Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. To test the hypothesis that inhibition of cyclic nucleotide phosphodiesterase is the major mechanism of the bronchodilator action of theophylline in reversible airways disease, the effects of therapeutic plasma levels of the drug on human pulmonary phosphodiesterase activity were examined. 2. Therapeutic levels of theophylline inhibited the phosphodiesterase-catalysed hydrolysis of adenosine cyclic 3',5'-monophosphate (cAMP) and guanosine cyclic 3',5'-monophosphate (cGMP), but the percentage inhibition was relatively small. 3. The results, while supporting the assumed contribution of phosphodiesterase inhibition to the overall mechanism of theophylline action, suggest that other presently unknown factors must also be taken into consideration to fully explain the beneficial effects of theophylline in reversible airways disease.
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PMID:Inhibition of human pulmonary phosphodiesterase activity by therapeutic levels of theophylline. 21 63

1. Reactive Blue 2 (Cibacron Blue 3G-A) is a competitive inhibitor of bovine heart cyclic nucleotide phosphodiesterase (K(i) 0.3mum). The K(i) increases with increasing temperature, suggesting that hydrophobic interactions are not largely responsible for the binding of the dye. Another 25 sulphonated aromatic dyes are also competitive inhibitors of the cyclic nucleotide phosphodiesterase (K(i) values in the range of 0.06-13.6mum). 2. These dyes (covalently linked to Dextran 40) inhibit bovine heart cyclic nucleotide phosphodiesterase. Reactive Blue 2 (covalently linked to Dextran 40) is a competitive inhibitor of the phosphodiesterase (K(i) 0.4mum). 3. Bovine heart cyclic nucleotide phosphodiesterase is retained on a column of Reactive Blue 2-Sephacryl S-200 and can be eluted from the column by 3':5'-cyclic AMP. 4. A variety of the dyes (either free or covalently linked to Dextran 40) are competitive inhibitors of rabbit muscle lactate dehydrogenase. 5. The effectiveness of a wide range of structurally dissimilar dyes as competitive inhibitors of lactate dehydrogenase and cyclic nucleotide phosphodiesterase compromises proposals for the use of Reactive Blue 2 as a specific probe for the dinucleotide-binding structural domain present in many dehydrogenases and kinases. Detailed information of the various dyes used has been deposited as Supplementary Publication SUP 50089 (7 pages) at the British Library Lending Division, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1978) 169, 5.
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PMID:The specific interaction of cibacron and related dyes with cyclic nucleotide phosphodiesterase and lactate dehydrogenase. 21 44

1. A heat-stable modulator protein was partially purified from mouse epidermis. The protein stimulated modulator-depleted cyclic AMP phosphodiesterase from bovine brain in the presence of Ca2+. 2. DEAE-cellulose chromatography of epidermal extracts demonstrated the presence of two main phosphodiesterase activities that hydrolysed both cyclic AMP and cyclic GMP. A minor peak was eluted between 0.1 and 0.3 M-sodium acetate and a major peak was eluted between 0.3 and 0.45 M-sodium acetate. 3. Cyclic AMP phosphodiesterase activity eluted at low salt concentrations was markedly activated by the epidermal modulator protein in the presence of Ca2+. Storage of the enzyme led to a decrease in its sensitivity to the protein modulator. 4. Treatment of mouse skin with the tumour promoter 12-O-tetradecanoylphorbol 13-acetate, which leads to an increase in epidermal cyclic nucleotide phosphodiesterase activity, did not alter the amount of modulator present in soluble epidermal extracts. The tumour promoter decreased the amount of modulator extractable from particulate epidermal preparations with Triton X-100.
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PMID:Calcium-dependent protein modulator of cyclic nucleotide phosphodiesterases from mouse epidermis. 21 52

Properties of cyclic 3',5'-nucleotide phosphodiesterase in the 100,500 X g supernatant of the bovine thyroid were investigated. The enzyme activity was measured by a radioisotopic method using an anionic-exchange resin, and it was found that the activity was stimulated by Mg2+. Sephadex G-200 gel filtration separated the supernatant into an activating factor, which required the presence of Ca2+, and an enzyme form dependent on the factor. The molecular weights were estimated to be 25,000 and 130,000, respectively. There appeared to be another enzyme form of cAMP phosphodiesterase with different dependence on the activating factor as suggested by gel filtration, but this enzyme form could not be clearly separated. cGMP phosphodiesterase purified by gel filtration showed biphasic kinetic behavior in the absence of Ca2+ and the activating factor, whereas, in their presence, the Lineweaver-Burk plot gave a single Km. The activating mechanism of phosphodiesterase may play a role in the control of concentrations of intracellular cyclic 3',5'-nucleotides in the bovine thyroid.
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PMID:Phosphodiesterase and its Ca2+-dependent activating factor in bovine thyroid. 21 80

