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)

A series of new analogues of 1-beta-D-ribofuranosylbenzimidazole 3',5'-phosphate (cBIMP) has been designed according to the properties predicted by the MNDO method, and synthesised from substituted benzimidazoles. Dipole vectors and HOMO and LUMO energies for each benzimidazole base were calculated by the MNDO method and the lipophilicities of the cBIMP derivatives were determined. In general, the cBIMP derivatives activate cAMP-dependent protein kinases I and II and preferentially bind to site B, especially for the type II kinase, with 2-trifluoromethyl-cBIMP and 5,6-difluoro-cBIMP exhibiting the highest site selectivity. Each cBIMP derivative can stimulate cGMP-stimulated cyclic phosphodiesterase (cGS-PDE), with 5,6-dimethyl-cBIMP being as potent as cGMP, and also inhibit cGMP-inhibited phosphodiesterase (cGI-PDE). Only the 2-trifluoromethyl-cBIMP and the Rp-phosphorothioates (cBIMPS) (equatorial P = S) were resistant to hydrolysis by cPDE. The Sp-phosphorothioates were hydrolysed slowly, if at all. In addition to exhibiting a high lipophilicity, the most active compounds for the induction of apoptosis and inhibition of proliferation were also resistant to cPDE (Sp-5,6-dichloro-cBIMPS) and/or were potent activators of cAMP-dependent protein kinase (5,6-dichloro-cBIMP).
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PMID:Derivatives of 1-beta-D-ribofuranosylbenzimidazole 3',5'-phosphate that mimic the actions of adenosine 3',5'-phosphate (cAMP) and guanosine 3',5'-phosphate (cGMP). 133

A phosphodiesterase (EC 3.1.4.1) was purified to homogeneity from the fruit body of Flammulina velutipes. The enzyme had considerable activity toward oligonucleotides. The Km values were 0.66 mM for ApA, 2.47 mM for (Ap)2A, and 3.03 mM for (Ap)3A. The enzyme hydrolyzed oligodeoxyribonucleotides as well as oligoribonucleotides. The oligoribonucleotides bearing a phosphate residue at the 3' end were not hydrolyzed by the enzyme. The enzyme hydrolyzed the oligoribonucleotides exonucleolytically from the 3' to 5' end. Thus the PDase of F. velutipes is considered to function in vivo as an oligonucleotidase (EC 3.1.13.3), which efficiently converts oligonucleotides to 5'-mononucleotides in the cell.
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PMID:Oligonucleotidase activity of phosphodiesterase from the fruit body of Flammulina velutipes. 136 59

An enzyme capable of hydrolyzing 4-methylumbelliferyl phenylphosphonate to 4-methylumbelliferone and phenylphosphonic acid has been detected in human serum. It has a Km value of 1.72 x 10(-4) mol/L, has an optimum pH of 8.8-9.1 in Tris buffer, and shows maximum activity at 60 degrees C (30 min). The enzymic activity can be inhibited by Na3PO4, EDTA, and cysteine. We saw no effect of CuSO4, adenosine, thymidine, NaN3, diethyl p-nitrophenyl phosphate, p-chloromercuribenzoate, isopropyl fluorophosphate, or eserine on the enzymic activity. The enzyme cannot hydrolyze substrates of phosphodiesterase I or alkaline phosphatase. The enzyme is considered a phosphonate esterase.
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PMID:Specific detection and properties of enzyme hydrolyzing phosphonate ester in serum. 154 54

