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)

In rat pancreatic islets perifused in the presence of 2-cyclohexene-1-one (CHX; 1.0 mM), the secretory response to either D-glucose or 2-ketoisocaproate, but not that evoked by the association of L-leucine and L-glutamine, was severely decreased. This coincided with a decreased stimulation of [45Ca] efflux from prelabelled islets, whereas the inhibitory action of D-glucose or 2-ketoisocaproate upon both [86Rb] and [45Ca] efflux appeared little or not affected. In the presence of D-glucose, the islets exposed to CHX were virtually unresponsive to either forskolin, theophylline or cytochalasin B. A severe decrease in the secretory response to forskolin was also observed in CHX-treated islets exposed to L-leucine and L-glutamine. Except for a somewhat lower sensitivity to NaF, no major change in adenylate cyclase activity or cyclic AMP production was observed in CHX-treated islets. The activity of protein kinase A was decreased in such islets but its responsiveness to cyclic AMP appeared unaltered. Transglutaminase activity was severely decreased in homogenates derived from CHX-treated islets. These findings suggest that CHX, possibly by lowering the GSH content of islet cells, impairs the functional capacity of the effector system for insulin release, in addition to and independently of any effect that it may exert upon nutrient catabolism and cationic fluxes in the islet cells.
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PMID:The coupling of metabolic to secretory events in pancreatic islets: inhibition by 2-cyclohexene-1-one of the secretory response to cyclic AMP and cytochalasin B. 287 68

Mutations in the SSN6 gene suppress the invertase derepression defect caused by a lesion in the SNF1 protein kinase gene. We cloned the SSN6 gene of Saccharomyces cerevisiae and identified its 3.3-kilobase poly(A)-containing RNA. Disruption of the gene caused phenotypes similar to, but more severe than, those caused by missense mutations: high-level constitutivity for invertase, clumpiness, temperature-sensitive growth, alpha-specific mating defects, and failure to homozygous diploids to sporulate. In contrast, the presence of multiple copies of SSN6 interfered with derepression of invertase. An ssn6 mutation was also shown to cause glucose-insensitive expression of a GAL10-lacZ fusion and maltase. The mating defects of MAT alpha ssn6 strains were associated with production of two a-specific products, a-factor and barrier, and reduced levels of alpha-factor; no deficiency of MAT alpha 2 RNA was detected. We showed that ssn6 partially restored invertase expression in a cyr1-2 mutant, although ssn6 was clearly not epistatic to cyr1-2. We also determined the nucleotide sequence of SSN6, which is predicted to encode a 107-kilodalton protein with stretches of polyglutamine and poly(glutamine-alanine). Possible functions of the SSN6 product are discussed.
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PMID:Molecular analysis of SSN6, a gene functionally related to the SNF1 protein kinase of Saccharomyces cerevisiae. 331 83

To characterize the regulation of ammoniagenesis and gluconeogenesis in renal proximal tubule, ammonia and glucose productions were measured in suspensions of canine proximal tubular segments incubated with 10 mM L-glutamine. Productions were linear functions of time for 120 min and were decreased as extracellular pH was increased from 7.0 to 7.5 To ascertain whether activation of protein kinase c affects either process, we incubated segments with tumor-promoting phorbol esters, 12-O-tetradecanoylphorbol-13-acetate (TPA), or phorbol 12,13-dibutyrate, or with the inactive phorbol ester 4 alpha-phorbol. Ammoniagenesis and gluconeogenesis were inhibited by incubation with 10(-6) M of the two former compounds but not the latter compound. Inhibition of ammoniagenesis and gluconeogenesis occurred after incubation with as little as 10(-9) M phorbol 12,13-dibutyrate. Phorbol ester-induced inhibition was observed under conditions such that extracellular [Na+] was greater than intracellular [Na+], but not when extracellular [Na+] equaled intracellular [Na+], and was not observed in the presence of amiloride. Our findings are consistent with a role for protein kinase c in the control of ammoniagenesis and gluconeogenesis in proximal tubule. Such control could be mediated via stimulation of Na+-H+ exchange.
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PMID:Phorbol esters inhibit ammoniagenesis and gluconeogenesis in proximal tubular segments. 347 39

Ornithine decarboxylase may undergo posttranslational modifications which alter its function. Both transamidation of glutamine residues in the enzyme catalyzed by TGase and phosphorylation of serine and threonine residues catalyzed by a polyamine-stimulated protein kinase have been demonstrated. Data are presented which suggest that these modifications result in translocation of the modified protein to the nucleolus where it regulates the activity of RNA polymerase I to transcribe rDNA, the only active nucleolar genes. Transamidation of specific proteins with primary amines catalyzed by intracellular TGase may be an important posttranslational modification, capable of altering genetic transcription. The rapid half-life of ODC (10-15 min) may be related to rapid posttranslational modification with loss of enzymatic activity rather than to protein degradation.
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PMID:Ornithine decarboxylase may be a multifunctional protein. 608 23

