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)

At toxic doses, cardiotropic drugs may compromise cardiac output leading to circulatory shock. Specific treatment varies depending on the nature and the dose of the drugs ingested as well as causal mechanism including vasopegia, hypovolaemia, cardiogenic effects and sepsis. Progress in our understanding of the pharmacodynamic aspects of intoxication and the development of specific antidotes has led to reduced morbidity and mortality. In addition to the classical inotropes, mainly catecholamines and phosphodiesterase inhibitors, other therapeutic agents may have specific inotrope effects in such ad hoc situations. These include hypertonic alkaline saline solution, calcium, glucagon, hydroxocobalamine and other cobalt salts, oxygen and immunotoxicotherapy. Together with volum replacement, dobutamine at the dose of 7 to 20 micrograms/kg/min can usually restore cardiac performance in cases of carbamate-induced circulatory shock. In case of tricyclic antidepressant overdose, treatment should include respiratory assistance and infusion of alkaline sodium solutions to both reverse the extracellular acidosis and correct sodium balance. Catecholamines may be necessary in cases with severe hypotension. Major vasoplegia and impaired intraventricular conduction may be induced by overdoses of chloroquine and class I antiarrhythmic drugs. Signs of gravity are: ingested dose above 4 g, QRS > or = 0.12 s or systolic arterial pressure < or = 80 mmHg. Treatment with epinephrine, respiratory assistance and diazepam has been proven effective during the acute phase, but right catheterism is often required due to major haemodynamic instability during the first 72 first hours. Beta-blockers have both a bronchoconstrictor and respiratory depressor effects favouring cardiovascular failure by hypoemia. Symptoms occur in 30-40% of the cases of overdose. Shock results from the reduction in blood pressure and cardiac inotropism. Glucagon, isoprenaline and epinephrine, prescribed in that order, can considerably reduce mortality to less than 4%. Despite the development of specific molecules, the risk of mortality due to toxic shock caused by antiarrhythmics, chloroquine, colchicine, calcium inhibitors and paraquat remains high.
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PMID:[Shock caused by poisoning. Use of cardiotropic agents]. 797 61

We have created a series of deletion mutants of a human cardiac cAMP phosphodiesterase in order to define sequences necessary for function and to identify residues required for inhibition by cGMP and by the drugs milrinone and trequinsin. These truncated constructs were expressed in yeast cells, and their biochemical properties were analyzed. The mutations define an amino acid sequence that is essential for function. Among the active constructs, there was considerable variability in the level of expression and in the stability of the proteins, with the full-length and near full-length constructs being the least stable. There were, however, no significant changes in Km values among the active enzymes. Cation studies confirmed that Mn2+ is a more efficient cofactor than Mg2+ or Co2+. Interestingly, Mn2+ acts as a more efficient cofactor for cGMP inhibition as well. Although IC50 values for the drugs trequinsin and milrinone were not significantly altered by deletions, there was a decrease in cGMP IC50 values for the smaller constructs, indicating a role for amino acid residues outside the catalytic region in cGMP inhibition. We also demonstrate in vivo inhibition of this enzyme in yeast cells grown in the presence of pharmacological inhibitors, allowing for the selection of drug-resistant mutants. Finally, we have constructed and analyzed chimeric genes in which portions of this phosphodiesterase are replaced with homologous sequences from a closely related phosphodiesterase isozyme that is expressed in brain. Our results demonstrate that sequence variations between related isozymes account for more than just pharmacological distinctions and may reflect significant structural differences.
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PMID:Mutational mapping of kinetic and pharmacological properties of a human cardiac cAMP phosphodiesterase. 798 87

