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PubMed1979

Determination of binding parameters of cyclic AMP and its analogs to cyclic AMP-dependent protein kinase by the fluorescent probe method.

The method for determination of dissociation constants for cyclic AMP and its analogs bound to cyclic AMP-dependent protein kinase from pig brain is described. The technique for measuring the binding parameters of the ligands is based on the changes in the fluorescent spectrum of etheno cyclic AMP once it is bound to protein kinase. The dissociation constants for a number of nonfluorescent cyclic AMP analogs were determined in the competitive displacement of etheno cyclic AMP by these analogs. The number of cyclic AMP-binding sites in the pig brain protein kinase was found to be 2.2; no cooperativity was observed upon binding. The holoenzyme complex (Mr = 180,000) of the protein kinase under study was established to have the stoichiometry of R2C2 type under native conditions.

Animals↗
PubMed2005

Development of quality evaluation sensor for fish freshness control based on KI value.

Recently, raw fish, sashimi, is becoming a popular dish in countries other than Japan. Therefore, in order to assure that the raw fish and shellfish are safe for human consumption, a quality evaluation sensor, which shows, at a glance, the quality of sashimi, was developed. The proposed sensor is based on the principle that the freshness of sashimi, which is judged from the KI value, can be determined from the degree of color change of thiazole blue (MTT: 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) due to the redox reaction of MTT accompanying the oxidation of hypoxanthine (Hx) by xanthine oxidase (XOD). The proposed sensor consists of 5 ml of 80% ethanol-1 M Tris-HCl buffer (pH 7.8) containing 2.0 mg of Hx, 2.0 mg of MTT and 0.38 unit of XOD. The proposed sensor and fish were kept together at 5, -10 and -20 degrees C, and the freshness of sashimi stored at each temperature was determined from the color change of the sensor. The concept "freshness of sashimi" can be expressed as remaining of validity (RDV), which is described in our previous study. A good relationship was obtained between the KI value and the RDV determined by the proposed sensor. From these results, the proposed sensor system can be used to non-destructively determine the fish freshness and RDV.

Animals↗
PubMed1976

Isolation and properties of a cyclic guanosine-monophosphate sensitive intracellular ribonuclease from Bacillus subtilis.

A ribonuclease was isolated and completely purified from sporulating cells of Bacillus subtilis. This RNase has a M.W. of about 150,000 daltons. It hydrolyzes single stranded RNA and single stranded synthetic polynucleotides yielding nucleoside 5'-monophosphates. The enzyme is an exonuclease which degrades polynucleotides from the 3'-end in the direction of the 5'-terminal. The RNase activity is strikingly inhibited by cGMP and to a lesser extent by cAMP. This inhibition (Ki = 0.1 mM) is of a non competitive nature. It appeared that in addition to the inhibition site, the enzyme contains a high affinity binding site for the two cyclic mononucleotides (K (cAMP) = 8.3 x 10-8; K (cGMP) = 2.5 x 10-7). The RNase activity is also strongly inhibited by spermidine. This inhibition appeared to be due to the polyamine binding with the RNA, thus lowering the affinity of the substrate for the active site of the enzyme. This RNase may play a role in vivo in selective degradation of newly synthesized mRNA during sporulation.

Bacillus subtilis↗
PubMed1976

2' Derivatives of guanosine and inosine cyclic 3',5'-phosphates. Synthesis, enzymic activity, and the effect of 8-substituents.

