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 concentrations of cAMP and the activity of adenyl cyclase and specific cAMP-phosphodiesterase were determined in certain structures of rabbit brain. Statistically significant differences were found in the concentrations of cAMP; and enzyme activity between certain structures of the brain, particularly in the structures of the brain stem: mesencephalon, diencephalon and the pontine structures.
Acta Physiol Pol
PMID:Concentrations of cAMP and activity of pertinent enzymes in certain brain structures of the rabbit. 630 97

Studies on the rats with genetically-controlled hypertension (spontaneously hypertensive rats, SHR) in which myocardiopathy had been produced by isoproterenol (ISP) administration (2 X 80 mg/kg sc daily for two days) have shown that the myocardiopathy results in a fall of the activity of adenylate cyclase (AC) lasting from the second to the fourth day after administration of ISP, while the activity of phosphodiesterase (PDE) remained unchanged. In vitro, ISP (10(-7)-10(-4)M), Mg2+ (4-25nM), GTP (10(-6)-10(-5)M) and GTP (10(-5)M) given in combination with ISP (10(-6)-10(-5)M) elevated the AC activity in the cardiac muscle of SHR similarly in controls and the rats with ISP-induced myocardiopathy. The results indicate that the depression of AC activity in the cardiac muscle of SHR following ISP-induced myocardiopathy is a result of reduction of the number of AC molecules rather than a consequence of the structural damage of AC.
Pol J Pharmacol Pharm 1983
PMID:The activity of adenylate cyclase and phosphodiesterase in the isoproterenol-damaged cardiac muscle of spontaneously hypertensive rats. 631 39

Anagrelide is a quinazoline compound developed as a potent inhibitor of platelet aggregation. During studies in human it has produced rapid and selective thrombocytopenia and has therefore been evaluated for use in conditions associated with thrombocythaemia. Anagrelide significantly inhibits human megakaryocyte colony development in vitro by preventing full megakaryocyte maturation, and inhibits platelet aggregation as a result of potent inhibition of cyclic adenosine monophosphate (cAMP) phosphodiesterase activity. In 60 to 93% of patients with essential or myeloproliferative thrombocythaemia anagrelide produces sustain reductions in platelet counts and also reduces the incidence of disease-related symptoms. Most adverse effects are related to its vasodilatory or positive inotropic properties. This new agent appears promising in the treatment of thrombocytosis in patients with chronic myeloproliferative diseases, especially in younger persons in whom the risk of leukaemogenic transformation with some alternative drugs is of particular concern.
Acta Haematol Pol 1994
PMID:[Anagrelide--new antiplatelet drug]. 784 31

Considering the ever growing number of new discoveries and changes in ideas in the field of psychopharmacology, the authors present the actual state of knowledge about the mechanism of action of antidepressant drugs. Three periods characterize the research and the development of antidepressants. In the first period the presynaptic monoamine neuron was considered as the target structure both with respect to the search for the origin of depression and the mechanism of action of antidepressants. Two types of antidepressants, monoamine uptake inhibitors and monoamine oxidase inhibitors (IMAO) are representative of this period. In the second period, the research focused its interest primarily on monoaminergic receptors, anticipating that they were critically involved in the pathophysiology of depression. Such research sought to explain the antidepressant properties of iprindole and mianserine which are neither monoamine uptake inhibitors nor inhibitors of MAO. The onset of the third period is recent and it is characterized by the shift in research emphasis to intracellular transmission events. This period started with the discovery of the antidepressant properties of the phosphodiesterase inhibitor rolipram.
Psychiatr Pol
PMID:[Current views of the mechanism of action of antidepressants]. 835 78