cGMP-binding cGMP-specific phosphodiesterase (cG-BPDE) binds tightly to a Zn(2+)-chelate column (Francis, S. H., and Corbin, J. D. (1988) Methods Enzymol. 159, 722-729). Using three different approaches, Zn2+ is now shown to bind to cG-BPDE, and the Kd is determined to be approximately 0.5 microM, with a binding stoichiometry of approximately 3 mol of Zn2+/mol of monomer. A similar concentration range of Zn2+ (0.05-1 microM Zn2+) also supports phosphodiesterase (PDE) catalytic activity. The Zn2+ binding to cG-BPDE is not diminished by, nor is catalysis supported by, relatively high concentrations of Cu2+, Cd2+, Ca2+, or Fe2+. Neither cGMP nor 3-isobutyl-1-methylxanthine affects Zn2+ binding under the conditions used. Mn2+, Co2+, or Mg2+ supports catalysis, but only at significantly higher concentrations (4-, 15-, and 250-fold, respectively) than that required for Zn2+. Two tandem amino acid sequences, which are conserved in the catalytic domains of all characterized mammalian PDEs, resemble the single sequence motif that has been shown to coordinate Zn2+ in the catalytic sites of Zn2+ hydrolases such as thermolysin.
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PMID:Zinc interactions and conserved motifs of the cGMP-binding cGMP-specific phosphodiesterase suggest that it is a zinc hydrolase. 807 92

An injection of cobalt chloride solution into the unilateral sensorimotor cortex of rats induced electrographic epileptic activity, which was followed by a peripheral motor disturbance. Brain slices were prepared from the cortical region including the injection site and from the other cortical regions of rats between 8 and 50 days after the injection. In the cortical slices, we examined cyclic AMP accumulations elicited by adenosine and its stable analogue 2-chloroadenosine. Adenosine and 2-chloroadenosine at their maximal dose increased cyclic AMP accumulation six- to 10-fold and 10-15-fold, respectively, and the elicitation was markedly inhibited by the adenosine antagonist 8-phenyltheophylline. The cyclic AMP accumulation was increased in the primary epileptic region of the cortex adjacent to the injection site of cobalt chloride solution, whereas it was unchanged in the other cortical regions. The increase in cyclic AMP accumulation was observed regardless of the presence or absence of the adenosine uptake inhibitor dipyridamole, the phosphodiesterase inhibitor DL-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone, and adenosine deaminase. Such an increased accumulation of cyclic AMP in the primary epileptic cortex was detected as early as 8 days after the injection. The cyclic AMP accumulation continued to increase and reached a peak level 17-19 days after the injection, and it returned to the control levels after 40-50 days, in correspondence with the electrographic and behavioral findings. It is concluded that alterations in adenosine receptor-mediated generation of cyclic AMP in the primary epileptic cortex are closely associated with the central process of cobalt-induced epilepsy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Involvement of adenosine-sensitive cyclic AMP-generating systems in cobalt-induced epileptic activity in the rat. 824 69

A Zn(2+)-glycerophosphocholine cholinephosphodiesterase was purified with a specific activity of 4.6 mumole/min.mg protein from bovine brain membranes by procedures involving PI-PLC solubilization, concanavalin A affinity chromatography, CM-sephadex chromatography and Sephadex G-150 chromatography. Based on molecular weight determination gel chromatography and SDS polyacrylamide gel electrophoresis, the phosphodiesterase activity appears to be a dimeric protein (110 kDa) composed of two subunits with a molecular weight of approximately 54 kDa. The K(m) value for p-nitrophenylphosphocholine and the optimum pH were found to be 16 microM and pH 10.5, respectively. The phosphodiesterase was inhibited by Cu2+, but not the other divalent metal ions. The activity of the apoenzyme was remarkably activated by Co2+ or Zn2+, but not Mn2+ or Mg2+. In addition, the inactivation of the enzyme in glycine buffer was prevented by Mn2+ or Zn2+, but not Co2+ or Mg2. In a separate experiment, comparing properties of the purified and membrane-bound phosphodiesterases, the forms of two enzymes were quite similar except in stability. Both enzymes were more stable at pH 7.4 than pH 5 or 10. However, the membrane-bound enzyme was more stable than the soluble enzyme at all three pHs. These data suggest that the activity of the phosphodiesterase may be stabilized in-vivo.
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PMID:Properties of a Zn(2+)-glycerophosphocholine cholinephosphodiesterase from bovine brain membranes. 892 80

