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At least 1,369 records · Page 76Linked to original sources
PubMed1980

Optimal spatial requirements for the location of basic residues in peptide substrates for the cyclic AMP-dependent protein kinase.

The specificity of the cyclic AMP-dependent protein kinase was examined using two series of dodecapeptides as substrates. One series consisted of peptides of the general sequence (Gly)x-Arg-Arg-(Gly)y-Ala-Ser-Leu-Gly in which x + y = 6. The other series consisted of peptides of the sequence (Gly)x-Lys-Arg-(Gly)y-Ala-Ser-Leu-Gly in which x + y was again equal to 6. The peptides Gly-Gly-Gly-Gly-Gly-Gly-Gly-Arg-Arg-Ser-Leu-Gly and Gly-Gly-Gly-Gly-Gly-Gly-Gly-Lys-Arg-Ser-Leu-Gly were also examined. In the series in which the adjacent arginines were located various distances from the serine, the substrate for which the enzyme clearly exhibited optimal kinetic constants contained one amino acid residue between the basic residues and serine. Direct binding studies of N alpha-[3H]acetyl peptides to catalytic subunit of cyclic AMP-dependent protein kinase revealed a correlation between binding affinity and the ability to serve as substrate for the enzyme. In the second series in which the adjacent basic amino acids were Lys-Arg, optimal kinetic constants were again obtained when these residues were separated from serine by a single amino acid. This latter result was surprising in view of phosphorylation site sequences in the known physiologically significant protein substrates for the kinase, since those containing Lys-Arg all contain two amino acids between these residues and serine.

Amino Acid Sequence↗
PubMed2000

Insulin increased cAMP phosphodiesterase activity antagonizing metabolic actions of glucagon in rat hepatocytes cultured with herbimycin A.

The baseline activity of cyclic nucleotide phosphodiesterase 4 was markedly lowered by primary culture of rat hepatocytes with herbimycin A for 4 h [Eur. J. Biochem. 260 (1999) 398-408.]. We now report that insulin added to this preparation of hepatocytes, which had been completely freed of herbimycin, increased the thus lowered phosphodiesterase activity, consequently antagonizing glucagon-induced production of cAMP and activation of glycogen phosphorylase. The insulin receptor beta-subunits and alpha-tubulin were tyrosine-phosphorylated upon the addition of insulin. The phosphorylation of alpha-tubulin afforded conditions unfavorable for microtubule assembly that is responsible for phosphodiesterase inhibition. These effects of insulin observed in herbimycin-pretreated hepatocytes were not inhibited by wortmannin that actually abolished insulin-induced activation of phosphatidylinositol 3-kinase (PtdIns 3-kinase) under the same conditions. The physiological significance of the insulin action not mediated by PtdIns 3-kinase in herbimycin-pretreated hepatocytes is discussed.

1-Methyl-3-isobutylxanthine↗
PubMed1992

Regulation of the (Ca(2+)+Mg2+)-ATPase of basolateral membranes from kidney proximal tubules by kinase-mediated phosphorylation and by insulin.

Membrane vesicles derived from the basolateral aspect of kidney proximal tubule cells are phosphorylated by ATP in the absence of Ca2+. This Mg(2+)-dependent, hydroxylamine-resistant phosphorylation was associated with a 50% inhibition of the (Ca(2+)+Mg2+)-ATPase activity measured upon addition of micromolar Ca2+ concentrations, enough to saturate the high-affinity sites of the Ca2+ pump. The presence of either the protein kinase inhibitor H7 or insulin during phosphorylation virtually eliminated the inhibitory effect associated with phosphorylation. However, insulin itself inhibited ATP hydrolysis by the (Ca(2+)+Mg2+)-ATPase when it was present in the assay medium containing buffer, ATP, Mg2+ and Ca2+, the hydrolytic activity being initiated by addition of the membranes without prior phosphorylation. These results suggest that insulin may play a role in regulating transepithelial Ca2+ transport in renal proximal tubules, and that its effects may be linked with a kinase-mediated process that depends on the functional state of the (Ca(2+)+Mg2+)-ATPase.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Secondary loss of deoxyguanosine kinase activity in purine nucleoside phosphorylase deficient mice.

The T-cell immunodeficiency associated with purine nucleoside phosphorylase (PNP) deficiency in man is believed to be due to the accumulation of dGTP which may be preferentially formed from deoxyguanosine in T-lymphocytes or their precursor cells. We found no evidence for dGTP accumulation in thymocytes or spleen leucocytes, < 1 nmol/10(9) cells, nor in erythrocytes, < 0.05 nmol/10(9) cells, of the B6-NPE- or B6-NPF PNP-deficient mice strains. There were no changes in purine or pyrimidine ribonucleotide pools. As these mice had been previously shown to excrete PNP nucleoside substrates, we examined the metabolism of deoxyguanosine. Deoxyguanosine kinase activity as compared to control mice was 6 to 52% for the B6-NPE mutant, 2 to 22% for the B6-NPF mutant. Fractionation of erythrocyte and liver lysates from the F mutation and the background strain, C57BL/6J, by anion exchange chromatography confirmed the secondary deficiency of deoxyguanosine kinase and demonstrated that this activity was distinct from adenosine kinase and two major peaks of deoxycytidine kinase activity. Mouse PNP, expressed and purified as a fusion protein, did not show evidence of being bifunctional and having deoxyguanosine kinase activity. Metabolic modelling revealed that the ratio of deoxyguanosine phosphorylation versus phosphorolysis was < 0.06 in control mice, and < or = 0.3 in lymphocytes of PNP-deficient mice. Were deoxyguanosine kinase not reduced in the PNP-deficient mice, all tissues of the B6-NPF mutant would preferentially phosphorylate deoxyguanosine at low substrate concentrations.