Calmodulin-dependent phosphodiesterase was purified to apparent homogeneity from the total calmodulin-binding fraction of bovine heart in a single step by immunoaffinity chromatography. The isolated enzyme had significantly higher affinity for calmodulin than the bovine brain 60-kDa phosphodiesterase isozyme. The cAMP-dependent protein kinase was found to catalyze the phosphorylation of the purified cardiac calmodulin-dependent phosphodiesterase with the incorporation of 1 mol of phosphate/mol of subunit. The phosphodiesterase phosphorylation rate was increased severalfold by histidine without affecting phosphate incorporation into the enzyme. Phosphorylation of phosphodiesterase lowered its affinity for calmodulin and Ca2+. At constant saturating concentrations of calmodulin (650 nM), the phosphorylated calmodulin-dependent phosphodiesterase required a higher concentration of Ca2+ (20 microM) than the nonphosphorylated phosphodiesterase (0.8 microM) for 50% activity. Phosphorylation could be reversed by the calmodulin-dependent phosphatase (calcineurin), and dephosphorylation was accompanied by an increase in the affinity of phosphodiesterase for calmodulin.
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PMID:Phosphorylation and characterization of bovine heart calmodulin-dependent phosphodiesterase. 164 4

1. The effects of zaprinast (M&B 22948), a selective guanosine 3':5'-cyclic monophosphate (cyclic GMP) phosphodiesterase inhibitor, and sodium nitroprusside on cyclic GMP content, phosphoinositide hydrolysis and airway smooth muscle tone were examined in flurbiprofen pretreated bovine tracheal smooth muscle (BTSM). 2. Anion-exchange chromatography of the soluble fraction of BTSM homogenates resolved three peaks of Ca2+/calmodulin-independent phosphodiesterase (PDE) activity that corresponded to type Ia (cyclic GMP-specific, zaprinast-inhibitable), type II (cyclic GMP-stimulated) and type IV (Ro 20 1724-inhibitable) PDE isoenzymes. Zaprinast caused a selective inhibition of the type Ia PDE isoenzyme (IC50 0.94 microM) with respect to the type II and IV (IC50 s 93 microM and 197 microM respectively) isoenzymes. 3. Pretreatment of BTSM strips with zaprinast (10 microM) for 20 min affected neither the initial rate of force development, nor the resultant magnitude of contraction induced by methacholine (10 microM). In addition, zaprinast (10 microM; 20 min) did not affect the cumulative concentration-response relationship induced by methacholine. In contrast, sodium nitroprusside (300 microM) either alone, or in combination with zaprinast (10 microM), significantly attenuated tone induced by low, but not high concentrations of methacholine. This resulted in a non-parallel, rightwards shift of the methacholine concentration-response curves (nitroprusside: 4.0 fold; nitroprusside/zaprinast: 4.8 fold at the EC50 values), without a reduction in the maximum tone generated. 4. In BTSM slices, zaprinast (10 or 100 microM) did not influence basal or methacholine (10 microM)-stimulated cyclic GMP accumulation or inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) mass accumulation over a 60s incubation period, although it did significantly increase cyclic GMP content over longer (30 min) stimulation periods. 5. In [3H]-inositol prelabelled BTSM slices, stimulated in the presence of 5mM LiCl, methacholine (10 microM) caused a marked increase in total [3H]-inositol phosphate accumulation. This effect was not inhibited by zaprinast (10 microM), sodium nitroprusside (300 microM), or a combination of these drugs despite these agents markedly increasing tissue cyclic GMP content. 6. These findings demonstrate that despite zaprinast being a potent and selective inhibitor of the type Ia PDE isoenzyme in a cell-free system, this drug only increases cyclic GMP content in BTSM following prolonged agonist-stimulation. This may explain its lack of inhibitory effect on methacholine-induced tone. The inability of drugs which increase tissue cyclic GMP content and exhibit anti-spasmogenic activity to inhibit methacholine-stimulated Ins(1,4,5)P3 formation suggests that, unlike vascular smooth muscle, cyclic GMP-dependent mechanisms do not regulate receptor-mediated phosphoinositide hydrolysis in BTSM.
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PMID:Lack of effect of zaprinast on methacholine-induced contraction and inositol 1,4,5-trisphosphate accumulation in bovine tracheal smooth muscle. 165 39

