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At least 19 recordsLinked to original sources

PubMed1986

Extraction, purification, identification and metabolism of 3',5'-cyclic UMP, 3',5'-cyclic IMP and 3',5'-cyclic dTMP from rat tissues.

The large-scale extraction and partial purification of endogenous 3',5'-cyclic UMP, 3',5'-cyclic IMP and 3',5'-cyclic dTMP are described. Rat liver, kidney, heart, spleen and lung tissues were subjected to a sequential purification procedure involving freeze-clamping, perchlorate extraction, alumina and Sephadex ion-exchange chromatography and preparative electrophoresis. The samples thus obtained co-chromatographed with authentic cyclic UMP, cyclic IMP and cyclic dTMP on t.l.c. and h.p.l.c. and the u.v. spectra of the extracted samples were identical with those of the standards. Fast atom bombardment of the three cyclic nucleotide standards yielded mass spectra containing a molecular protonated ion in each case; mass-analysed ion kinetic-energy spectrometry ('m.i.k.e.s') of these ions produced a spectrum unique to the parent cyclic nucleotide. The extracted putative cyclic UMP, cyclic IMP and cyclic dTMP each produced a m.i.k.e.s. identical with that obtained with the corresponding cyclic nucleotide standard. Rat liver, heart, kidney, brain, intestine, spleen, testis and lung protein preparations were each found capable of the synthesis of cyclic UMP, cyclic IMP and cyclic dTMP from the corresponding nucleoside triphosphate, of the hydrolysis of these cyclic nucleotides and of their binding, with the exception that cyclic dTMP was not synthesized by the kidney preparation.

Animals↗

PubMed1979

Rat thyroid phosphofructokinase. Comparison of the regulatory and molecular properties with those of rat muscle enzyme.

The kinetic and molecular properties of rat thyroid phosphofructokinase (specific activity 134 units/mg) were compared with those of rat muscle phosphofructokinase (specific activity 135 units/mg). Thyroid and muscle phosphofructokinase showed similar sedimentation patterns in sucrose density gradients; their affinity for DEAE-cellulose was similar but not identical. A comparison of the kinetic properties revealed differences in the pH optima. Striking differences in the kinetic properties were shown below pH 7.4; the thyroid enzyme was less inhibited by ATP or citrate and more sensitive to activation by cyclic 3':5'-AMP than the muscle enzyme. A study of the effects of some cyclic as well as linear mononucleotides, such as cyclic AMP, cyclic IMP, cyclic GMP, cyclic CMP, cyclic UMP, 5'-AMP, and 3'-AMP on thyroid phosphofructokinase showed that at concentrations as low as 1 micrometer only cyclic AMP and cyclic IMP were able to activate thyroid enzyme in the presence of low fructose-6-P and high ATP concentrations.

Animals↗

PubMed1979

Comparison of cyclic nucleotide specificity of guanosine 3',5'-monophosphate-dependent protein kinase and adenosine 3',5'-monophosphate-dependent protein kinase.

Guanosine 3',5'-monophosphate-dependent protein kinase (cyclic GMP-dependent protein kinase) and adenosine 3',5'-monophosphate-dependent protein kinase (cyclic AMP-dependent protein kinase) exhibited a high degree of cyclic nucleotide specificity when hormone-sensitive triacylglycerol lipase, phosphorylase kinase, and cardiac troponin were used as substrates. The concentration of cyclic GMP required to activate half-maximally cyclic dependent protein kinase was 1000- to 100-fold less than that of cyclic AMP with these substrates. The opposite was true with cyclic AMP-dependent protein kinase where 1000- to 100-fold less cyclic AMP than cyclic GMP was required for half-maximal enzyme activation. This contrasts with the lower degree of cyclic nucleotide specificity of cyclic GMP-dependent protein kinase of 25-fold when histone H2b was used as a substrate for phosphorylation. Cyclic IMP resembled cyclic AMP in effectiveness in stimulating cyclic GMP-dependent protein kinase but was intermediate between cyclic AMP and cyclic GMP in stimulating cyclic AMP-dependent protein kinase. The effect of cyclic IMP on cyclic GMP-dependent protein kinase was confirmed in studies of autophosphorylation of cyclic GMP-dependent protein kinase where both cyclic AMP and cyclic IMP enhanced autophosphorylation. The high degree of cyclic nucleotide specificity observed suggests that cyclic AMP and cyclic GMP activate only their specific kinase and that crossover to the opposite kinase is unlikely to occur at reported cellular concentrations of cyclic nucleotides.