DARPP-32 is a neuronal phosphoprotein of Mr = 32,000, originally identified in rat brain (Walaas, S.I., D.W. Aswad, and P. Greengard (1983) Nature 301: 69-72). This protein has now been identified in bovine caudate nucleus cytosol and purified 435-fold to apparent homogeneity as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The purification procedure involved acid extraction at pH 2, CM-cellulose chromatography, DEAE-cellulose chromatography, hydroxylapatite chromatography, and gel filtration on Ultrogel AcA 44. The purified catalytic subunit of cAMP-dependent protein kinase catalyzed the incorporation of 0.96 mol of phosphate/mol of purified DARPP-32. Phosphorylation occurred exclusively on threonine. The isoelectric point of dephospho-DARPP-32 was 4.7, and that of phospho-DARPP-32 was 4.6. The amino acid composition showed a high content of glutamate/glutamine and proline, and a low content of hydrophobic amino acids. DARPP-32 was found to have a Stokes radius of 34 A and a sedimentation coefficient of 2.05 S, indicating that it exists as an elongated monomer.
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PMID:DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. II. Purification and characterization of the phosphoprotein from bovine caudate nucleus. 631 28

Insulin secretion has been studied in isolated rat pancreatic islets under stringent Ca(2+)-depleted, Ca(2+)-free conditions. Under these conditions, the effect of 16.7 mM glucose to stimulate insulin release was abolished. Forskolin, which activates adenylyl cyclase, also failed to stimulate release in the presence of either low or high glucose concentrations. A phorbol ester (phorbol 12-myristate 13-acetate; PMA) increased the release rate slightly and this was further increased by 16.7 mM glucose. Remarkably, in the presence of both forskolin and PMA, 16.7 mM glucose strongly augmented insulin release. The augmentation was concentration dependent and monophasic and had a temporal profile similar to the "second phase" of glucose-stimulated insulin release, which is seen under normal conditions when Ca2+ is present. Metabolism is required for the effect because mannoheptulose abolished the glucose response. Other nutrient secretagogues, alpha-ketoisocaproate, and the combination of leucine and glutamine augmented release under the same conditions. Norepinephrine, a physiological inhibitor of insulin secretion, totally blocked the stimulation of release by forskolin and PMA and the augmentation of release by glucose. Thus, under the stringent Ca(2+)-free conditions imposed, the stimulation of insulin release by forskolin and PMA, as well as the augmentation of release by glucose, is under normal physiological control. As no increase in intracellular [Ca2+] was observed, the results demonstrate that glucose can increase the rate of exocytosis and insulin release by pancreatic islets in a Ca(2+)-independent manner. This interesting pathway of stimulus-secretion coupling for glucose appears to exert its effect at a site beyond the usual elevation of intracellular [Ca2+] and is not due to an activation by glucose of protein kinase A or C.
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PMID:Glucose stimulation of insulin release in the absence of extracellular Ca2+ and in the absence of any increase in intracellular Ca2+ in rat pancreatic islets. 747 73

(1) Glucagon activates hepatic glutaminase in vivo. Mitochondria from glucagon-injected rats retain an enhanced capacity to catabolize glutamine and this is more sensitive to activation by inorganic phosphate. The glucagon-elicited stimulation of glutaminase is not evident in broken mitochondria. A similar activation of glutaminase occurs in a number of situations which are associated with elevated glucagon levels in vivo, i.e., after a high-protein meal, after injection of bacterial endotoxin and in diabetes mellitus. (2) Studies in isolated hepatocytes revealed that glutaminase could be activated, not only by glucagon, but also by a cell-permeable protein kinase A activator (Sp-cAMPS) and by a cell-permeable protein phosphatase 1 and 2A inhibitor (okadaic acid). However, the activation of glutaminase by glucagon was not inhibited by a cell-permeable protein kinase A inhibitor (Rp-8-Br-cAMPS). We suggest that the signalling pathway, for glutaminase activation by glucagon, is complex and possibly contains redundant elements.
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PMID:Hormonal control of hepatic glutaminase. 757 40

