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)

The biochemical properties of cyclic nucleotide phosphodiesterases in a nonmetastasizing and a spontaneously metastasizing rat mammary carcinoma were compared. The phosphooiesterases in both tumors had a pH optimum of around 8.0 and preferentially hydrolysed cyclic purine nucleotides. The rate of hydrolysis of purine nucleotides in the nonmetastasizing tumor was two times higher than in the metastasizing tumor, but the rate of pyrimidine nucleotide hydrolysis was equal in both tumors. Theophylline, caffeine, and D,L-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro20-1724) inhibited the enzyme activity in both tumors; the percent inhibition was the same by each inhibitor. The cyclic nucleotie phosphodiesterase activity in either tumor was stimulated by Mg++, Mn++, and Co++ and suppressed by Ca++, Zn,++, and Ni++. EDTA inhibited the activity below the basal level (activity in the absence of added cation), an this inhibition could be recovered up to the basal level by an equimolar quantity of either Mn++ or Mg++. Further stimulation of the enzyme activity with increasing concentrations of divalent cations was observed only with Mn++. Similar effects were observe with ethylene glycol bis(beta-aminoethyl ether)-tn,n-tetraacetic acid. The stimulatory cations affected both the low and high Michaelis constant (tkm) enzymes in these tumors by increasing the maximum velocity. In the low Km enzyme, the Km was also slightly increased. Neither guanosine 3',5'-cyclic monophosphate nor adenosine 3',5'-cyclic monophosphate had any effect on the hydrolysis of the other at physiologic levels.
 ...
PMID:Biochemical properties of cyclic nucleotide phosphodiesterase in metastasizing and nonmetastasizing rat mammary carcinomas. 0 60

A number of 3-bromo-, 3-nitro-, and 3-ethoxycarbonyl-5,7-dialkylpyrazolo[1,5-a]pyrimidines were synthesized and screened as in vitro cAMP phosphodiesterase inhibitors. The condensation of 3-aminopyrazole with symmetrical beta-diketones (acetylacetone, heptane-3,5-dione, etc.) afforded symmetrical dialkylpyrazolo[1,5-a]pyrimidines (5). The reaction of 3-aminopyrazole with unsymmetrical beta-diketones (hexane-2,4-dione, heptane-3,5-dione, etc.) gave a mixture of 5-methyl-7-alkylpyrazolo[1,5-a]pyrimidine (3) and 5-alkyl-7-methylpyrazolo[1,5-a]pyrimidines (4). The technique for the separation of 3 from 4 is described. The inhibition constants, alpha (the ratio of the molar I50 of theophylline to the molar I50 of the test compounds), were subjected to a Hansch correlation analysis. The results indicated that PDE isolated from beef heart tissue was most sensitive to changes in the length of the alkyl group in the 5 position of the pyrazolo[1,5-a]pyrimidine ring, whereas the PDE isolated from rabbit lung tissue was more sensitive to changes in the length of the 7-alkyl group. Experimentally and theoretically, the n-propyl group was found to approximate the ideal size for the alkyl group in both the 5 and 7 positions;5,7-di-n-propyl-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine (5e) was the most potent inhibitor of both lung and heart PDE.
 ...
PMID:Adenosine cyclic 3',5',-monophosphate phosphodiesterasr inhibitors. 2.3-Substituted 5,7-dialkylpyrazolo [1,5-a]pyrimidines. 16 80

5-Methyl-7-diethylamino-s-triazolo-(1,5-alpha)pyrimidine (Rocornal, trapidil), which has been introduced in clinical medicine as a coronary vasodilatator, competitively inhibits the cyclic AMP splitting nucleotidehydrolase (phosphodiesterase) from the heart muscle. The K1 value for Rocornal is 0.14 +/- 0.016 mM. The enzyme inhibition by this compound is abolished after an exchange of the diethylamino-group in C-7 position against dimethylamine and chloride. The proved triazolo-pyrimidines were without effect on myocardial adenylate cyclase activity. It is concluded that the vasodilatory effect of Rocornal may be realized in smooth muscle cells by an inhibition of cyclic AMP breakdown.
 ...
PMID:[Inhibition of the cyclic AMP splitting myocardial nucleotide gydrolase by 5-methyl-7-diethylamino-s-triazol-(1,5-alpha)pyrimidine (rocornal)]. 18 92