1. The effects of increases in intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) on mitogen-induced generation of inositol phosphates and increases in intracellular Ca2+ concentration were investigated in human peripheral blood mononuclear leukocytes (MNL). 2. The mitogens concanavalin A (Con A), pokeweed mitogen (PWM) and phytohaemagglutinin (PHA) concentration-dependently stimulated generation of inositol phosphates. Catecholamines inhibited this process with an order of potency: isoprenaline greater than adrenaline greater than noradrenaline indicating involvement of beta 2-adrenoceptors. This order of potency was also consistent with the catecholamine potencies for stimulating the generation of cyclic AMP. 3. In addition to catecholamines, the cyclic AMP formation-stimulating agents prostaglandin E1 (PGE1) and forskolin concentration-dependently inhibited mitogen-induced inositol phosphate generation, too. Moreover, the inhibitory effect of isoprenaline was potentiated by co-incubation with the phosphodiesterase inhibitor isobutylmethylxanthine demonstrating that these inhibitory effects were mediated by cyclic AMP. 4. Con A and PHA concentration-dependently increased the intracellular Ca2+ concentration in human MNL (assessed by the fluorescent indicator dye Fura-2). This increase was almost completely blocked by chelation of extracellular Ca2+, demonstrating influx rather than mobilization from intracellular stores. 5. The elevation of intracellular Ca2+ was not blocked by pretreatment with pertussis toxin, 100 ng ml-1, for 16 h. 6. Isoprenaline, PGE1, and forskolin, however, inhibited the mitogen-stimulated elevation of intracellular Ca2+. This inhibition was enhanced by the phosphodiesterase inhibitors isobutylmethylxanthine and Ro 20-1724, demonstrating mediation by cyclic AMP. 7. We conclude that catecholamines and other cyclic AMP increasing agents can inhibit mitogen-stimulated generation of inositol phosphates and elevation of intracellular Ca2+ in resting human MNL.
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PMID:Cyclic AMP counteracts mitogen-induced inositol phosphate generation and increases in intracellular Ca2+ concentrations in human lymphocytes. 165 68

During the visual transduction process in rod photoreceptor cells, transducin (T) mediates the flow of information from photoexcited rhodopsin (R*) to the cGMP phosphodiesterase (PDE) via a cycle of GTP binding and hydrolysis. The pre-steady-state kinetics of GTP hydrolysis by T was studied by rapid quenching and filtration techniques in a reconstituted system containing purified R* and T. Kinetic analyses have shown that the turnover of T-bound GTP can be dissected into four partial reactions: (1) the R*-catalyzed GTP binding via a GDP/GTP exchange reaction, (2) the on-site hydrolysis of bound GTP, which leads to the formation of a T-GDP.Pi complex, (3) the release of the tightly bound inorganic phosphate (Pi) from T-GDP.Pi, and (4) the recycling of T-GDP. The R*-catalyzed GTP binding was estimated to occur in less than 1 s. In rapid acid quenching experiments, the rate of Pi formation due to GTP hydrolysis exhibited biphasic characteristics. An initial burst of Pi formation occurred between 1 and 4 s, which was followed by a slow steady-state rate. Increasing T concentration yielded a proportional increase in the burst and steady-state rate. The addition of Gpp(NH)p decreased both parameters. D2O decreased the rise of the initial burst with a kinetic isotope effect of approximately 1.7 but has no effect on the steady-state rate of Pi formation. These results indicate that the burst represents the fast hydrolysis of GTP at the binding site of T, which results in the accumulation of T-GDP.Pi complexes. The steady-state rate represents the slow release of Pi. This finding was further supported by rapid filtration experiments that monitored the formation of free Pi in solution. An initial lag time in the formation of free Pi was observed before a steady-state rate was established, indicating that the initially formed Pi was tightly bound to T. Finally, the release of GDP from T-GDP.Pi was not detected. This suggests that another cycle of GTP exchange catalyzed by R* should occur before the release of bound GDP. The rate of Pi release from T-GDP.Pi was measured under single-turnover conditions and had a half life of approximately 20 s, which was identical with the rate of deactivation of the PDE due to GTP hydrolysis by T.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular mechanism of GTP hydrolysis by bovine transducin: pre-steady-state kinetic analyses. 165 84