Adrenaline has recently been shown to stimulate both glucose metabolism and H2O2 release by macrophages but the activity of the key pentose phosphate pathway enzyme, glucose-6-phosphate dehydrogenase (which generates the NADPH crucial for the reduction of molecular oxygen), was reduced under these conditions [Costa Rosa, Safi, Cury and Curi (1992) Biochem. Pharmacol. 44, 2235-2241]. We report here that adrenaline activates another NADPH-producing enzyme, NADP(+)-dependent 'malic' enzyme, while also inhibiting glucose-6-phosphate dehydrogenase, via cyclic AMP-dependent protein kinase (PKA) activation. Regulation of glucose-6-phosphate dehydrogenase activity by PKA has not been reported elsewhere. The sparing of some glucose from pentose phosphate pathway consumption may be important in the provision of glycerol 3-phosphate which in the macrophage may be required for new phospholipid synthesis. Glutamine oxidation was also stimulated by adrenaline thus providing increased substrate (malate) for NADP(+)-dependent 'malic' enzyme and therefore shifting some of the burden of NADPH production from glucose to glutamine metabolism. We also report a novel synergistic effect of adrenaline and some bacterial products and/or gamma-interferon in stimulating secretory and metabolic pathways in macrophages which may be a part of a larger network of signals that lead to enhanced macrophage activity.
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PMID:Effect of adrenaline and phorbol myristate acetate or bacterial lipopolysaccharide on stimulation of pathways of macrophage glucose, glutamine and O2 metabolism. Evidence for cyclic AMP-dependent protein kinase mediated inhibition of glucose-6-phosphate dehydrogenase and activation of NADP+-dependent 'malic' enzyme. 765 15

Gq is the heterotrimeric guanine nucleotide-binding protein that activates the beta isoforms of phosphatidyl-inositol-specific phospholipase C (PI-PLC). The Gq alpha-subunit polypeptide (alpha qa) was N-terminally modified by addition of a 9-aa sequence, YPYDVPDYA. Placement of the 9-aa epitope tag at the N terminus allowed expression of functional alpha q polypeptides and selective identification of plasmid-expressed wild-type and mutant G-protein alpha subunits. Mutation of glutamine-209 to leucine in the N-terminally epitope-tagged alpha q (N(epi) alpha qQ209L) inhibited GTPase activity and persistently activated PI-PLC, resulting in high steady-state levels of inositol phosphates. The elevated levels of inositol phosphates resulting from N(epi) alpha qQ209L expression were similar to those obtained with carbachol activation of the M1 muscarinic acetylcholine receptor. The Gq-coupled M1 receptor, which stimulates PI-PLC activity, and phorbol esters, acting via protein kinase C, activate the cytoplasmic mitogen-activated protein kinase in COS cells. However, the constitutive activation of PI-PLC enzymatic activity resulting from expression of GTPase-deficient alpha q was unable to persistently activate this kinase. The results indicate that persistent PI-PLC activation is insufficient to sustain the stimulation of a cytoplasmic serine/threonine protein kinase regulated by Gq-coupled receptor signal-transduction pathways.
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PMID:Epitope-tagged Gq alpha subunits: expression of GTPase-deficient alpha subunits persistently stimulates phosphatidylinositol-specific phospholipase C but not mitogen-activated protein kinase activity regulated by the M1 muscarinic acetylcholine receptor. 768 19

It was previously proposed that the activation of rat liver phenylalanine hydroxylase (EC 1.14.16.1) by cAMP-dependent protein kinase-mediated phosphorylation of Ser-16 is due to the introduction of the negatively charged phosphate group. To explore the validity of this proposal, we have applied site-directed mutagenesis to specifically replace Ser-16 with negatively charged amino acids, glutamic and aspartic; with polar uncharged amino acids, asparagine and glutamine; with the positively charged amino acid lysine; and with the nonpolar hydrophobic amino acid alanine. The wild-type and mutant enzymes were purified to homogeneity, and the importance of Ser-16 in the activation of phenylalanine hydroxylase was examined by comparing the state of activation of the phosphorylated form of the wild-type hydroxylase with that of the mutants. The kinetic studies carried out on the wild-type phosphorylated hydroxylase showed that all the activation could be accounted for by an increase in Vmax with no change in Km for either phenylalanine or the pterin cofactor. Replacement of Ser-16 with a negatively charged residue, glutamate of aspartate, resulted in the activation of the hydroxylase by 2- to 4-fold, whereas replacement with glutamine, asparagine, lysine, or alanine resulted in a much more modest increase. Further, lysolecithin was found to stimulate the phosphorylated hydroxylase and the mutant enzymes S16E and S16D by a factor of 6-7. In contrast, the mutants S16Q, S16N, and S16A all showed the same magnitude of activation as the wild-type with lysolecithin. Therefore, this study demonstrates that activation of the enzyme by phosphorylation of Ser-16 by cAMP-dependent protein kinase is due to the introduction of negative charge(s) and strongly suggests the involvement of electrostatic interaction between the regulatory and catalytic domains of the hydroxylase.
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PMID:Further studies of the role of Ser-16 in the regulation of the activity of phenylalanine hydroxylase. 776 94


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