAMP with glucagon, minimal increases with epinephrine, and little or no changes with phenylephrine, indicating that the two catecholamine stimulated these processes largely by mechanisms not involving cAMP accumulation. DEAE-cellulose chromatography of homogenates of liver cells revealed two major peaks of cAMP-dependent protein kinase activity. These eluted at similar salt concentrations as the type I and II isozymes from rat heart. Optimal conditions for preservation of hormone effects on the activity of the enzyme in the cells were determined. High concentrations of phenylephrine (10(-5) M and 10(-4) M) produced a small increase (10 tp 16%) in the activity ratio (-cAMP/+cAMP) of the enzyme. This was abolished by propranolol, but not by phenoxybenzamine, indicating that it was due to weak beta activity of the agonist. The increase in the activity ratio of the kinase with 10(-5) M phenylephrine was much smaller than that produced by a glycogenolytically equivalent dose of glucagon. The changes in protein kinase induced by phenylephrine and the blockers and by glucagon were thus consistent with those in cAMP. Theophylline and 1-methyl-3-isobutylxanthine, which inhibit cAMP phosphodiesterase, potentiated the effects of phenylephrine on glycogenolysis and gluconeogenesis. The potentiations were blocked by phenoxybenzamine, but not by propranolol. Methylisobutylxanthine increased the levels of cAMP and enhanced the activation of protein kinase in cells incubated with phenylephrine. These effects were diminished or abolished by propanolol, but were unaffected by phenoxybenzamine. It is concluded from these data that alpha-adrenergic activation of glycogenolysis and gluconeogenesis in isolated rat liver parenchymal cells occurs by mechanisms not involving an increase in total cellular cAMP or activation of the cAMP-dependent protein kinase. The results also show that phosphodiesterase inhibitors potentiate alpha-adrenergic actions in hepatocytes mainly by a mechanism(s) not involving a rise in cAMP.
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PMID:Studies on the alpha-andrenergic activation of hepatic glucose output. II. Investigation of the roles of adenosine 3':5'-monophosphate and adenosine 3':5'-monophosphate-dependent protein kinase in the actions of phenylephrine in isolated hepatocytes. 0 57

Preincubation of isolated epididymal fat cells with dexamethasone or treating rats with cortisol enhances the epinephrine-stimulated lipolysis of the cells as well as cAMP-dependent protein kinase activity in homogenates of these fat cell suspensions. During maximal inhibition of phosphodiesterase activity by theophylline or dibutyryl cAMP, this potentiating effect of glucocorticoids on the fat cells was also present. There was no lowering of the total phosphodiesterase activity in homogenates of fat cell suspensions of rats that were treated with cortisol, but there appeared to be a lower activity of the low KM phosphodiesterase activity. It is concluded that induction of protein kinase by glucocorticoid hormone is responsible for its special type of stimulative action on lipolysis.
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PMID:The mechanism of the potentiating effect of glucocorticoids on catecholamine-induced lipolysis. 16 65

A number of 2-substituted cyclic nucleotide derivatives were synthesized and investigated as activators of cAMP-dependent protein kinase and as substrates for and inhibitors of cAMP phosphodiesterase. Ring closure of 5-amino-1-beta-D-ribofuranosylimidazol-4-carboxamide cyclic 3',5'-phosphate (1) with various aldehydes according to a new procedure (Meyer, R. B., Jr., Shuman, D.A., and Robins, R. K. (1974), J. Am. Chem. Soc. 96, 4962) gave new derivatives of adenosine cyclic 3',5'-phosphate with the following 2-substituents: n-propyl, n-hexl, n-octyl, n-decyl, styryl, o-methoxyphenyl, and 2-thienyl. Alkylation of 2-mercaptoadenosine cyclic 3',5'-phosphate (20, Meyer et al., 1974) gave new cAMP derivatives with the following 2-substituent: ethylthio, n-propylthio, isopropylthio, allylthio, n-decylthio, and benzylthio. Deamination of 2-methyl-,2-n-butyl-, and 2-ethylthioadenosine cyclic 3',5'-phosphate. Using multiple regression analysis, a striking relationship was found between the relative potency of the compounds as activators of bovine brain cAMP-dependent protein kinase and parameters describing the hydrophobic, steric, and electronic character of the substituents on these compounds. All compounds were substrates for a cyclic nucleotide phosphodiesterase preparation from rabbit kidney. Additionally, the compounds were as a group, good inhibitors of the hydrolysis of cAMP by phosphodiesterase preparations from rabbit lung, beef heart, and dog heart.
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PMID:2-substituted derivatives of adenosine and inosine cyclic 3',5'-phosphate. Synthesis, enzymic activity, and analysis of the structural requirements of the binding locale of the 2-substituent on bovine brain protein kinase. 16 24

