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 substrate specificity of diadenosine 5',5"'-P1,P4-tetraphosphate pyrophosphohydrolase from Physarum polycephalum for dinucleoside polyphosphates has been determined by high-performance liquid chromatography (HP-LC). Elution of a strong anion-exchange resin with a pH and ionic strength gradient of ammonium phosphate separates a series of monoadenosine and diadenosine polyphosphates. Most of the corresponding guanine nucleotides are also resolved on this HPLC system. One mole each of Ap4A and Gp4G is symmetrically hydrolyzed to 2 mol of ADP and GDP, respectively. Ap3A, Ap5A, Ap6A, and Ap4 are hydrolyzed, and in each case ADP is one of the products. Gp3G, Gp5G, Gp6G, and Gp4 are also substrates, and in each case GDP is one of the products. AMP, ADP, ATP, Ap2A, ADPR, GMP, GDP, GTP, NAD+, and NADP+ are not substrates. No hydrolysis of the cap dinucleotides m7Gp3Am and m7Gp3Cm was detected by HPLC. Diadenosine tetraphosphate pyrophosphohydrolase preparations were also assayed for adenylate kinase, nucleotide diphosphate kinase, NAD(P)+ pyrophosphohydrolase, phosphodiesterase, cyclic nucleotide phosphodiesterase, phosphatase, and ribonuclease activities. These enzymic activities were not detectable in diadenosine tetraphosphate pyrophosphohydrolase. The symmetrical hydrolysis of Ap4A and Gp4G is an unique catalytic property that distinguishes diadenosine tetraphosphate pyrophosphohydrolase from P. polycephalum from diadenosine tetraphosphate phosphohydrolases from other organisms.
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PMID:Diadenosine 5',5"'-P1,P4-tetraphosphate pyrophosphohydrolase from Physarum polycephalum. Substrate specificity. 629 57

Cyclic-AMP phosphodiesterase activity in the homogenate of the anterior pituitary gland was 2-fold higher than that in the homogenate of the posterior pituitary, whereas cyclic-GMP phosphodiesterase activity was dominant in the posterior homogenate. There were two peaks of cyclic-AMP phosphodiesterase activity with different isoelectric points of 4.3 and 5.2. Fraction I had a molecular weight of 240 000 and a sedimentation coefficient of 6.2 S; fraction II had a molecular weight of 180 000 and a sedimentation coefficient of 3.1 S. Cyclic AMP hydrolytic activity in the supernatant of the posterior lobe corresponded to fraction I in the anterior lobe. Cyclic GMP hydrolytic activity in both the anterior and posterior lobes (activated by Ca2+/calmodulin) had an isoelectric point of 5.2, a molecular weight of 240 000 and a sedimentation coefficient of 6.2 S. Cyclic AMP and GMP hydrolytic activities in both the anterior and posterior lobes appeared in fraction I and did not separate when the preparations were mixed before electric focusing or sucrose density gradient procedures. Cyclic AMP hydrolytic activity in fraction II could be separated from cyclic GMP hydrolytic activity.
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PMID:3':5'-cyclic-nucleotide phosphodiesterase in the bovine pituitary gland. 629 13

Quinazolinesulfonamides are synthetic compounds which calcium-independently stimulate Ca2+-dependent cyclic nucleotide phosphodiesterase. As this activation was observed with 2,4-dipiperidino-6-quinazolinesulfonamides but not with 4-piperidino-6-quinazolinesulfonamides, the activation seems to be dependent on the piperidine residue at the 2 and 4 position of the quinazoline ring, and the extent of hydrophobicity of each compound was thus enhanced. 2,4-Dipiperidino-6-quinazolinesulfonamide activates Ca2+-dependent phosphodiesterase in the absence of Ca2+-calmodulin (CaM). These quinazolinesulfonamides did not further enhance the activity of Ca2+-dependent phosphodiesterase activated by the Ca2+-CaM complex. These compounds are also potent inhibitors of cyclic AMP and GMP phosphodiesterases. CaM antagonists such as N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), its derivatives, and chlorpromazine and prenylamine inhibited selectively the quinazolinesulfonamide-induced activations of the phosphodiesterase. These quinazolinesulfonamides, in a high concentration, had only a slight stimulatory effect on myosin light chain kinase activity. All these findings suggest that the quinazolinesulfonamides are calcium-independent activators of Ca2+-dependent phosphodiesterase and they are proving to be useful tools for the study of CaM and phosphodiesterase, in vitro.
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PMID:Calcium-independent activation of calcium ion dependent cyclic nucleotide phosphodiesterase by synthetic compounds: quinazolinesulfonamide derivatives. 630 35