A potential role for cAMP in regulating the differentiation of myoblasts has led us to examine the components of the cAMP signaling system, including the type IV, cAMP-specific phosphodiesterases. The full coding sequence of the phosphodiesterase PDE4D1 was inserted in the bacterial expression vector pGEX-KG. N- and C-terminal truncations were also placed in the same vector, allowing the expression and purification of glutathione S-transferase (GST)-PDE fusion proteins using glutathione-Sepharose. The purified PDE was active [V(max) = 318 +/- 18 nmol min(-1)(mg of protein)(-1)] and inhibited by RO 20-1724, rolipram, and MIX (IC50 values of 2, 0.4, and 40 microM, respectively). The requirement of PDE4D1 for a divalent cation was also examined. It was able to use Mg2+, Co2+, and Mn2+, but not Zn2+, suggesting that it is not a zinc hydrolase as has been proposed for other PDE types. Deletion of both C- and N-terminal regions affected the apparent native size of the enzyme. The C-terminal region was involved in dimer formation, whereas an N-terminal region was responsible for larger aggregates. Removal of the last 35 amino acids of an N-terminal 80-residue highly conserved region (UCR2) resulted in a 6-fold increase in PDE activity, providing evidence that this part of the molecule acts as an intramolecular inhibitor. The availability of a highly purified, enzymatically active protein in substantial quantities has allowed us to directly examine PDE4D1 for the first time.
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PMID:Recombinant expression of a type IV, cAMP-specific phosphodiesterase: characterization and structure-function studies of deletion mutants. 906 27

The effect of divalent metal ions on the activity of glycerophosphocholine cholinephosphodiesterse from ox brain was examined. Zn(2+)- and Co(2+)-glycerophosphocholine cholinephosphodiesterases were prepared from the exposure of apoenzyme to Zn2+ and Co2+, respectively, and the properties of two metallo-phosphodiesterases were compared to those of native phosphodiesterase. Although two metallo-enzymes were similar in expressing Km value, optimum pH or sensitivity to Cu2+, they differed in the susceptibility to the inhibition by thiocholine or tellurite; while Co(2+)-phosphodiesterase was more sensitive to tellurites, Zn(2+)-phosphodiesterase was more susceptible to inhibition by thiocholine. In addition, Zn(2+)-phosphodiesterase was more thermo-stable than Co2+ enzyme. Separately, when properties of native phosphodiesterase were compared to those of each metallo-phosphodiesterase, native phosphodiesterase was found to be quite similar to Zn(2+)-phosphodiesterase in many respects. Even in thermo-stability, native enzyme resembled Zn(2+)-phosphodiesterase rather than Co(2+)-enzyme. Consistent with this, the stability of native phosphodiesterase was maintained in the presence of Zn2+, but not Co2+, Mn2+ was also as effective as Zn2+ in the stabilization of the enzyme. Noteworthy, the native enzyme was found to be inhibited competitively by Cu2+ with a Ki value of 20 microM, and its inhibitory action was antagonized effectively by Zn2+ or Co2+. Also, choline, another competitive inhibitor of the enzyme, appeared to antagonize the inhibitory action of Cu2+. Taken together, it is suggested that there may be multiple binding sites for divalent metal ions in the molecule of glycerophosphocholine cholinephosphodiesterase.
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PMID:Interaction of divalent metal ions with Zn(2+)-glycerophosphocholine cholinephosphodiesterase from ox brain. 935 12