DNA polymerase beta (beta-Pol) consists of an N-terminal ssDNA binding domain with deoxyribose phosphodiesterase activity and a C-terminal domain with nucleotidyltransferase activity. The solution structure of the cloned N-terminal domain of beta-Pol has been determined by multidimensional heteronuclear NMR using experimental restraints that included 1030 distances based on analysis of NOE connectivities, 68 phi, chi 1, and chi 2 torsion angles based on analysis of couplings, and 22 hydrogen bonds. Hydrogen bonds were assessed only within helices by the absence of saturation transfer from water at pH 6.7, by NOEs and JNH alpha couplings indicative of well-structured helices, and by 13C alpha chemical shifts characteristic of helices. The root mean square deviation for heavy backbone atoms within the helices was 0.64 A in 55 structures. The solution structure of the N-terminal domain is formed from four helices packed as two antiparallel pairs crossing at 50 degrees in a V-like shape. The domain binds p(dT)8, a template analogue, as a 1:1 complex in 100 mM NaCl (KD = 10 microM). Analysis of the binding equilibria at increasing NaCl concentrations indicated that ionic contacts contribute to the complex. The binding interaction was mapped to one face of the domain by characterizing backbone 1H and 15N chemical shift changes. Assigned intermolecular NOEs from 2D NOESY support the assessment of the binding interface. The structure that forms the interaction surface includes an antiparallel helix-3-turn-helix-4 motif and residues adjacent to an omega-type loop connecting helix-1 and helix-2. Sites appropriate for nucleotide contact on the structure are described. The mapped interaction interface for a ssDNA template is the first described for a DNA polymerase.
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PMID:Three-dimensional solution structure of the N-terminal domain of DNA polymerase beta and mapping of the ssDNA interaction interface. 863 59

Theophylline and other methylxanthines are the strongest and most widely used antiasthmatic drugs. Mechanism of theophylline effect is complicated. The first observations of this way, depend on inhibition of phosphodiesterase by increase of cAMP what is the reason of bronchorelaxation. As a results a theophylline action we can observe induction of adenosine receptors, inhibition of the some prostaglandin synthesis or allergic reaction mediatores and decrease of the level of calcium in muscles cells. It is probably (especially in bronchial asthma or acute lymphoblastic leukemia-ALL) that the one important effect of theophylline is the some cells apoptosis. For the good results of the therapeutics effect apart of important factors deciding of the theophylline metabolism (age of patients, kind of the diet, period of menstruation and smoking), we always should consider interactions of theophylline with other drugs. In this paper we presented the most often reasons of interactions between theophylline and others drugs.
Pol Merkur Lekarski 2000 Sep
PMID:[Undesirable pharmacokinetic interactions of theophylline]. 1112 90

Several of the nucleoside analogs used in the treatment of AIDS exhibit a delayed clinical toxicity limiting their usefulness. The toxicity of nucleoside analogs may be related to their effects on the human mitochondrial DNA polymerase (Pol gamma), the polymerase responsible for mitochondrial DNA replication. Among the AIDS drugs approved by the FDA for clinical use, two are modified cytosine analogs, Zalcitabine (2',3'-dideoxycytidine (ddC)) and Lamivudine (beta-d-(+)-2',3'-dideoxy-3'-thiacytidine ((-)3TC])). (-)3TC is the only analog containing an unnatural l(-) nucleoside configuration and is well tolerated by patients even after long term administration. In cell culture (-)3TC is less toxic than its d(+) isomer, (+)3TC, containing the natural nucleoside configuration, and both are considerably less toxic than ddC. We have investigated the mechanistic basis for the differential toxicity of these three cytosine analogs by comparing the effects of dideoxy-CTP), (+)3TC-triphosphate (TP), and (-)3TC-TP on the polymerase and exonuclease activities of recombinant human Pol gamma. This analysis reveals that Pol gamma incorporates (-)3TC-triphosphate 16-fold less efficiently than the corresponding (+)isomer and 1140-fold less efficiently than dideoxy-CTP, showing a good correlation between incorporation rate and toxicity. The rates of excision of the incorporated analogs from the chain-terminated 3'-end of the DNA primer by the 3'-5'-exonuclease activity of Pol gamma were similar (0.01 s(-)1) for both 3TC analogs. In marked contrast, the rate of exonuclease removal of a ddC chain-terminated DNA occurs at least 2 orders of magnitude slower, suggesting that the failure of the exonuclease to remove ddC may play a major role in its greater toxicity. This study demonstrates that direct analysis of the mitochondrial DNA polymerase structure/function relationships may provide valuable insights leading to the design of less toxic inhibitors.
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PMID:Insights into the molecular mechanism of mitochondrial toxicity by AIDS drugs. 1132 13