The presence and properties of cyclic 3',5'-adenosine monophosphate phosphodiesterase (cAMP-PDIE) and cyclic 3',5'-guanosine monophosphate phosphodiesterase (cGMP-PDIE) were studied in glomeruli isolated from rat renal cortex by sieving and density gradient centrifugation. The specific activity of cGMP-PDIE was higher than the specific activity of cAMP-PDIE in glomeruli; in tubules and renal cortical slices, the specific activity of cAMP-PDIE was higher than that of cGMP-PDIE. In homogenates, X 100,000g supernate of homogenate (cytosol) and X 100,000g pellet (membrane fraction) from glomeruli, the specific activity of cGMP-PDIE was significantly higher than it was in analogous preparations from tubules or renal cortical slices. Cyclic 3',5'-GMP (10(-6)M to 10(-5)M) stimulated glomerular cAMP-PDIE, but it was without effect on cAMP-PDIE from tubules. Structural analogs of cyclic 3',5'-GMP or 5'-GMP did not stimulate glomerular cAMP-PDIE. Cyclic 3',5'-AMP slightly inhibited cGMP-PDIE from both glomeruli and tubules. N6-,2'-0-dibutyryl cyclic 3',5'-AMP inhibited cAMP-PDIE, but not cGMP-PDIE. The addition of calcium increased the activity of cGMP-PDIE, mainly in tubules, but was without effect on cAMP-PDIE. These results suggest the predominance of cyclic 3',5'-GMP catabolism in glomeruli in comparison with other cortical structures, and they demonstrate that both the specific activities and regulatory properties of cyclic nucleotide phosphodiesterase in glomeruli differ markedly from tubules or unfractionated renal cortical tissue.
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PMID:Cyclic nucleotide phosphodiesterases in glomeruli of rat renal cortex. 22 Apr 59

The Ca2+-dependent regulator protein (CDR) of cyclic nucleotide phosphodiesterase (PDE) was reported to be a Ca2+-dependent regulator of microtubule (MT) assembly in the preceding paper. In this paper, the binding of Ca2+-CDR complex to tubulin dimer was investigated in order to elucidate the Ca2+-dependent inhibitory action of CDR on MT assembly. Purified microtubular proteins (PMPs) isolated from porcine brain did not affect the ability of CDR to activate Ca2+-activatable PDE, and did not include any inhibitory protein of Ca2+-activatable PDE. The binding of CDR to the tubulin dimer was observed on Sephadex G-200 gel filtration and ammonium sulfate fractionation in a Ca2+-dependent manner. CDR did not bind to microtubule associated proteins. We now assume that Ca2+-dependent inhibition of MT assembly by CDR is due to the binding of CDR to tubulin dimer in a Ca2+-dependent manner.
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PMID:The interactions between calcium-dependent regulator protein of cyclic nucleotide phosphodiesterase and microtubule proteins. II. Association of calcium-dependent regulator protein with tubulin dimer. 22 51

Some characteristics of the cyclic 3',5'-nucleotide phosphodiesterase (phosphodiesterase) activity associated with the synaptosomal plasma membrane (synaptic membrane) and the synaptic junction fractions of rat brain are reported. Kinetic analysis revealed that only one type of phosphodiesterase activity, with a Km of 2.10 19(-4) M for cyclic AMP, is associated with both fractions. The specific activities of the phosphodiesterase in synaptic membranes and synaptic junctions have been estimated at 23.4 nmol/min per mg protein and 22.5 nmol/min per mg protein, respectively. The synaptic junction-associated activity undergoes a 30% stimulation by Ca2+ while no Ca2+ sensitivity of the synaptic membrane-associated activity could be detected. Cytochemical studies performed on the synaptic membrane fraction demonstrated a predominant localization of phosphodiesterase activity over postsynaptic densities, while dense deposits were sometimes observed over the synaptic cleft region.
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PMID:Characterization of the cyclic 3',5'-nucleotide phosphodiesterase actitivty associated with synaptosomal plasma membranes and synaptic junctions. 22 47

