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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Based on the chemotactic activity of approximately 50 different adenosine 3',5'-cyclic-monophosphate (cyclic AMP) derivatives with substitutions at the phosphate, ribose and adenine moieties, a model for the cyclic AMP-chemoreceptor interaction in Dictyostelium discoideum is proposed. In this model the cyclic AMP molecule is bound to the receptor by three hydrogen bonds at, respectively, the 3'-oxygen of the ribose and the 6-amino and the 7-nitrogen of the base, and possibly by one ionic interaction of the negatively charged phosphate group. The conformation of the adenine moiety is in the anti range and binds additionally to the receptor by hydrophobic interactions betueen its pi-electron system and a corresponding acceptor at the active site. Although this receptor clearly differs from that involved in protein kinase activation in higher organisms, the existence of striking similarities suggests a basic mechanism for cyclic AMP interaction conserved during evolution.
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PMID:A model for cyclic AMP-chemoreceptor interaction in Dictyostelium discoideum. 21 55

The cAMP receptor site in the regulatory subunit of adenosine 3':5'-monophosphate (cAMP)-dependent protein kinase type I was mapped using analogues of cAMP in which the ribose phosphate moiety was systematically modified. Electronical alteration of the cyclophosphate ring at the 3' and 5' positions by sulfur and nitrogen decreased the affinity of these analogues towards the kinase. Substituents at these positions are not tolerated. Testing the separated diastereomers of derivatives in which one of the exocyclic oxygens at the phosphorus has been substituted by sulfur, it was found that one diastereoisomer is preferentially recognized. Based on these results it is proposed that the hydrophylic cyclic phosphate-ribose moiety of cAMP is bound to the kinase via its 3' and 5'-oxygens, the 2'-hydroxy group and the negative charge in a fixed position. Based on our and other published results it is further proposed, that the adenine moiety is bound in a hydrophobic cleft without any hydrogen bond interactions. The chemical interactions between cAMP and the R subunit of protein kinase type I differ from those found for the binding of cAMP to the chemoreceptor of Dictyostelium discoideum [18].
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PMID:A model for the chemical interactions of adenosine 3':5'-monophosphate with the R subunit of protein kinase type I. Refinement of the cyclic phosphate binding moiety of protein kinase type I. 23 34

Influenza A virus (IAV) activates the human neutrophil, but induces a dysfunctional state as well. Cell activation may contribute to the containment of the virus and/or cause local tissue damage. Certain features of the neutrophil activation response elicited by IAV are distinctive when compared with that triggered by formyl-methyl-leucyl-phenylalanine (FMLP). An atypical respiratory burst response occurs in which hydrogen peroxide, but no superoxide, is formed. This unusual respiratory burst stoichiometry persists despite marked priming of the IAV-induced response. A comprehensive examination of the activation cascade initiated by these stimuli failed to show an explanation for these differences. Both IAV and FMLP comparably stimulate inositol trisphosphate and phosphatidic acid production. The subsequent increase in intracellular calcium (Ca2+i) upon FMLP stimulation was more dependent on extracellular Ca2+ than with IAV activation, but both stimuli induced Ca2+ influx. FMLP and IAV exhibited equal susceptibility to inhibition by protein kinase inhibitors in eliciting the respiratory burst, and actin polymerization occurred in response to each agonist. A possible explanation for the anomalous respiratory burst induced by IAV is that O2- is generated at an intracellular site inaccessible to assay, and/or virus binding to sialic acid constituents of the plasma membrane alters the O2- generating capacity of the respiratory burst oxidase; evidence for each mechanism is offered.
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PMID:Comparison of influenza A virus and formyl-methionyl-leucyl-phenylalanine activation of the human neutrophil. 131 Jun 28

The structure of the cyclic GMP-binding domain of the cyclic GMP-gated ion channel from bovine retinal rod photoreceptors has been modeled by analogy to the crystal structure of the homologous cyclic AMP-binding domain of catabolite gene activator protein (CAP). The modeled cyclic GMP-binding domain has a three-residue deletion and a five-residue insertion between beta strands compared to CAP. The major interactions of the ion channel with cyclic GMP are similar to those observed for cyclic AMP bound to CAP and predicted for cGMP bound to the cGMP-dependent protein kinase: Gly 543 and Glu 544 make hydrogen-bond interactions with the ribose 2'-OH, Arg 559 forms an ion pair with the charged phosphate oxygen, and Thr 560 forms hydrogen-bond interactions with an exocyclic phosphate oxygen and with the 2-amino group of cGMP. Three additional potential interactions were predicted from the model structure. Ile 545 O and Ser 546 OH form hydrogen-bond interactions with an exocyclic phosphate oxygen, and Phe 533 may interact with the aromatic ring of cGMP. This model is in agreement with both the analogue binding experiments and the mutational analysis of Thr 560.
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PMID:Molecular model of the cyclic GMP-binding domain of the cyclic GMP-gated ion channel. 131 56