A series of representative derivatives of guanosine cyclic 3',5'-phosphate (cGMP) and inosine cyclic 3',5'-phosphate (cIMP) which contained modifications in either the 2' position or the 8 and 2' positions were synthesized. Three types of derivatives were investigated: (1) derivatives in which the 2' position has been altered to produce a 2'-deoxynucleoside cyclic 3',5'-phosphate or a 9-beta-D-arabinofuranosylpurine cyclic 3',5'-phosphate; (2) 2'-omicron-acyl derivatives; and (3) doubly modified derivatives containing a 2' modification [as in (1) and (2)] and an 8-substitution. 2'-Deoxyinosine cyclic 3',5'-phosphate and 9-beta-D-arabinofuranosylhypoxanthine cyclic 3',5'-phosphate were obtained by HNO2 deamination of 2'-deoxyadenosine cyclic 3',5'-phosphate and 9-beta-D-arabinofuranosyladenine cyclic 3',5'-phosphate (ara-cAMP), respectively. Treatment of 8-bromo-2'-omicron-(p-toluenesulfonyl) adenosine cyclic 3',5'-phosphate with NaSH yielded the intermediate 8,2'-anhydro-9-beta-D-arabinofuranosyl-8-mercaptoadenine cyclic 3',5-phosphate, which was converted directly to 2'-deoxyadenosine cyclic 3',5'-phosphate (dcAMP) by treatment with Raney nickel. 8-Bromo-2'-omicron-(p-toluenesulfonyl) guanosine cyclic 3',5'-phosphate was converted to 8,2'-anhydro-9-beta-D-arabinofuranosyl-8-mercaptoguanine cyclic 3',5'-phosphate, and the latter was desulfurized with Raney nickel to give 2-deoxyguanosine cyclic 3',5'-phosphate. Ara-cAMP, 9-beta-D-arabinofuranosylguanine cyclic 3',5'-phosphate, and 9-beta-D-arabinofuranosyl-8-mercaptoguanine cyclic 3',5'-phosphate have been previously reported (Mian et al. (1974), J. Med. Chem. 17, 259). 8-Bromo-2'-omicron-acetylinosine cyclic 3',5'-phosphate and 8-[(p-chlorophenyl)thio]-2'-omicron-acetylinosine cyclic 3',5'-phosphate were produced by acylation of 8-bromoinosine cyclic 3',5'-phosphate and 8-[(p-chlorophenyl)thio]inosine cyclic 3',5'-phosphate, respectively; while 8-bromo-2'-omicron-butyrylguanosine cyclic 3',5'-phosphate was synthesized by bromination of 2'-omicron-butyrylguanosine cyclic 3',5'-phosphate.

Animals↗
PubMed1975

2-substituted derivatives of adenosine and inosine cyclic 3',5'-phosphate. Synthesis, enzymic activity, and analysis of the structural requirements of the binding locale of the 2-substituent on bovine brain protein kinase.

A number of 2-substituted cyclic nucleotide derivatives were synthesized and investigated as activators of cAMP-dependent protein kinase and as substrates for and inhibitors of cAMP phosphodiesterase. Ring closure of 5-amino-1-beta-D-ribofuranosylimidazol-4-carboxamide cyclic 3',5'-phosphate (1) with various aldehydes according to a new procedure (Meyer, R. B., Jr., Shuman, D.A., and Robins, R. K. (1974), J. Am. Chem. Soc. 96, 4962) gave new derivatives of adenosine cyclic 3',5'-phosphate with the following 2-substituents: n-propyl, n-hexl, n-octyl, n-decyl, styryl, o-methoxyphenyl, and 2-thienyl. Alkylation of 2-mercaptoadenosine cyclic 3',5'-phosphate (20, Meyer et al., 1974) gave new cAMP derivatives with the following 2-substituent: ethylthio, n-propylthio, isopropylthio, allylthio, n-decylthio, and benzylthio. Deamination of 2-methyl-,2-n-butyl-, and 2-ethylthioadenosine cyclic 3',5'-phosphate. Using multiple regression analysis, a striking relationship was found between the relative potency of the compounds as activators of bovine brain cAMP-dependent protein kinase and parameters describing the hydrophobic, steric, and electronic character of the substituents on these compounds. All compounds were substrates for a cyclic nucleotide phosphodiesterase preparation from rabbit kidney. Additionally, the compounds were as a group, good inhibitors of the hydrolysis of cAMP by phosphodiesterase preparations from rabbit lung, beef heart, and dog heart.

Animals↗
PubMed2006

Structural determinants for N1/N7 cyclization of nicotinamide hypoxanthine 5'-dinucleotide (NHD+) derivatives by ADP-ribosyl cyclase from aplysia californica: Ca2+-mobilizing activity of 8-substituted cyclic inosine 5'-diphosphoribose analogues in T-lymphocytes.

A series of nicotinamide hypoxanthine 5'-dinucleotide (NHD+) analogues modified at C-8 (2-5) and 7-deaza-NHD+ were synthesized, and cyclization in the presence of Aplysia ADP-ribosyl cyclase was studied. All 8-substituted NHD+ analogues were converted into their N1-cyclic forms by the enzyme, while in contrast, 7-deaza-NHD+ 17 was hydrolyzed into 7-deazainosine 5'-diphosphoribose (7-deaza-IDPR) 25. Correlations are made showing that the conformation of the NHD+ substrate is the key to successful cyclization. The pharmacological activities of these novel cIDPR derivatives were evaluated in both permeabilized and intact Jurkat T-lymphocytes. The results show that in permeabilized cells both 8-iodo 1g and 8-N3-N1-cIDPR 1d have an activity comparable to that of cADPR, while 8-iodo 1g and 8-phenyl-N1-cIDPR 1c have a small but significant effect in intact cells and can therefore be regarded as membrane-permeant; thus, cIDPR derivatives are emerging as important novel biological tools to study cADPR-mediated Ca2+ release in T-cells.