Extracts of vegetative cells of Blastocladiella emersonii contain 5% or less of the cyclic AMP phosphodiesterase activity in zoospore extracts. This difference in activity could be accounted for entirely by an increase in the differential rate of phosphodiesterase synthesis during sporulation, beginning after a lag period of about 60 min and extending for at least an additional 90 min into the 4-h sporulation process. To examine the relation between enzyme synthesis and cyclic nucleotide metabolicm, we determined the substrate specificity of phosphodiesterase synthesized during sporulation and partially purified from zoospores. Zoospore extracts contain two components, separable by gel filtration chromatography, with cyclic AMP phosphodiesterase activity. The larger component accounts for 20% of the total activity and the smaller component for 80%. Both components show essentially an absolute substrate specificity for cyclic AMP among several cyclic purine and cyclic pyrimidine nucleotides tested. Nevertheless, we found no change in the total cyclic AMP content of sporulating cells before, during, or after enzyme activity increased. We speculate that some other component of cyclic AMP metabolism or function limits the rate of cyclic AMP hydrolysis in sporulating cells.
 ...
PMID:Induction of cyclic AMP phosphodiesterase in Blastocladiella emersonii and its relation to cyclic AMP metabolism. 21 Nov 17

A ribonuclease (ribonucleate 3-pyrimidine-oligonucleotidohydrolase, EC 3.1.4.22) was purified 8300-fold from soluble fraction of beef brain and its properties were investigated. The enzyme is an endonuclease capable of hydrolyzing tRNA, rRNA, poly(C), but shows no activity towards poly(U), poly(A), and poly(G). The preparation is free of deoxyribonuclease, non-specific phosphodiesterase and phosphomonoesterase activity. The enzyme has a pH optimum of 7.6, is not heat stable, has a molecular weight of 25 000, and has a K-m of 134 mu rRNA and K-m of 1600 mug poly(C) per ml.
 ...
PMID:Purification of an alkaline ribonuclease from soluble fraction of beef brain. 23 61

Ethyl carbamate, labelled at C1 with 14C, bound in vivo to liver DNA of intact and partially hepatectomised mice. Isotope (18O) enrichment was not detected in the oxygen of liver DNA of mice injected with [18O] ethyl carbamate, C2H5--18O--CO--NH2. This suggests that it was the ethyl group and not the ethoxy group which bound to DNA. Chromatographic analysis of acid hydrolysates of liver DNA from mice treated with [1-14C] ethyl carbamate provided no evidence of alkylation or other form of binding to purine or pyrimidine bases. On relatively mild acid hydrolysis the alkyl group remained bound to the "apurinic acid" fraction, while more vigorous hydrolysis lead progressively first to its separation as highly ionisable hydrophilic non-volatile compounds and then to its loss as a volatile compound. DNAase I followed by phosphodiesterase hydrolysis also split off the 14C-containing group as a volatile compound. The volatile compound was identified as ethanol. These results suggest that the alkyl group was bound as an ester to a phosphate group in the DNA chain. Results with DNA from partially hepatectomised mice did not differ from those with DNA from intact mice.
 ...
PMID:The binding of ethyl carbamate to DNA of mouse liver in vivo: the nature of the bound molecule and the site of binding. 95 35

The effects of the triazolopyrimidine trapidil (5-methyl-7-diethylamino-s-triazolo [1,5-alpha]pyrimidine, CAS 15421-84-8) on force of contraction, beating frequency and phosphodiesterase (PDE) activity were investigated in isolated preparations from guinea-pig hearts. The effects of 3-isobutyl-1-methylxanthine (IBMX), theophylline and milrinone were studied for comparison. Trapidil exerted a concentration-dependent (1000-3000 mumol(s)/l) positive inotropic effect (EC50 562.4 mumol(s)/l) in guinea-pig papillary muscles. The positive inotropic effect was accompanied by a shortening of the duration of contraction as described for IBMX, or isoprenaline. The efficacy of trapidil was lower than that of IBMX or milrinone. Both agents maximally enhanced force of contraction to a 3fold (milrinone) or even 6fold greater amount (IBMX). The potency of trapidil was almost in the same order of magnitude as that of milrinone. The positive inotropic effect of trapidil is at least partially due to a cyclic adenosine monophosphate (cAMP)-dependent mechanism because carbachol antagonized the increase in force of contraction. Trapidil concentration-dependently but nonselectively inhibited the activities of cAMP PDE isoenzymes I-IV as did theophylline or IBMX. Based on IC50 values (275 mumol(s)/l on the average) trapidil had a potency similar to that of theophylline while IBMX was about one order of magnitude more potent. Regarding the inhibition of PDE III, IBMX was 49fold and milrinone 114fold more potent than trapidil. Trapidil revealed only a marginal positive chronotropic effect. The frequency of spontaneously beating right auricles was increased by 13% at most. Trapidil did not produce any tachyarrhythmias or contractures. It is concluded that the positive inotropic effect of trapidil is mainly due to PDE inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Effects of the triazolopyrimidine trapidil on force of contraction, beating frequency and phosphodiesterase I--IV activity in guinea-pig hearts. 171 91