Two molecular species of repressible extracellular phosphodiesterases showing cyclic 2',3'- and cyclic 3',5'-nucleotide phosphodiesterase activities were detected in mycelial culture media of wild-type Neurospora crassa and purified. The two molecular species were found to be monomeric and polymeric forms of an enzyme constituted of identical subunits having molecular weights of 50,000. This enzyme had the same electrophoretic mobility as repressible acid phosphatase. The enzyme designated repressible cyclic phosphodiesterase showed pH optima of 3.2 to 4.0 with a cyclic 3',5'-AMP substrate and 5.0 to 5.6 with a cyclic 2',3'-AMP substrate. Repressible cyclic phosphodiesterase was activated by MnCl2 and CoCl2 with cyclic 2',3'-AMP as substrate and was slightly activated by MnCl2 with cyclic 3',5'-AMP. The enzyme hydrolyzed cyclic 3',5'- and cyclic 2',3'-nucleotides, in addition to bis-rho-nitrophenyl phosphate, but not certain 5' -and 3'-nucleotides. 3'-GMP and 3'-CMP were hydrolyzed less efficiently. Mutant strains A1 (nuc-1) and B1 (nuc-2), which cannot utilize RNA or DNA as a sole source of phosphorus, were unable to produce repressible cyclic phosphodiesterase. The wild type (74A) and a heterocaryon between strains A1 and B1 produced the enzyme and showed growth on orthophosphate-free media containing cyclic 2',3'-AMP or cyclic 3',5'-AMP, whereas both mutants showed little or no growth on these media.
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PMID:Repressible extracellular phosphodiesterases showing cyclic 2',3'- and cyclic 3',5'-nucleotide phosphodiesterase activities in Neurospora crassa. 631 98

Cyclic nucleotides phosphodiesterase (PDE) was prepared from cerebrum of male rats and its kinetic properties were studied. The phosphodiesterase preparation exhibited two Michaelis constants, 8.7 microM and 83.3 microM. Adenine derivatives such as adenosine, 5'-AMP and 2'(3')-AMP inhibited the PDE activity at concentrations exceeding 7 X 10(-3)M, and 2'-deoxyadenosine inhibited the activity at lower concentrations (Ki = 1.8 X 10(-3)M); its inhibiting efficacy was almost the same as that of theophylline (Ki = 1.9 X 10(-3)M). Guanine derivatives, on the other hand, showed several different effects. Guanosine and 3',5'-cyclic GMP activated the PDE at 10(-5) M and inhibited at concentrations higher than 10(-4)M. 2'(3')-GMP showed no effect, but 5'-GMP activated markedly at concentrations of 10(-3) to 10(-2)M. Thymidine showed slight inhibitory effect, but cytidine or 2'-deoxycytidine had no effect. Uracil derivatives such as uridine, 5'-UMP, 3',5'-cyclic UMP and 2'(3')-UMP activated the PDE at concentrations exceeding 3 X 10(-3) M. These results indicate that individual nucleosides and nucleotides exhibit structure-activity relationship with PDE.
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PMID:Effects of nucleotides and nucleosides on the activity of cyclic AMP phosphodiesterase from rat brain. 631 97