DNA from Ehrlich ascites tumor (EAT) cells and from human placenta was examined for covalent bonds between hydroxy amino acid residues in peptides and nucleotide phosphate groups. The residual proteinaceous material in highly purified DNA was radiolabelled with 125Iodine and the linking-groups between peptides and nucleotides released by combined protease and nuclease treatment were investigated with respect to their chemical and enzymatic stabilities. The residual nucleotide(s)-peptide(s) fraction from DNA isolated after prolonged alkaline cell lysis and phenol extraction contains mainly alkali and acid-stable but phosphodiesterase-sensitive peptide-nucleotide complexes which indicates phosphodiesters between tyrosyl residues in peptides and nucleotide phosphates. In contrast, the linking-group fraction from DNA isolated under native conditions contains additional peptide components. (a) Phospho-peptides that co-purify with DNA but that are not covalently bound to nucleotides. (b) A fraction of peptides that is released from nucleotides by alkali in a time and concentration-dependent reaction. Evidence is presented indicating that the latter fraction involves phospho-triesters between hydroxy amino acid residues in peptides and internucleotide phosphates. The phosphodiesters between hydroxy amino acids and nucleotide phosphates representing the predominant class of peptide-nucleotide complexes in alkali-denatured DNA are most likely side products of peptide-nucleotide phospho-triester hydrolysis.
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PMID:Chemical and enzymatic analysis of covalent bonds between peptides and chromosomal DNA. 166 8

An investigation was made of a range of agents capable of elevating tissue cyclic AMP levels, or acting as a stable analogue of cyclic AMP, upon carbachol induced inositol phosphate responses in bovine tracheal smooth muscle slices. Whereas the beta 2 adrenoceptor agonist salbutamol (1 microM) and the membrane permeable analogue of cyclic AMP, 8-bromo-cyclic AMP (1 mM) were without effect upon total [3H]inositol phosphate formation induced by carbachol, 3-iso-butyl-1-methylaxanthine (IBMX) (EC50 140 microM), the high Km, cyclic AMP selective phosphodiesterase inhibitor rolipram (EC50 41 microM) and theophylline (EC50 76 microM) all inhibited the inositol phosphate response to low (1 microM) concentrations of carbachol. IBMX (IC50 13 microM), rolipram (IC50 4.6 microM) and theophylline (IC50 180 microM) all relaxed bovine tracheal muscle strips precontracted with methacholine (1 microM). The adenylate cyclase activator forskolin (1 microM), produced a much smaller (10% inhibition) effect upon inositol phosphate formation induced by carbachol. Carbachol (1 microM-1 mM) did not inhibit forskolin induced [3H]cyclic AMP formation. An inhibitor of the cyclic GMP preferring phosphodiesterase isozyme, M&B 22948 (1-100 microM), was without effect upon either carbachol induced inositol phosphate formation or trachealis tone. It is concluded that IBMX, rolipram and theophylline inhibit carbachol stimulated inositol phosphate formation, possibly through a cyclic AMP independent mechanism.
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PMID:Modulation of carbachol-induced inositol phosphate formation in bovine tracheal smooth muscle by cyclic AMP phosphodiesterase inhibitors. 169 Sep 98

The repair of apurinic/apyrimidinic (AP) sites is described. The major pathway involves hydrolysis of the stable phosphodiester bond on the 5' side of the lesion by an AP endonuclease. The 5' terminal deoxyribose-phosphate residue is excised by a separate phosphodiesterase which does not appear to be an exonuclease. Repair replication of the single missing nucleotide residue by a DNA polymerase and ligation complete the excision-repair process. The possibility that minor DNA lesions may accumulate with time in long-lived cells is considered. Such lesions should be chemically stable and should not be recognized by DNA-repair enzymes.
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PMID:Repair of intrinsic DNA lesions. 169 69


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