A series of novel adenosine 3',5'-cyclic monophosphate (cAMP) analogues, as well as their 6-deamino and 6-nitro derivatives, were synthesized where the purine ring was replaced by indazole, benzotriazole, and benzimidazole. The 3',5'-cyclic monophosphates of indazole and benzotriazole ribofuranosides, where the sugar-phosphate moiety is attached to the N-2 nitrogen atoms of the heterocycles, were also prepared. The biological efficiency of the analogues was tested by their ability to activate purified cAMP-dependent protein kinase I (PK-I) from rabbit skeletal muscle and cAMP-dependent protein kinase II (PK-II) from bovine heart. Each cyclic nucleotide is capable of activating both PK isozymes in half-maximum concentrations (Ka) ranging from 2.0 x 10(-8) to 4.8 x 10(-6) M. The cyclic phosphate of N-1-beta-D-ribofuranosylindazole (13) proved to be a very poor activator for both PK-I and PK-II, but when indazole binds by N-2 to ribose or when the hydrogen atom at C-4 is substituted by a nitro or amino group, activities of the analogues increase considerably. The activating potencies of benzotriazole derivatives are similar to that of cAMP, irrespective of the C-4 substituents. The Ka' values of cyclic nucleotides containing benzimidazole were found to be higher for PK-II than for PK-I; e.g. the activity of 4-nitro-1-beta-D-ribofuranosylbenzimidazole 3',5'-cyclic monophosphate (32) is nearly 20 times as high for PK-II than for PK-I.
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PMID:Synthesis and enzymatic activity of some new purine ring system analogues of adenosine 3',5'-cyclic monophosphate. 133 76

Flavonols are dietary compounds widely distributed in plants and characterized by a 2-phenyl-benzo(alpha)pyrane nucleus possessing hydroxyl and ketone groups at positions 3 and 4, respectively. Kaempferol, quercetin, and myricetin are flavonols that are further mono-, di-, or trihydroxylated on the phenyl ring, respectively. To test whether these ingested flavonols might exert a direct secretory effect on intestinal epithelial cells, monolayers of the T84 colonocyte cell line were mounted in Ussing chambers and examined for ion transport response. Twenty minutes after addition of 100 microM quercetin to either the serosal or mucosal side, the short-circuit current change was maximal at 16.6 microA/cm2. Kaempferol was less potent than quercetin, while myricetin and glycosylated quercetin (rutin) did not induce secretion. The secretion induced by quercetin did not seem to be mediated by the reactive oxygen species generated by quercetin through auto-oxidation and/or redox cycling (superoxide, hydrogen peroxide, and the hydroxyl radical) because it was neither enhanced by iron, nor inhibited by desferroxamine B or catalase (alone or in combination with superoxide dismutase). Like vasoactive intestinal peptide, quercetin induced a secretory response that was inhibited by barium chloride and bumetanide, and which exhibited synergism with carbachol. Quercetin also stimulated a modest increase in intracellular cAMP levels and the phosphorylation of endogenous protein substrates for cAMP-dependent protein kinase. Thus, quercetin is a potent stimulus of colonocyte secretion that resembles secretagogues which act via a cAMP-mediated signaling pathway.
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PMID:Stimulation of secretion by the T84 colonic epithelial cell line with dietary flavonols. 164 52

The treatment of human peripheral blood monocytes with serotonin at concentrations 10(-3) and 10(-5) M over 20 minutes decreases a zymosan-induced luminol-dependent chemiluminescence of cells, whereas a 5 minutes treatment with serotonin at the concentration of 10(-5) M increases the chemoluminescence. The correlated change in monocyte capacity of secreting hydrogen peroxide has been registered. Serotonin activates, to a little extent, the monocyte capacity of phagocytizing the opsonised sheep erythrocyte. The maximum increase (2-3 times) of intracellular cAMP content and the decrease in cytosol cAMP-binding capacity are registered after a 5 minutes incubation. The lowering of the share of irreversibly bound in vitro cAMP under the influence of serotonin may suggest a preferable binding of cyclic nucleotide in vivo by regulatory subunits of cAMP-dependent protein kinase I.
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PMID:[The effect of serotonin on the functional activity of monocytes]. 165 Sep 68