Cyclic nucleotide phosphodiesterase activity (3':5'-cyclic-AMP 5'-nucleotidohydrolase, EC 3.1.4.17), which is activatable by Ca(2+)-dependent regulator protein (CDR), has been identified in cycled microtubule preparations from bovine brain. By using various methods to fractionate the microtubule preparation into subfractions (e.g., phosphocellulose chromatography to obtain purified 6S tubulin and soluble microtubule-associated proteins, and gel exclusion chromatography on Bio-Gel A-150m to obtain 10-nm filaments), we found that all the fractions exhibited some enzymic activity, but that most of the phosphodiesterase activity was localized in the 10-nm filament fraction. By using cyclic GMP as substrate, a specific activity of 921 +/- 168 pmol/mg of filament protein.min was determined. Also, 10-nm filaments were prepared directly from brain homogenates by differential centrifugation and gel exclusion chromatography. This fraction also contained phosphodiesterase activity but of slightly lower specific activity (752 +/- 9 pmol/mg of protein.min). The filament-associated enzymic activity was stable during storage (-70 degrees C) and to several salt extractions at moderate ionic strength (0.5 M); the latter finding indicates that the phosphodiesterase is not adsorbed to the filaments via nonspecific electrostatic interactions. Although a chelating agent was present in the initial homogenization buffer and generally in all buffers used in preparing fractions, an activator of a smooth muscle phosphodiesterase was released upon boiling the 10-nm filaments. This activator obtained in the boiled supernatant was Ca(2+)-sensitive, trifluoperazine-sensitive, and stimulated smooth muscle phosphodiesterase to nearly the same extent as purified (exogenous) CDR; thus, it probably represents filament-associated CDR.
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PMID:Cyclic nucleotide phosphodiesterase activity in 10-nm filaments and microtubule preparations from bovine brain. 22 49

Beef heart cAMP phosphodiesterase (EC 3.1.4.17) was isolated and partially purified using fractionation by ammonium sulfate and gel filtration on the columns with Sephadex G-200 and Sepharose 6B. This method allowed to preserve the enzyme binding to the low-molecular weight thermostable protein regulator of the phosphodiesterase activity. The enzyme preparation was purified 130--180-fold as compared to the original homogenate. The pH-dependence of the enzyme activity in the imidazole and tris -- buffers for the fraction with maximal activity was carried out. The kinetic analysis of this fraction revealed an abnormal kinetic behaviour with two Km values. The enzyme is represented by four forms differing in their molecular weights and possessing different capacity for activation by Ca2+ and protein regulator. No activation was observed in the forms with higher molecular weights, whereas the activity of the forms with lower molecular weights depended on the presence of Ca2+ and protein regulator. It is assumed that some of the above-described forms are capable of interconversions.
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PMID:[Some properties of partially purified preparations of cAMP phosphodiesterase from beef heart]. 22 72

A membrane fraction prepared from isolated rat adipocytes contained an insulin-sensitive cyclic nucleotide phosphodiesterase (EC 3.1.4.17) which catalyzed the hydrolysis of both adenosine 3',5'-monophosphate (cAMP) and guanosine 3',5'-monophosphate (cGMP). The rate of hydrolysis of cGMP was about one-third that of cAMP. The hydrolysis of the two nucleotides appeared to be assoicated with one catalytic site: one nucleotide interfered with the hydrolysis of the other, in a manner predictable from the kinetic constants in that the Km of one nucleotide as a substrate was comparable to its Ki as an inhibitor of the hydrolysis of the other nucleotide. Incubation of the adipocytes with insulin increased the Vmax of phosphodiesterase without affecting the Km values for either substrate. After adipocytes had been treated with filipin, a membrane perturbant, at a concentration that did not cause cell lysis, the response of phosphodiesterase to insulin was obliterated. Further, the insulin-stimulated phosphodiesterase activity was reversed when hormone-treated cells were subsequently incubated with this agent. These results suggest that the response of membrane phosphodiesterase to insulin is impaired once adipocytes have been exposed to filipin, either preceding or following the incubation with insulin.
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PMID:Filipin prevents and reverses insulin stimulation of rat adipocyte phosphodiesterase. 22 98


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