Animals↗

PubMed1994

Nucleotide Regulation of a calcium-activated cation channel in the rat insulinoma cell line, CRI-G1.

The nucleotide regulation of a calcium-activated nonselective cation (Ca-NS+) channel has been investigated in the rat insulinoma cell line CRI-G1. The activity of the channel is reduced by both AMP and ADP (1-100 microM) in a concentration-dependent manner, with AMP being more potent than ADP. At lower concentrations (0.1-5 microM), both ADP and AMP activate the channel in some patches. Examination of the nucleotide specificity of channel inhibition indicates a high selectivity for AMP over the other nucleotides tested with a rank order of potency of AMP > UMP > CMP > or = GMP. Cyclic nucleotides also modulate channel activity in a complex, concentration-dependent way. Cyclic AMP exhibits a dual effect, predominantly increasing channel activity at low concentrations (0.1-10 microM) and reducing it at higher concentrations (100 microM and 1 mM). Specificity studies indicate that the cyclic nucleotide site mediating inhibition of channel activity exhibits a strong preference for cyclic AMP over cyclic GMP, with cyclic UMP being almost equipotent with cyclic AMP. Cyclic IMP and cyclic CMP are not active at this site. The cyclic nucleotide site mediating activation of the channel shows much less nucleotide specificity than the inhibitory site, with cyclic AMP, cyclic GMP and cyclic IMP being almost equally active.

Adenosine Diphosphate↗

PubMed1985

Inhibition of growth of Rhizobium japonicum by cyclic GMP.

Exogenous cyclic guanosine-3',5'-monophosphate (cGMP) inhibited the growth of Rhizobium japonicum at less than 100 microM. Other nucleotides, including cyclic AMP, cyclic IMP, and cyclic CMP, had no inhibitory effect even at higher concentrations nor was the inhibition by cGMP reversed by cyclic AMP. The inhibitory effect was independent of the carbon and nitrogen source(s) used. cGMP did not inhibit the growth of any other species of bacterium tested, including several fast-growing Rhizobium species. The kinetics of growth inhibition are multiphasic, with no apparent effect for several hours after addition, followed by a period of total inhibition. Subsequently, growth resumed at a slower rate. Resumption of growth was not due to destruction of the nucleotide. Studies of the intracellular cGMP concentration did not reveal significant changes in cells grown under aerobic or microaerobic conditions. No effect of cGMP on the derepression of respiratory nitrate reductase was observed.

Bacterial Proteins↗

PubMed1977

Characterization of an adenosine 3':5'-cyclic monophosphate phosphodiesterase from baker's yeast. Its binding to subcellular particles, catalytic properties and gel-filtration behaviour.

1. The 3':5'-cyclic AMP phosphodiesterase in the microsomal fraction of baker's yeast is highly specific for cyclic AMP, and not inhibited by cyclic GMP, cyclic IMP or cyclic UMP. Catalytic activity is abolished by 30 micrometer-EDTA. At 30 degrees C and pH8.1, the Km is 0.17 micrometer, and theophylline is a simple competitive inhibitor with Ki 0.7 micrometer. The pH optimum is about 7.8 at 0.25 micrometer-cyclic AMP, so that over the physiological range of pH in yeast the activity changes in the opposite direction to that of adenylate cyclase [PH optimum about 6.2; Londesborough & Nurminen (1972) Acta Chem. Scand. 26, 3396-3398].2. At pH 7.2, dissociation of the enzyme from dilute microsomal suspensions increased with ionic strength and was almost complete at 0.3 M-KCl. MgCl2 caused more dissociation than did KCl or NaCl at the same ionic strength, but at low KCl concentrations binding required small amounts of free bivalent metal ions. In 0.1 M-KCl the binding decreased between pH 4.7 and 9.3. At pH 7.2 the binding was independent of temperature between 5 and 20 degrees C. These observations suggest that the binding is electrostatic rather than hydrophobic. 3. The proportion of bound activity increased with the concentration of the microsomal fraction, and at 22 mg of protein/ml and pH 7.2 was 70% at I0.18, and 35% at I0.26. Presumably a substantial amount of the enzyme is particle-bound in vivo. 4. At 5 degrees C in 10 mM-potassium phosphate, pH 7.2, the apparent molecular weight of KCl-solubilized enzyme decreased with enzyme concentration from about 200 000 to 40 000. In the presence of 0.5M-KCl, a constant mol.wt. of about 55 000 was observed over a 20-fold range of enzyme concentrations.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1978