ADP-ribosyl Cyclase↗
PubMed1974

A study of 3':5'-cyclic mononucleotide-dependent protein kinase from canine prostate glands.

1. An adenosine 3':5'-cyclic monophosphate (cyclic AMP)-dependent protein kinase, located predominantly in the cytosol, was studied in canine prostate. 2. The enzyme exhibited cyclic AMP-binding activity, and could be isolated by chromatography on diethylaminoethyl cellulose. 3. The enzyme was maximally stimulated (fourfold) by 1mum-cyclic AMP, and half-maximal activation of the enzyme was observed in presence of 50nm-cyclic AMP. 4. Equilibrium studies at pH5.0 indicated the presence of one major class of binding site for cyclic AMP, with an association constant of approx. 10(8)m(-1). 5. Stimulation of the enzyme was also observed with the 3':5'-cyclic monophosphate derivatives of cytidine, inosine, guanosine and uridine as well as with dibutyryl cyclic AMP, but higher concentrations of these cyclic nucleotides were required to provide the same degree of activation as that seen with cyclic AMP. 6. Comparing alpha-casein, protamine and different histone subfractions as substrates, highest cyclic AMP stimulation was demonstrated with histones. 7. Although maximum velocity of the enzyme was enhanced approximately fivefold in presence of cyclic AMP, kinetic studies indicated that the apparent K(m) for histone (0.5mg/ml) remained the same whether determined in the presence or absence of the cyclic nucleotide. 8. In addition, cyclic AMP did not significantly change the apparent K(m) for ATP (1.2x10(-5)m). 9. The purified enzyme showed an absolute requirement for bivalent metal ion. Substitution of Mn(2+) for Mg(2+) decreased basal protein kinase activity as well as the stimulation noted with cyclic AMP. Similarly, the basal activity was lowered when Mg(2+) was replaced by Ca(2+) and cyclic AMP produced only little stimulation of the prostatic enzyme.

Adenosine Triphosphate↗
PubMed1997

Identification of critical determinants for autoinhibition in the pseudosubstrate region of type I alpha cAMP-dependent protein kinase.

The consensus substrate site for cAMP-dependent protein kinase (PKA) is Arg-Arg-Xaa-Ser(P)-Xaa and the autoinhibitory domain of the PKA type I alpha regulatory subunit (RI subunit) contains a similar sequence, Arg92-Arg-Arg-Arg-Gly-Ala-Ile-Ser-Ala-Glu. The italicized amino acids form a putative pseudosubstrate site (Ser is replaced with Ala), which together with adjacent residues could competitively inhibit substrate phosphorylation by the PKA catalytic subunit (C subunit). The present studies determine the contributions of Arg92-95, Ile98, and Glu101 to inhibitory potency. Amino-terminal truncation of RI subunit through Arg92 (delta1-92) or Arg93 (delta1-93) had no detectable effect on inhibition of C subunit. Truncation through Arg94 (delta1-94), or point mutation of Arg95 within truncated mutants (delta1-93.R95A or delta1-92.R95A), caused a dramatic reduction in inhibitory potency. Truncation through Arg95 (delta1-95) had a greater effect than did replacement or deletion of Arg94 or Arg95 alone. Using full-length RI subunit, the inhibitory potency was reduced by replacing Ile98 with Ala, Gly, or Gln, but not by replacing it with Val. The inhibitory potency of RI subunit was unchanged when Glu101 was replaced with Ala or Gln. It is concluded that Arg94, Arg95 and, to a lesser extent, Ile98 are vital constituents of PKA autoinhibition by type I alpha R subunit.

Animals↗
PubMed1981

Distribution of cyclic-GMP-dependent protein kinase in various rat tissues and cell lines determined by a sensitive and specific radioimmunoassay.