DNA polymerase eta synthesizes DNA in vitro with low fidelity. Based on this, here we report the effects of deletion or increased expression of yeast RAD30 gene, encoding for polymerase eta (Pol eta), on spontaneous mutagenesis in vivo. Deletion of RAD30 did not affect spontaneous mutagenesis. Overproduction of Rad30p was slightly mutagenic in a wild-type yeast strain and moderately mutagenic in strains with inactive 3'-->5'-exonuclease of DNA polymerase epsilon or DNA mismatch repair. These data suggest that excess Rad30p reduces replication fidelity in vivo and that the induced errors may be corrected by exonucleolytic proofreading and DNA mismatch repair. However, the magnitude of mutator effect (only up to 10-fold) suggests that the replication fork is protected from inaccurate synthesis by Pol eta in the absence of DNA damage. Overproduction of catalytically inactive Rad30p was also mutagenic, suggesting that much of the mutator effect results from indirect perturbation of replication rather than from direct misincorporation by Pol eta. Moreover, while excess wild-type Pol eta primarily induced base substitutions in the msh6 and pms1 strains, excess inactive Rad30p induced both base substitutions and frameshifts. This suggests that more than one mutagenic mechanism is operating when RAD30 is overexpressed.
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PMID:Mutator effects of overproducing DNA polymerase eta (Rad30) and its catalytically inactive variant in yeast. 1140 77

The wild-type form of p53 contains an intrinsic 3'-5'-exonuclease activity. As p53 forms a complex with DNA polymerase alpha-primase (pol-prim) in vivo this finding suggests that p53 might cooperate with pol-prim to stabilize the genetic information of living cells. To test this hypothesis, exonuclease-free DNA pol-prim was expressed alone or together with p53 for purification. Pol-prim formed a complex with p53, which was purified by ion exchange and immunoaffinity chromatography from baculovirus-infected insect cells. The p53-containing pol-prim fractions removed a 3'-unpaired nucleotide with a 1.5-2-fold higher rate than a paired nucleotide, whereas the four subunit pol-prim did not have any exonuclase activity. Therefore, only p53/pol-prim was able to elongate a primer-template that contained a 3'-unpaired primer end in vitro. To achieve this, the 3'-5'-exonuclease activity of p53 excised the unpaired nucleotide at the 3'-end of the primer and created a paired 3'-end, which pol-prim was able to elongate. The exonuclease activity of p53 as well as the elongation of a primer with a mispaired 3'-end was inhibited specifically by the anti-p53 monoclonal antibodies PAb240 and PAb421.
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PMID:Physical and functional interactions of the tumor suppressor protein p53 and DNA polymerase alpha-primase. 1191 9

Intact rat peritoneal macrophages (rPM) treated with 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterases (PDEs), accumulated more cGMP than untreated cells. A PDE activity toward [(3)H]cGMP was detected in the soluble and particulate fractions of rPM. The hydrolysis of cGMP was Ca(2+)/calmodulin-independent but increased in the presence of cGMP excess. Similar results were obtained when [(3)H]cAMP was used as a substrate. The hydrolytic activity towards both nucleotides was inhibited in the presence of IBMX. Therefore, the PDEs of families 2, 5, 10 and 11 are potential candidates for cGMP hydrolysis in the rPM. They may not only regulate the cGMP level in a feedback-controlled way but also link cGMP-dependent pathways with those regulated by cAMP.
Acta Biochim Pol 2002
PMID:Hydrolysis of cyclic GMP in rat peritoneal macrophages. 1254 95


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