The cAMP-dependent protein kinase contains two different cAMP-binding sites referred to as the slow and fast sites. Mutation of Ala-334 to a threonine in the slow site of the bovine type I regulatory subunit created a site with marked increase in cGMP affinity without changing cAMP affinity (Shabb, J. B., Ng. L., Corbin, J. D. (1990) J. Biol. Chem. 265, 16031-16034). The corresponding fast site residue (Ala-210) was changed to a threonine by oligonucleotide-directed mutagenesis, and a double mutant containing a threonine in each site was also made. Holoenzymes were formed from native catalytic subunit and each recombinant regulatory subunit. The fast site mutant holoenzyme exhibited an improved cGMP activation constant and an impaired cAMP activation constant. The double mutant cGMP/cAMP selectivity was 200-fold greater than that of wild-type holoenzyme, making it as responsive to cGMP as native cGMP-dependent protein kinase. The increased intrinsic binding energies of mutated sites for cGMP were 2.7-3.0 kcal mol-1, consistent with the presence of an extra hydrogen bond. Cyclic nucleotide analog studies implied that this hydrogen bond was between the threonine hydroxyl and the 2-amino of cGMP. Comparisons of amino acid sequences and cyclic nucleotide specificities suggested that the Ala/Thr difference may also impart cAMP/cGMP binding selectivity to related proteins such as cyclic nucleotide-gated ion channels.
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PMID:Mutating protein kinase cAMP-binding sites into cGMP-binding sites. Mechanism of cGMP selectivity. 166 9

Each regulatory (R) subunit of cAMP-dependent protein kinase contains an autoinhibitor site that lies approximately 90-100 residues from the amino terminus. In order to study the importance of this autoinhibitor site in the type I R-subunit for interacting with the catalytic (C) subunit, recombinant techniques were used to replace Ala-97 with Gln, His, Lys, and Arg and to replace Ser-99 with Gly and Lys. All of the mutant proteins having a replacement at Ala-97 showed reduced affinity for the C-subunit ranging from 14- to 55-fold. In general, the decrease in affinity of the Ala-97 mutants for the C-subunit correlated with the increase in size of the side chain. In contrast to wild type R-subunit, where MgATP facilitates holoenzyme formation, MgATP inhibits the reassociation in all of the Ala-97 mutants suggesting that the larger side chains sterically interfere with bound MgATP in the active site of the C-subunit. Whereas MgATP slowed holoenzyme formation, AMP actually accelerated the reassociation of the A97K, A97H (pH 6.0), and A97Q mutants with the C-subunit. Therefore, the side chains of Lys-97, His-97, and Gln-97 can interact either electrostatically or by hydrogen bonding with the phosphate of AMP. This interpretation is reinforced by the fact that the stimulatory effect of AMP on the A97H mutant was pH-dependent. The affinities of the S99G and S99K mutants for the C-subunit were reduced 7- and 24-fold, respectively, suggesting that Ser-99 also may contribute to interactions between the R- and C-subunits.
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PMID:Mutations in the autoinhibitor site of the regulatory subunit of cAMP-dependent protein kinase I. Replacement of Ala-97 and Ser-99 interferes with reassociation with the catalytic subunit. 184 75

In luteal and granulosa cells, hydrogen peroxide abruptly inhibits activation of adenylate cyclase by receptor-bound gonadotropin and blocks steroidogenesis. In the present studies a post-cAMP site of peroxide action on inhibition of steroidogenesis was investigated. Steroidogenesis, stimulated by dibutyryl or 8-bromo-cAMP, was inhibited by hydrogen peroxide. Yet, cAMP-dependent protein kinase activation in cytosol or intact cells was unaffected by peroxide treatment. Hydrogen peroxide also did not inhibit the activity of cholesterol esterase and acyl coenzyme-A:acyltransferase. Progesterone synthesis was maximally increased 5- to 50-fold with 25- and 22-hydroxycholesterol, respectively. Unlike that seen with cAMP analogs and LH, however, progestin synthesis stimulated by these cell- and mitochondria-permeant cholesterol analogs was not inhibited by hydrogen peroxide. Treatment of animals with amino-glutethimide produces a marked accumulation of steroidogenic cholesterol substrate and a large increase in hormone-independent steroidogenesis in subsequently isolated and washed luteal tissue. In this paradigm, hydrogen peroxide did not inhibit elevated basal progesterone synthesis in luteal cells produced by in vivo aminoglutethimide treatment, yet LH-stimulated steroidogenesis was blocked. However, treatment of luteal cells with hydrogen peroxide inhibited pregnenolone synthesis in isolated mitochondria, an effect partially reversed by the addition of luteal cell cytosol. In summary, while peroxide inhibited cAMP-dependent steroidogenesis, it did not appear to inhibit protein kinase activation or mobilization of cholesterol from intracellular esterified stores. Although peroxide inhibited pregnenolone synthesis, it had no effect on steroidogenesis when substrate was made available by either addition of cholesterol analogs or prior treatment with aminoglutethimide in vivo. We conclude, therefore, that hydrogen peroxide inhibits steroidogenesis by blocking intracellular transport of cholesterol to mitochondria or translocation of cholesterol across the outer mitochondrial membrane.
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PMID:Evidence that hydrogen peroxide blocks hormone-sensitive cholesterol transport into mitochondria of rat luteal cells. 203 71


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