Adenosine 3', 5'-cyclic monophosphate-binding proteins from Trypanosoma gambiense.

Two cyclic AMP-binding proteins, not identical with regulatory subunits of protein kinases, have been isolated from Trypanosoma gambiense. The cyclic AMP receptors were separated by gel chromatography on the basis of their molecular weights. The binding constants of the high and the low molecular weight receptors for cyclic AMP were determined to be 0.4 muM and 0.6 muM, respectively. Cyclic IMP and cyclic GMP compete with cyclic AMP for the binding sites of both receptors. The cyclic AMP binding of the low molecular weight receptor was competitively inhibitied by adenine derivatives. The binding capacity of the high molecular weight receptor was enhanced about two-fold by proteolytic modification with trypsin.

Adenosine↗

PubMed1975

The binding of cyclic AMP to renal brush border membranes.

The binding of cyclic AMP to the proximal tubule luminal (brush border) membrane isolated from the rabbit renal cortex was studied. The rate of binding was dependent on temperature; at 37 degrees equilibrium was attained in 45 min, whereas at 0 degrees 120 min was required. The final levels of binding were identical. The binding of 3H-cyclic AMP was reversed by dilution or addition of unlabeled cyclic nucleotide. Debinding was markedly temperature sensitive. Binding was only partially saturable with respect to cyclic AMP concentration, apparently with more than one binding site. The cyclic AMP bound to the membrane was recovered unchanged. When bound to the membrane cyclic AMP was resistant to hydrolysis by endogenous membrane or exogenously added phosphodiesterase. The binding to the membranes was relatively specific for cyclic AMP, although other cyclic purine nucleotides inhibited, cyclic IMP greater than dibutyryl cyclic AMP greater than cyclic GMP. The renal membranes did bind cyclic GMP, but this binding was relatively non-specific. Hormones and drugs, that mediate cyclic AMP generation or renal function, as well as other compounds common to the proximal tubule were without significant effect on cyclic AMP binding. Binding was inhibited by sulfhydryl reacting agents and this inhibition could be blocked and partially reversed by mercaptoethanol.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1978

Cyclic AMP-dependent histone-specific nucleoplasmic protein kinase from rat liver.

A nucleoplasmic histone kinase activity was isolated from livers of adult rats and purified 39-fold compared with whole nuclei by ultracentrifugation of the nuclear extract and Sephadex G-200 gel filtration in the presence of cyclic AMP. Analysis by polyacrylamide-gel electrophoresis as well as by gel filtration indicates a mol.wt. of approx. 60,000 for the catalytic subunit and 130000-150000 for the cyclic AMP-binding activity. The purified enzyme displays a 20-fold greater preference for histone fractions 1 and 2b than for any non-histone substrate, including alpha-casein. Endogenous protein in the preparation is not appreciably phosphorylated. The unfractioned enzyme is stimulated significantly by cyclic GMP, cyclic IMP and dibutyryl cyclic AMP as well as by cyclic AMP. The catalytic reaction requires Mg2+ (Km 1.9mM) and ATP (Km 15.4 micron). Half-maximal activity of the enzyme is observed with histone 2b at 12micron and histone 1 at a higher substrate concentration. The pH optima are 6.1 and 6.5 with histones 2b and 1 respectively. This nuclear protein kinase appears to be distinct from other nuclear enzymes that have been reported, on the basis of histone specificity, univalent-salt-sensitivity, pH optima and nuclear location. However, the enzyme possesses many properties similar to those of the cytoplasmic kinases, including cyclic AMP-dependence, Mg2+ and ATP affinities and pH optima. It differs from cytoplasmic protein kinase type I, the major form in the liver, with respect to bivalent-cation effects and response to the heat-stable protein kinase inhibitor protein isolated from ox heart.