Properties of active site of Zn2+-glycerophosphocholine cholinephosphodiesterase from ox brain were examined using substrates and inhibitors of the phosphodiesterase. The anionic binding site expressed a selectivity for a positively-charged group. Meanwhile, the glyceryl moiety-binding site appeared to be a narrow crevice of a limited size, excluding the entry of acylglycerophospholipids containing long acyl chains. While endogenous quaternary ammonium compounds such as phosphocholine, choline or carnitine inhibited the enzyme, divalent metal ions such as Co2+, Mn2+ or Zn2+ enhanced the activity by 1.5 to 2-folds. The pH dependence for the inhibition by phosphocholine or the hydrolysis of substrate implies the involvement of a basic amino acid residue with a pK value of 9.6-9.7, probably lysine, in the binding of phosphoryl group. In further support, the lysine modifiers such as trinitrobenzene sulfonic acid or diethylpyrocarbonate expressed some inactivation. The pH-rate profile indicates that an amino acid residue with a pK value of 10.2, presumably tyrosine, may participate as a nucleophile in the catalysis. This might be further supported by the inactivation of the enzyme by tyrosine modifiers such as tetranitromethane or HOI-generating system. Separately, the phosphodiesterase was observed to be susceptible to the action of hydrogen peroxide or peroxynitrite-generating system. From these results, it is implied that the phosphodiesterase may be affected by endogenous sources.
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PMID:Active site of brain Zn2+-glycerophosphocholine cholinephosphodiesterase and regulation of enzyme activity. 970 95

Since many isoforms of adenylyl cyclase and adenosine 3', 5'-monophosphate (cAMP) phosphodiesterase have been cloned, it is likely that receptors of each hormone have a specific combination of these isoforms. Types I, III and VIII adenylyl cyclases are reported to be stimulated by Ca(2+)-calmodulin, type I phosphodiesterase by Ca(2+)-calmodulin, but types IV and VII (cAMP-specific) phosphodiesterases by Co2+. In the present study, we examined different effects of Ca2+ and Co2+ on hormone-induced cAMP response in the isolated perfused rat liver.The removal of Ca2+ from the perfusion medium (0 mM CaCl(2 ) + 0.5 mM EGTA) did not affect glucagon (0.1 nM)-responsive cAMP but reduced secretin (1 nM)-, vasoactive intestinal polypeptide (VIP, 1-10 nM)- and forskolin (1 microM)-responsive cAMP considerably. The addition of 1 mM CoCl2 reduced glucagon- and secretin-responsive cAMP considerably, forskolin-responsive cAMP partly, did not affect 1 nM VIP-responsive cAMP, but enhanced 10 nM VIP-responsive cAMP. Forskolin- and VIP-responsive cAMP was greater in the combination (0 mM CaCl(2) + 0.5 mM EGTA + 3 mM CoCl2) than in the Ca(2+)-free perfusion alone. These results suggest that secretin, VIP1 and VIP2 receptors are linked to Ca(2+)-calmodulin-sensitive adenylyl cyclase; glucagon receptor to Ca(2+)-calmodulin-insensitive adenylyl cyclase; VIP1 receptor to Ca(2+)-calmodulin-dependent phosphodiesterase; glucagon, secretin and VIP2 receptors to cAMP-specific phosphodiesterase, respectively, in the rat liver.
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PMID:Hormone-specific combinations of isoforms of adenylyl cyclase and phosphodiesterase in the rat liver. 1125 14

A phosphodiesterase was purified from the venom of the snake Bothrops alternatus by a combination of gel filtration and ion exchange chromatographies. In SDS-PAGE, the enzyme gave a single band with a molecular mass of 105 kDa, which was unaltered in the presence of beta-mercaptoethanol, indicating that the protein contained no subunits. A single protein band was also observed in native PAGE. There were no contaminating 5'-nucleotidase, alkaline phosphatase and protease activities. The enzyme was recognized by commercial bothropic antiserum and gave a single band in immunoblotting. The enzyme had a pH optimum in the range of 7.5-9.5 and the optimum temperature was 60 degrees C, with activity being rapidly lost within 1 min at > or = 70 degrees C. The Km of the enzyme was 2.69 mM. PDE activity was potentiated by cobalt and, to a lesser extent, by calcium, whereas copper, manganese, zinc, EDTA, and beta-mercaptoethanol were inhibitory. These properties show that this enzyme is very similar to that isolated from other snake venoms.
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PMID:Purification and characterization of a phosphodiesterase from Bothrops alternatus snake venom. 1263 51


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