Chemotactic stimulation of Dictyostelium discoideum cells induces a fast transient increase of cGMP levels which reach a peak at 10 s. Prestimulation levels are recovered in approximately 30 s, which is achieved mainly by the action of a guanosine 3',5'-monophosphate cGMP-specific phosphodiesterase. This enzyme is activated about fourfold by low cGMP concentrations. The phosphodiesterase has two distinct cGMP-binding sites: a catalytic site and an activator site. cAMP does not bind to either site; inosine 3',5'-monophosphate (cIMP) binds only to the catalytic site, whereas 8-bromoguanosine 3',5'-monophosphate (c-b8-GMP) preferentially binds to the activator site. For detailed kinetical measurements we have used [3H]cIMP as the substrate and c-b8-GMP as the activator. c-b8-GMP activated the hydrolysis of [3H]cIMP by reducing the Km, whereas the Vmax was not altered. The hydrolysis of [3H]cIMP was measured at 5-s intervals by using a new method for the separation of 5'-nucleotides from cyclic nucleotides. The hydrolysis of [3H]cIMP by nonactivated enzyme or by preactivated enzyme was linear with time, which indicates that a steady state is reached at the catalytic site within 5 s after addition of the substrate. In contrast, the hydrolysis of [3H]cIMP immediately after activation by 0.1 microM c-b8-GMP was not linear with time, but increased in a quasi-exponential manner with a time constant of 21 s. This suggests that a steady state at the activator site is only reached in 30-45 s after addition of the activator. The on-rate of activation (k1) was 3 X 10(5) M-1s-1 for c-b8-GMP and 1.4 X 10(5) M-1s-1 for cGMP. The off-rate of activation (k-1) was 0.03 s-1 for both c-b8-GMP and cGMP. The significance of these kinetic constants for the chemoattractant-mediated cGMP response in vivo is discussed.
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PMID:Transient kinetics of a cGMP-dependent cGMP-specific phosphodiesterase from Dictyostelium discoideum. 631 30

Ultrastructural localization of adenylate cyclase (AC) activity was investigated in suspensions of unfixed isolated rat thymocytes using a medium containing 0.6 mM 5'-adenylylimidodiphosphate (AMP-PNP) as a substrate, 10 mM MgSO4 as an activator, 5 mM theophylline as an inhibitor of 3' 5'-AMP-phosphodiesterase and 2 mm lead nitrate as a capturing agent. AC activity was demonstrated in plasma membrane, perinuclear space, endoplasmic reticulum, Golgi complex, centriole microtubules and mitochondria. AC was activated with 10(-4) M adrenaline in the presence of 5'-guanylylimido-diphosphate (GMP-PNP) as well as with 10(-2) M NaF. In the cells incubated in a medium devoid of theophylline and containing 5'-AMP instead of AMP-PNP, 5'-nucleotidase activity was observed in the same cell structures as AC activity, Hydrolysis of 5'-AMP in the nucleus was much stronger than that of AMP-PNP. 10 mM NaF markedly inhibited hydrolysis of 5'-AMP in all cell structures. No staining was observed with 2 mM beta -glycerophosphate as a substrate. Incubation of unfixed thymocytes in media containing AMP-PNP, 5'-AMP or p-nitrophenyl phosphate, but not beta -glycerophosphate, induced both in the nucleus and in the cytoplasm in some cells an appearance of a transitory reticular formation consisting of about 303nm thick strands which could penetrate the nuclear envelope and plasma membrane and form connections with adjacent cells. The transitory reticular formation seems to belong to the cytoskeleton and to be involved in cell aggregation.
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PMID:Ultracytochemical localization of adenylate cyclase activity in rat thymocytes. 729 93

Whole-cell patch-clamp recordings from Vicia faba mesophyll protoplasts reveal that outward K+ current is increased in a dose-dependent fashion by intracellular application of cAMP. The enhancement of the outward current by cAMP is specific and it cannot be mimicked by a series of nucleotides that includes AMP, cGMP, and GMP. The enhancement is evoked by micromolar concentrations of cAMP in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine. PKI or Walsh inhibitor, a specific peptide inhibitor of cAMP-dependent protein kinase (PKA), inhibits the outward K+ current. Adenosine 3',5'-phosphothioate, a competitive inhibitor of PKA, has a similar effect. Conversely, the catalytic subunit of PKA (cAMP independent) from bovine brain enhances the magnitude of the outward K+ current in the absence of added cAMP. Our results indicate that cAMP modulates K+ channel activity in mesophyll cells and suggest that this modulation occurs through a cAMP-regulated protein kinase.
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PMID:Cyclic AMP stimulates K+ channel activity in mesophyll cells of Vicia faba L. 752 28