Animals↗

PubMedDate not supplied

Pharmacological inhibition of calmodulin-sensitive phosphodiesterases.

Two cyclic nucleotide phosphodiesterases sensitive to calmodulin were partially purified from bovine brain and bovine aorta. The enzyme from bovine brain exhibited the properties of the "high Km phosphodiesterase", with a higher Km for cyclic AMP than for cyclic GMP. The enzyme from bovine aorta hydrolyzed both cyclic AMP and cyclic GMP with similar kinetics. The hydrolysis of cyclic AMP by the brain enzyme was selectively inhibited by papaverine and 2' deoxy cyclic AMP. The hydrolysis of cyclic GMP by this enzyme was selectively inhibited by cyclic IMP, 2' deoxy cyclic GMP, 1-methyl-3-isobutyl-xanthine, ICI 74917 and M & B 22948. All these inhibitors were identically potent on the hydrolysis of both substrates by the aorta enzyme. Ro-20 1724, an imidazolidinone, and ZK 62711, a pyrrolidone, two compounds known to be potent inhibitors of cyclic AMP phosphodiesterase insensitive to calmodulin, were inefficient inhibitors of both calmodulin-sensitive phosphodiesterases.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1975

Protein kinase and phosphatases from human polymorphonuclear leucoytes.

Purified preparations of human polymorphonuclear leucocytes contain a protein kinase in the cytosol which is stimulated by cyclic AMP and cyclic IMP but not by other cyclic nucleotides. The holoenzyme had a molecular weight of 66000 estimated by gel filtration; when it was incubated with histone or cyclic AMP, it dissociated into two smaller subunits of molecular weight 45000 and 30000; the former remained cyclic AMP-sensitive, whereas the latter had become independent of added cyclic AMP. By means of substrate-affinity chromatography on histone-Sepharose 4B, cyclic [3H5AMP-binding activity (regulatory or R subunit) could be resolved into two peaks of enzyme activity, one again independent of added cyclic AMP, with a molecular weight of 30000 (catalytic or C subunit). Also by means of substrate-affinity chromatography it was possible to resolve 'specific' polymorphonuclear leukocyte histone phosphatases from 'non-specific' phosphomonesterases capable of dephosphorylating histone previously phosphorylated by the protein kinase. Specific histone phosphatase displayed greatest affinity for histone-Sepharose 4B, followed by acid p-nitrophenyl phosphatase, and the unretained acid beta-glucerophosphatase. Polymorphonuclear leucocyte histone phosphatase, purified approx. 40-fold, was further resolved from the other phosphatases by gel filtration on Sephadex G-150 from which it was eluted with apparent molecular weights of 45000 and 18700. The apparent Km values for dephosphorylation of histone are 4.3 X 10-6M and 3.6 X 10-6M. Most (69%) of cytoplasmic histone phosphatase was found in the cell sap, whereas 20% remained tightly associated with polymorphonuclear leucocyte lysosomes from which it could not be solubilized by treatments (Triton X-100, freeze-thawing) that released approx. 70% of lysosomal beta-glucuronidase or acid phosphatases. Although both soluble and particulate enzymes required 5-10 mM-Mn2 for maximal activation, and showed a pH maximum of 6.5-7.0, only the particulate enzyme was partly inhibited by ammonium molybdate. Polymorphonuclear leucocyte histone phosphatases were neither inhibited nor stimulated by those cyclic nucleotides that greatly stimulate the protein kinase of the same subcellular fraction

Acid Phosphatase↗

PubMed1975

Cylic nucleotide phosphodiesterase in silkworm. Characterization of cyclic GMP phosphodiesterase.