Cyclic-GMP-dependent protein kinase purified from bovine lung was radioiodinated by the Bolton-Hunter procedure yielding a specific radioactivity of 2200 Ci/mmol of enzyme, Using a specific precipitating rabbit antiserum to the cyclic-GMP-dependent protein kinase, a sensitive radioimmunoassay was developed which can detect 200 pg (1.33 fmol) of cyclic GMP-dependent protein kinase. Immunoreactivity like that of cyclic-GMP-dependent protein kinase was detectable in extracts of all rat tissues tested, in extracts of cultured rat brain and heart cells, and in extracts of rat glioma (C6) and neuroblastoma x glioma hybrid cells. In extracts of several tissues and cell lines the presence of cyclic-GMP-dependent protein kinase was also demonstrated by a photoaffinity-labeling procedure using 8-azidoinosine 3',5'-[32P]monophosphate. The results suggest that cyclic-GMP-dependent protein kinase is ubiquitously distributed although its level varies significantly from tissue to tissue and cell type to type. The results also support the hypothesis that cyclic-GMP-dependent protein kinase is involved in mediating some of the intracellular effects of those hormones, neurotransmitters and drugs which regulate the intracellular level of cyclic GMP.

Animals↗
PubMed1975

Transient repression of catabolite-sensitive enzyme synthesis elicited by 2,4-dinitrophenol.

Transient inhibition of catabolic enzyme synthesis in Escherichia coli occurred when a low concentration of 2,4-dinitrophenol (DNP) was simultaneously added with inducer. Using mutant strains defective for gamma-gene product or constitutive for lac enzymes, it was found that the inhibition is not due to the exclusion of inducer by uncoupling. The addition of cyclic adenosine 3',5'-monophosphate overcame repression. The components of the lac operon coordinately responded to DNP inhibition. From deoxyribonucleic acid-ribonucleic acid hybridization experiments, it was found that the inhibition of beta-galactosidase induction occurred at the level of messenger ribonucleic acid synthesis specific for the lac operon. It seems probable that DNP represses induction in a similar manner to that of transient repression observed upon the addition of glucose. Furthermore, it was found that transient repression disappeared if cells were preincubated with DNP before induction. This indicates that new contact of cells with DNP is obligatory for transient repression. From these results, it is suggested that the cell membrane may be responsible for regulation of catabolite-sensitive enzyme synthesis.

Biological Transport, Active↗
PubMed1982

Cyclic nucleotide antagonists of cholecystokinin: structural requirements for interaction with the cholecystokinin receptor.

Previously, we have found that, in pancreatic acini, butyryl derivatives of cGMP antagonize the action of cholecystokinin by inhibiting binding of the peptide to its membrane receptors. In the present study, we found that derivatives of cAMP and cIMP can also inhibit binding of cholecystokinin as well as its actions on acinar cell function. Moreover, the inhibition caused by cyclic nucleotide derivatives did not require the presence of a butyryl moiety, because certain 8-bromo-cyclic nucleotides also inhibited the interaction of cholecystokinin with its receptors. Cyclic nucleotide derivatives can also increase pancreatic enzyme secretion; however, for the various cyclic nucleotides tested, there was no apparent correlation between their abilities to stimulate enzyme secretion and their abilities to antagonize the actions of cholecystokinin. Finally, cyclic nucleotide derivatives also inhibited binding of 125I-cholecystokinin to antibodies that were specific for the biologically active, C-terminal region of cholecystokinin. Thus, certain cyclic nucleotide derivatives possess a conformational structural which resembles that of the biologically active portion of cholecystokinin, and this structural similarity accounts for the abilities of these nucleotide derivatives to interact with cholecystokinin receptors and, by so doing, to inhibit the action of cholecystokinin on its target tissues.

Animals↗
PubMed1977

Comparison of the effects of 6- thio- and 6-methylthiopurine ribonucleoside cyclic monophosphates withtheir corresponding nucleosides on the growth of rat hepatoma cells.

The cyclic nucleotide forms of 6-mercaptopurine and 6-methylmercaptopurine have been found to be cytotoxic to rat hepatoma cells. Studies with an inhibitor of phosphodiesterase suggest that the cytotoxicity of both cyclic nucleotides results principally from conversion to the 5'-nucleotide. A comparison of the two thiopurine cyclic nucleotides with their nucleoside counterparts has suggested that (a) the thio derivatives act by a common mechanism which is different from that exerted by the methylthio derivatives, and (b) the methylthio cyclic nucleotide acts, at least in part, by a mechanism which differs from that exerted by the methylthio nucleoside.

Carcinoma, Hepatocellular↗