5'-Exonuclease-2 has been purified 17,000-fold from whole cell extracts of Saccharomyces cerevisiae. A 116-kDa polypeptide parallels the enzyme activity when the purified protein is examined by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. Amino-terminal sequencing of the 116-kDa protein shows that the sequence agrees with that encoded by the HKE1 gene, previously reported to encode exonuclease-2. A 45-kDa polypeptide also parallels the enzyme activity upon purification, and Sephacryl S-200 molecular sieve chromatography of the purified enzyme shows a parallel elution of most of the 116- and 45-kDa polypeptides, suggesting a close association of the two. Enzyme instability has precluded a more detailed analysis of their associative properties. The enzyme hydrolyzes RNA substrates to 5'-mononucleotides in a processive manner. Measurements of its substrate specificity and mode of action are compared with 5'-exonuclease-1. Restriction cut single-stranded T7 DNA is hydrolyzed at approximately 5-7% of the rate of 18 S rRNA of yeast by both enzymes. That 5'-exonuclease-2 hydrolyzes in a processive manner and lacks endonuclease activity is shown by the finding that [5'-32P]GMP is the only product of its hydrolysis of [alpha-32P]GTP-labeled synthetic RNAs. That 5'-exonuclease-2 hydrolyzes by a 5'-->3' mode is shown by: 1) its poor hydrolysis of both 5'-capped and triphosphate-ended RNA substrates; 2) the products of its hydrolysis of [5'-32P,3H](pA)4; and 3) the accumulation of 3'-stall fragments when a strong artificial RNA secondary structure is present in synthetic RNAs. 5'-Exonuclease-1 hydrolyzes the synthetic RNAs and (pA)4 in an identical manner.
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PMID:5'-exonuclease-2 of Saccharomyces cerevisiae. Purification and features of ribonuclease activity with comparison to 5'-exonuclease-1. 760 67

1. We tested the hypothesis that increasing myocardial cyclic GMP levels would reduce myocardial O2 consumption and areas of low O2 supply/consumption balance, using zaprinast, a selective cyclic GMP-phosphodiesterase inhibitor. 2. The study was conducted in three groups (vehicle, 10(-3) and 3 x 10(-3) mol/L zaprinast) of anaesthetized open-chest New Zealand white rabbits (n = 24). Coronary blood flow (radioactive microspheres), arterial and venous O2 saturation (microspectrophotometry), O2 consumption, cyclic GMP content (competitive binding) and cyclic GMP-phosphodiesterase activity (conversion of 3H-cyclic GMP to 3H-GMP) were determined. 3. Agents were applied to a patch on the myocardial surface and did not cause significant haemodynamic changes, except for bradycardia in the vehicle and low dose group. 4. The total myocardial cyclic GMP-phosphodiesterase activity was 148 +/- 14 while the zaprinast (10 mumol/L) inhibitable activity averaged 63 +/- 8 pmol/mg protein per min. Cyclic GMP content was increased with increasing doses of zaprinast (vehicle, 4.308 +/- 0.349 pmol/g; low dose zaprinast, 4.803 +/- 0.279 and high dose zaprinast, 7.938 +/- 1.304 pmol/g). 5. Coronary blood flow was not different after treatment (198 +/- 11, 209 +/- 10 and 153 +/- 9 mL/min per 100 g for the vehicle, low and high dose zaprinast, respectively). 6. Under control conditions, 48% of the small veins had O2 saturations below 50%. With zaprinast, this value was reduced to 19% for the low and 24% for the high dose. 7. Average venous O2 saturation increased with zaprinast (49 +/- 2%, 61 +/- 3% and 59 +/- 1%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of increased myocardial cyclic GMP induced by cyclic GMP-phosphodiesterase inhibition on oxygen consumption and supply of rabbit hearts. 781 20


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