The existence of cyclic GMP phosphodiesterase (EC 3.1.4.-) was demonstrated in silkworm larva by gel filtration of the homogenate. The cyclic GMP phosphodiesterase was separated from cyclic AMP phosphodiesterases by column chromatography on hydroxyapatite and Sephadex G-200. The enzyme has a molecular weight of approx. 260 000, and optimum pH of 8.3 and a Km value of 2 muM. The enzyme is activated by 5 mM of Mg2+ and 2 mM of Mn2+. The cyclic GMP phosphodiesterase activity was greatly inhibited by low concentrations of cyclic IMP but to a lesser extent by cyclic AMP even at a high concentration. The activity was also inhibited by caffeine and theophylline.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1982

Studies on the function of the two different intrachain cyclic AMP binding sites of heart protein kinase.

The regulatory subunit of bovine heart isozyme II cAMP-dependent protein kinase contains two different intrachain cAMP binding sites which differ in their rates of cyclic nucleotide dissociation and specificity of cyclic nucleotide analogue binding. The dissociation of cAMP from intrachain Site 1 is slow compared with that from Site 2. Cyclic nucleotide analogues with C-8 alterations show a marked relative preference for Site 1, whereas N6-modified analogues select Site 2. Cyclic IMP, which prefers Site 2, activates the partially purified heart protein kinase holoenzyme as efficiently as, or more efficiently than, cAMP itself. Dissociation studies indicate that the binding of subsaturating or saturating concentrations of cAMP to isolated regulatory subunit occurs at both sites, whereas cAMP in low concentrations binds mainly to Site 1 of the holoenzyme and occupies both sites as the cAMP concentration is raised. Cyclic IMP binding to Site 2 is stimulated by the simultaneous binding of 8-Br-cAMP to Site 1, indicating that at least one function of Site 1 is cooperativity. It is concluded that Site 2 occupancy, either alone or in combination with Site 1 occupancy, is responsible for protein kinase activation. The catalytic subunit of the holoenzyme may prevent cAMP binding to Site 2, but this restraint is relieved as Site 1 becomes occupied.

Animals↗

PubMed1975

Observations on the binding of adenosine 3':5'-monophosphate to cell membrane fragments from ox cerebral cortex.

Microsomal or synaptosome membrane fragments from ox brain bind cyclic AMP with a pH optimum of 7.0. Scatchard analysis shows the presence of at least two binding sites. Cyclic GMP and cyclic IMP only inhibit binding at concentrations 5000 times that of cyclic AMP and even higher concentration ratios of ATP and AMP have no effect. Membrane fragments saturated with cyclic [3-H]AMP lost less than 7% of bound nucleotide on incubation at 0 degrees C for 45 min but lost 25 % in the same period in the presence of 10 muM non-radioactive cyclic AMP.

Acetylcholine↗

PubMed1980

Preparation of cyclic nucleotide antisera with thyroglobulin-cyclic nucleotide conjugates.

Antisera to cyclic AMP and cyclic GMP were obtained by immunizing rabbits with antigens prepared by conjugating the 2'0-succinyl derivative of the cyclic nucleotides to thyroglobulin. The cyclic nucleotide-thyroglobulin conjugates were injected intradermally into multiple sites on the backs of the animals. This immunization procedure resulted in the production of antiserum in four of five animals capable of binding at a final serum dilution of greater than 1:10,000, 20% of the corresponding iodinated cyclic nucleotide derivative added. The antisera were also highly specific. The antiserum for cyclic AMP had a 2500-fold or greater relative affinity for cyclic AMP than other nucleotides or nucleosides, while that for cyclic GMP had a 5000-fold or greater affinity for 2'0 acetylated nucleotides or nucleosides except for acetylated cyclic IMP. The obstacles to measuring cyclic nucleotides, particularly cyclic GMP, in tissues were also overcome by refining and simplifying the methods for iodination, purification and assay. Furthermore, a "disequilibrium" incubation was developed as an alternative to the acetylation method to increase the sensitivity of the radioimmunoassay. Thus, the levels of both cyclic GMP and cyclic AMP can be determined rapidly and easily in the same tissue sample.