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

Derivatives of adenosine 3',5'-cyclic phosphate (cAMP) with modifications in both the 2' and the 8 positions were synthesized and their enzymic activities as activators of cAMP-dependent protein kinase and as substrates for and inhibitors of cAMP phosphodiesterases were determined. Three types of derivatives were investigated: 8-substituted derivatives of O2'-Bt-cAMP, 8-substituted derivatives of 9-beta-D-arabinofuranosyladenine 3',5'-cyclic phosphate (ara-cAMP), and 8-substituted derivatives of 8,2'-anhydro-9-beta-D-arabinofuranosyladenine 3,'5'-cyclic phosphate (8,2'-anhydro-cAMP). The 8-substituted O2'-Bt-cAMP derivatives were synthesized by acylation of the preformed 8-substituted cAMP (8-HS-cAMP, 8-MeS-cAMP, and 8-PhCH2S-cAMP). 8-Br-O2'-tosyl-cAMP was sued as an intermediate for the preparation of 8,2'-anhydro-cAMP derivatives (8-HO-, 8-SH-, 8-H2N-, and 8-H3 CHN derivatives of 8,2'-anhydro-cAMP). 8-Substituted ara-cAMP derivatives were obtained by ring opening of 8-HO-8,2'-anhydro-cAMP with H+/H2O, NH3/MeOH, or MeONa/MeOH (to yield the 8-HO-, 8-H2N-, and 8-MeO-ara-cAMP derivatives). All of these doubly modified derivatives of cAMP are less than one-hundredth as active as cAMP at activating protein kinase and did not serve as substrates for the phosphodiesterase. These data show that the general inactivity of 2' derivatives of cAMP with kinase was not overcome by addition of an 8-substituent, even though many 8-substituted derivatives of cAMP activate the kinase more efficiently than does cAMP itself. In addition they show that while 2'-modification were tolerated by the phosphodiesterase, addition of an 8-substituent countermanded the allowable 2'-modification. The 8-substituted derivates of 02'-Bt-cAMP were found in general to be slightly better inhibitors of phosphodiesterase than the parent compounds containing no o2'-Bt substitution. As a group, the 8-substituted ara-cAMP derivatives were poorer inhibitors of phosphodiesterase than 8-substituted cAMP derivatives while the 8,2'-anhydro-cAMP derivatives were much poorer inhibitors than the 8-substituted ara-cAMP derivatives.
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PMID:8-Substituted derivatives of adenosine 3',5'-cyclic phosphate require an unsubstituted 2'-hydroxyl group in the ribo configuration for biological activity. 17 Sep 58

Compared to the wild-type parental line of S49 mouse lymphoma cells, intact cells of a mutant line (kin.A) are 10-fold less sensititive to biologic effects of exogenous cyclic adenosine 3':5'-monophophosphate (cAMP), such as induction of cAMP phosphodiesterase, cell cycle-specific growth inhibition, and cytolysis. The cAMP-dependent protein kinase (ATP:protein phosphotransferase; EC 2.7.1.37) activity of kin.A cells exhibits an apparent Ka for activation by cAMP 10-fold greater than that of wild type, and is much more resistant to inactivation by heat. These differences between the wild-type and mutant enzymes persist through a high degree of purification, suggesting a structural alteration in the kin.A holoenzyme. Heterologous reconstitution experiments, using separated R and C subunits of the wild-type and kin.A cAMP-dependent kinases, show that the altered cAMP affinity and thermolability are conferred by the R component of the kin.A enzyme. These results are most consistent with a structural mutation in the kin.A gene coding for the R subunit of cAMP-dependent protein kinase. Evidence for a structural mutation helps to define one mechanism of heritable variation in cultured somatic cells. The phenotype produced by the kin.A structural mutation also greatly strengthens the conslusion that cAMP-dependent protein kinase is essential for cAMP regulation of growth and enzyme induction in intact S49 cells.
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PMID:A structural gene mutation affecting the regulatory subunit of cyclic AMP-dependent protein kinase in mouse lymphoma cells. 17 91

Experiments with cold exposure confirmed previous studies indicating that the endogenous protein acitvator of phosphodiesterase (PDEA) isolated by Cheung participates in the in vivo regulation of 3':5'-cyclic adenosine monophosphate (cAMP) in adrenal medulla. This activator of cAMP phosphodiesterase (PDE) (3':5'-cyclic-AMP 5'-nucleotidohydrolase, EC 3.1.4.17) is present in the particulate as well as the soluble fractions of rat brain. It was found that a purified cAMP-dependent protein kinase (ATP:protein phosphotransferase, EC 2.7.1.37), in the presence of ATP and cAMP, stimulates 3-fold the release of PDEA from the particulate fraction of rat brain and adrenal medulla. The substrate for this phosphorylation could be either a membrane protein that binds PDEA or PDEA itself. In vivo evidence, however, obtained by injecting rats intraventricularly with [gamma-32P]ATP, indicates that the PDEA does not contain radioactive phosphate in its structure. Also, PDEA could not be phosphorylated by protein kinase in vitro. The following mechanism is postulated: when the intracellular content of cAMP increases it activates a protein kinase which phosphorylates a PDEA-binding membrane protein and releases PDEA. In turn this binds to activator-deficient high Km PDE and decreases its Km to facilitate the hydrolysis of the increased concentration of cAMP.
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PMID:Regulation of transsynaptically elicited increase of 3':5'-cyclic AMP by endogenous phosphodiesterase activator. 17 3