The effects of pyrrolo[2,3-d]pyrimidine compounds (7-desazapurines) on cAMP hydrolyzing, calmodulin dependent and calmodulin independent phosphodiesterase were studied. Phosphodiesterase inhibition depended on the chemical nature of substituents attached to the pyrrolo-pyrimidine-nucleus at positions 2, 4, 5, 6 and 7. Among a total of 28 compounds tested, the 4-amino-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5,6-dicarbaldehyde (9) was the most potent inhibitor of phosphodiesterase activity (IC50 = 16 microM). In addition to the 5,6-disubstitution, position 2 of the pyrrolo-pyrimidine derivatives had to be unsubstituted and position 4 had to bear an amino-group for an optimal inhibitory effect. Calmodulin dependent and calmodulin independent isozymes were affected to the same extent. Inhibition of PDE activity was reversible upon removal of the pyrrolo-pyrimidine derivative 9 and non-competitive with respect to cAMP (Ki = 27 microM).
 ...
PMID:Pyrrolo[2,3-d]pyrimidines as inhibitors of cAMP-phosphodiesterase. Structure-activity relationship. 253 63

AA-2379 (methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl- 2H-pyrazolo [3,4-d]pyrimidine-2-carboxylate) has antiinflammatory, analgesic, and antipyretic activities, and inhibits the type III allergic (Arthus) reaction. In the studies reported here, we investigated the effect of AA-2379 on rat polymorphonuclear leukocyte (PMN) functions to clarify the mechanism of the antiinflammatory and antiallergic actions of AA-2379. AA-2379 at 10(-4) M inhibited lysozomal enzyme release. AA-2379 inhibits formyl methionyl-leucyl-phenylalanine (fMLP)- and C5a-induced arachidonic acid release; their 50% inhibitory concentrations were 2.8 x 10(-5) and 3.8 x 10(-5) M, respectively. Because dibutyryl cAMP, a cAMP analogue, and 3-isobutyl-1-methylxanthine, a cAMP phosphodiesterase inhibitor, inhibited fMLP-induced arachidonic acid release, and AA-2379 inhibited cAMP phosphodiesterase and increased cAMP content in PMNs, it is likely that AA-2379 inhibited arachidonic acid release by increasing cAMP content in rat PMNs. Furthermore, from the studies of fMLP-induced arachidonic acid release in Ca free medium it is suggested that AA-2379 inhibits the process which depends on Ca concentration in the medium. These results suggest that the inhibitory effect of AA-2379 on inflammation and allergic reactions such as the Arthus reaction is partly exerted by inhibiting PMN functions such as arachidonic acid and lysozomal enzyme release.
 ...
PMID:Inhibitory effects of methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl- 2H-pyrazolo[3,4-d]pyrimidine-2-carboxylate (AA-2379) on lysosomal enzyme and arachidonic acid release from rat polymorphonuclear leukocytes and its mode of action. 255 99

Cyclic GMP causes the release of endogenous Ca2+ from rod outer segments, whose plasma membrane has been made permeable, or from isolated discs. Approximately 11,000 Ca2+ ions are released per disc at saturating concentrations of cyclic GMP. The velocity and the amplitude of the release of Ca2+ are dependent on the concentration of cyclic GMP. The maximal rate of the Ca2+ efflux is approximately 7 X 10(4) Ca2+ ions s-1 rod-1. The Ca2+ release by cyclic GMP is independent of light. The activation of the efflux occurred within a narrow range of the cyclic GMP concentration (30-80 microM) and does not obey a simple Michaelis-Menten scheme. Instead, the kinetic analysis of the Ca2+ efflux suggests that a minimum number of 2 molecules of cyclic GMP activates the ion conductance in a cooperative fashion. The release of Ca2+ by cyclic GMP requires a gradient of Ca2+ ions across the disc membrane. If the endogenous Ca2+ gradient is dissipated by means of the ionophore A23187, the release of Ca2+ by cyclic GMP is abolished. Ca2+ is released by analogues of cyclic GMP which are either modified at the 8-carbon position of the imidazole ring or by the deaza-analogue of cyclic GMP. Congeners of cyclic GMP which are modified at the ribose, phosphodiester, or pyrimidine portion of the molecule are ineffective. The hydrolysis of cyclic GMP by the light-regulated phosphodiesterase of rod outer segments is not a necessary condition for the Ca2+ release because 8-bromo-cyclic GMP, a congener resistant to hydrolysis, is a more powerful activator of the release than cyclic GMP itself. Ca2+ release by cyclic GMP is inhibited by organic and inorganic blockers of Ca2+ channels. The l-stereoisomer of cis-diltiazem blocks the release of Ca2+ at micromolar concentrations, whereas the d-form is much less effective. These results suggest that disc membranes contain a cationic conductance which is permeable to Ca2+ ions and which is regulated through the cooperative binding of at least 2 molecules of cyclic GMP to regulatory sites of the transport protein. By this mechanism, subtle changes in the concentration of cyclic GMP could promote large changes in the flux of Ca2+ ions across the disc membrane.
 ...
PMID:Cyclic GMP directly regulates a cation conductance in membranes of bovine rods by a cooperative mechanism. 258 60


1 2 3 4 5 6 7 8 Next >>