Animals↗

PubMed1977

Stimulation by cyclic nucleotides of prostaglandin E production in isolated graafian follicles.

Rat Graafian follicles isolated intact responded to 8-Br-cyclic AMP and 8-Br-cyclic GMP with increased prostaglandin E (PGE) production during a 6 h incubation. By contrast, 8-Br-cyclic IMP, 8-Br-5' AMP and 8-Br-5' GMP were inactive in this respect. The effect of 8-Br-cyclic AMP and 8-Br-cyclic GMP was noted only after a lag period of about 4 h. Choleragen, LH, and the phosphodiesterase inhibitor (3-isobutyl-l-methyl-xanthine; IBMX) also stimulated PGE production. Actinomycin D and cycloheximide given simultaneously with 8-Br-cyclic AMP or LH prevented the stimulatory effect of these agents. Concomitant addition of arachidonic acid did not overcome the effect of these inhibitors. Administration of hCG in vivo or incubation with LH in vitro did not elevate endogenous ovarian free arachidonate, while PGE production was enhanced. Dexamethasone prevented this stimulatory effect of hCG. Collectively, the results suggest that stimulation of ovarian PGE production by cyclic nucleotides and LH is dependent on de novo synthesis of one or more components of the PG synthetase system rather than on substrate availability. Cyclic nucleotides may mediate the stimulatory effect of gonadotropins on PGE production.

Adenosine Monophosphate↗

PubMed1975

Cyclic adenosine monophosphate receptor: effect of cyclic AMP analogues on DNA binding and proteolytic inactivation.

The cyclic AMP receptor protein of Escherichia coli in the presence of cyclic AMP undergoes a conformational change resulting in an increased affinity for DNA and an increased susceptibility to attack by proteolytic enzymes resulting in loss of DNA binding capacity. Of several cyclic nucleotides tested only cyclic AMP and cyclic tubercidin monophosphate are able to effect the conformational transition in cyclic AMP receptor protein, prerequisite to proteolytic inactivation or DNA binding. Other analogues such as cyclic GMP or cyclic IMP which are competitive inhibitors of cyclic AMP do not support DNA binding or proteolytic inactivation.

Bacterial Proteins↗

PubMed1972

The effect of prostaglandins on ox pituitary content of adenosine 3':5'-cyclic monophosphate and the release of growth hormone.

1. An assay, based on competition between adenosine 3':5'-cyclic monophosphate (cyclic AMP) and cyclic [(3)H]AMP for binding to a rabbit skeletal muscle protein, has been used to measure tissue contents of cyclic AMP. The assay has a sensitivity of 0.05pmol of cyclic AMP. Cyclic GMP and cyclic CMP have 0.5%, and cyclic IMP 6.5%, of the ability of cyclic AMP to displace cyclic [(3)H]AMP from binding protein; AMP, ADP and ATP have no effect. 2. By using this method, the cyclic AMP content of ox pituitary slices exposed to prostaglandin was determined; release of growth hormone was measured by radioimmunoassay. 3. Release of growth hormone was increased by 45min incubation in 1mum-prostaglandin E(2) in the absence of theophylline, or in 10nm-prostaglandin E(2), 0.1mum-prostaglandin A(1) or 1mum-prostaglandin B(1) in the presence of 0.5mm-theophylline. 4. Pituitary cyclic AMP content was increased by 10min incubation in 1mum-prostaglandin E(2) in the absence of theophylline, or in 0.1mum-prostaglandin E(2) in the presence of 0.5mm-theophylline. 5. The maximum increase in cyclic AMP content was observed 10min, and significant changes in growth hormone release 30min, after introduction of prostaglandin E(2). 6. The increase in pituitary cyclic AMP content, but not in the rate of release of growth hormone, was observed in the absence of external Ca(2+). 7. The stimulation of release of growth hormone by prostaglandin was decreased by preincubation of tissue for 2h in colchicine (100mum) or cytochalasin B (10mug/ml). 8. These results support the suggestion that increased release of growth hormone after treatment with prostaglandin is the result of increased tissue cyclic AMP content, and possibly involves a microfilamentous or microtubular protein.

Animals↗