The sequenc of biochemical events associated with the action of follicle-stimulating hormone (FSH) in the testis has been investigated using a Sertoli cell-enriched testis model system. The Sertoli cell-encriched testis, created by irradiation of male rats in utero, is devoid of germinal elements but contains a normal complement of supportive Sertoli cells. Comparison of the Sertoli cell-enriched testis with normal testis, demonstrates that the two types of testes contain equal numbers of FSH specific receptors, judged by the binding of labeled hormone. In addition, FSH over a concentration range from 6 X 10(-11) to 6 X 10(-9)M will stimulate the production of adenosine 3',5' monophosphate (cAMP) in the Sertoli cell-enriched testis in a manner indistinguishable from that of the normal testis. Incubation of Sertoli cell enriched testis also results in the activation of soluble cAMP-dependent protein kinase. This response to FSH is dependent upon the age of the animal and disappears at about 32 days of age. While sensitivity to the hormone can still be detected in mature Sertoli cell-enriched animals by the addition of the phosphodiesterase inhibitor 1-methyl-3-isobutyl-xanthine, no detectable increase in phosphodiesterase activity is apparent after 30 days of age. Injection of FSH into Sertoli cell-enriched animals results in an increase in total testicular protein synthesis as well as in the production of the Sertoli cell-specific protein, androgen-binding protein within 30 minutes. Furthermore, while hypophysectomy of Sertoli cell-enriched animals result in a decline of the testicular concentration of androgen-binding protein, the injection of FSH will stimulate and maintain the levels of androgen-binding protein in such animals. These results demonstrate that the Sertoli cell-enriched testis is capable of carrying out the sequence of biochemical events previously described for FSH in the normal testis and therefore, suggest that the Sertoli cell is the primary target cell for FSH action.
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PMID:Biochemical actions of follice-stimulating hormone in the sertoli cell of the rat testis. 17 98

1, 8-Disubstituted derivatives of adenosine cyclic 3', 5'-phosphate (cAMP) were synthesized by N-oxidation or N-methylation of previously reported 8-substituted cAMP derivatives to yield 8-bromoadenosine cyclic 3', 5'-phosphate 1-oxide and 8-(benzylthio)-1-methyladenosine cyclic 3', 5'-phosphate. Substituents were introduced into the 8 position of 2-methyladenosine cyclic 3', 5'-phosphate and 2-butyladenosine cyclic 3', 5'-phosphate by bromination, followed by treatment with sodium benzylmercaptide, sodium p-chlorothiophenolate, or, in the former case, sodium azide. Each of the 1,8- and 2,8-disubstituted derivatives of cAMP was tested as activators of cAMP-dependent protein kinase and as substrates for the inhibitors of cyclic nucleotide phosphodiesterases. Depending on the substitutions, examples were found where the disubstituted derivatives were either more active, equally as active or less active than the monosubstituted parent compounds as protein kinase activators. For the compounds reported, 8-substitution completely or substantially eliminated the ability of 1- or 2-substituted derivatives of cAMP to serve as substrates for phosphodiesterase and diminished the ability of these latter derivatives to inhibit cAMP hydrolysis.
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PMID:Synthesis of some 1, 8- and 2, 8-disubstituted derivatives of adenosine cyclic 3', 5'-phosphate and their interaction with some enzymes of cAMP metabolism. 17 60

Membranes of rat caudate nucleus contain a dopamine-dependent adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] and a Ca++ binding protein that activates phosphodiesterase (3':5'-cyclic-AMP 5'-nucleotidohydrolase, EC 3.1.4.17). This activator can be released from the membranes by a phosphorylation with a 3':5' cAMP-dependent protein kinase (ATP-protein phosphotransferase, EC 2.7.1.37). Under the conditions of membrane phosphorylation and activator release, dopamine fails to activate striatal adenylate cyclase. The basal activity of this enzyme is not decreased by the release of the protein activator but the activation by NaF is reduced. Adenylate cyclase is not phosphorylated when the dopamine activation is blocked after the release of the activator, but other membrane proteins are phosphorylated. It is postulated that the endogenous protein stored in striatal membranes can regulate the intracellular concentration of cAMP by an activation of adenylate cyclase while stored in striatal membrane, and by an activation of phosphodiesterase when released into the cytosol after membrane phosphorylation.
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PMID:Regulation of dopamine stimulation of striatal adenylate cyclase by an endogenous Ca++ -binding protein. 18 77


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