Amino Acid Sequence↗
PubMed2004

HPr kinase/phosphorylase, a Walker motif A-containing bifunctional sensor enzyme controlling catabolite repression in Gram-positive bacteria.

Carbon catabolite repression (CCR) in Gram-positive bacteria is regulated by the bifunctional enzyme HPr kinase/phosphorylase (HprK/P). This enzyme catalyses the ATP- as well as the pyrophosphate-dependent phosphorylation of Ser-46 in HPr, a phosphocarrier protein of a sugar transport and phosphorylation system. HprK/P also catalyses the pyrophosphate-producing, inorganic phosphate-dependent dephosphorylation (phosphorolysis) of seryl-phosphorylated HPr (P-Ser-HPr). P-Ser-HPr functions as catabolite co-repressor by interacting with the LacI/GalR-type repressor, catabolite control protein A (CcpA), and allowing it to bind to operator sites preceding catabolite-regulated transcription units. HprK/P thus indirectly controls the expression of about 10% of the genes of Gram-positive bacteria. The two antagonistic activities of HprK/P are regulated by intracellular metabolites, which change their concentration in response to the absence or presence of rapidly metabolisable carbon sources (glucose, fructose, etc.) in the growth medium. Biochemical and structural studies revealed that HprK/P exhibits no similarity to eukaryotic protein kinases and that it contains a Walker motif A (or P-loop) as nucleotide binding site. Interestingly, HprK/P has a structural fold resembling that in kinases phosphorylating certain low molecular weight substrates such as nucleosides, nucleotides or oxaloacetate. The structures of the complexes of HprK/P with HPr and P-Ser-HPr have also been determined, which allowed proposing a detailed mechanism for the kinase and phosphorylase functions of HprK/P.

Amino Acid Motifs↗
PubMed2005

Modeling kinase-substrate specificity: implication of the distance between substrate nucleophilic oxygen and attacked phosphorus of ATP analog on binding affinity.

Molecular dynamics simulations were performed on modeled kinase-substrate complexes in an attempt to establish a relationship between structural features and binding ability of the complexes. We found that the monitored distance between substrate nucleophilic oxygen (OG) and attacked phosphorus (PG) of ATP analog correlated closely with the binding affinity. With reference to 3.3 A, the van der Waals sum of oxygen and phosphorus, the calculated distances of good substrates were close to it whereas those of poor substrates were far apart from it. Therefore, it is reasonable to consider the OG-PG distance as a potential criterion to prefigure the kinase-substrate binding specificity and the simple computational techniques may work as an easy approach to distinguish good substrates from weak or poor substrates.

Adenosine Triphosphate↗
PubMed1983

Ca2+, calmodulin-dependent phosphorylation of glycogen synthase by a brain protein kinase.

A Ca2+, calmodulin-dependent protein kinase from brain with a Mr of 640 000 is capable of phosphorylating glycogen synthase from skeletal muscle. The reaction was inhibited by the addition of 1 mM EGTA and 50 microM trifluoperazine, but not by protein kinase inhibitor and heparin. The amount of phosphate incorporated into glycogen synthase was 1.4 mol/mol subunit. The phosphorylation sites of glycogen synthase were cyanogen bromide-treated peptides CB-1 and CB-2 and only the seryl residue was phosphorylated.

Animals↗
PubMed1992

Comparative characterization of liver glycogen metabolism in rat and guinea-pig.

1. Guinea-pig liver contained more phosphorylase in the active (phosphorylated) form and less synthase in the active (dephosphorylated) form when compared with rat liver. 2. Activities of cyclic AMP-dependent protein kinase and Ca(2+)-dependent phosphorylase kinase were the same in rat and guinea-pig livers. 3. Activities of phosphorylase phosphatase and synthase phosphatase in the extract and glycogen plus microsomal fraction of guinea-pig liver were significantly lower than those of rat liver. 4. The existence of inhibitor-1 in the liver of guinea-pig can maintain a lower activity of type-1 protein phosphatase, especially when inhibitor-1 is phosphorylated by cyclic AMP-dependent protein kinase.

Animals↗
PubMed1986

Stimulation of phosphatidylinositol phosphorylation in the sarcoplasmic reticular Ca2+-transport ATPase by vanadate.

Vanadate increases the initial phosphatidylinositolphosphate formation rate as well as the steady state level of the above lipid phosphate when phosphatidylinositol associated with the isolated Ca2+ transport ATPase is phosphorylated either by the membrane bound endogeneously present phosphatidylinositol-kinase or by exogeneously added lipid kinase. Employing an ultrasonicated mixture of pure phosphatidylinositol and Triton X 100 (without membrane proteins) no vanadate effect can be seen. This vanadate effect is probably not mediated through the lipid kinase activity, but more likely, through conformational changes of the Ca2+ transport ATPase protein. Such conformational changes would lead to a higher degree of phosphatidylinositol exposed on the Ca2+ transport ATPase and thus a higher substrate concentration. Consequently, the initial phosphatidylinositolphosphate formation rate and steady state level increase.

Calcium-Transporting ATPases↗
PubMed1966

Myoglobinuria and skeletal muscle phosphorylase deficiency: report of a case of McArdle's disease.

Investigation of a patient complaining of exercise-induced dark urine, pain, stiffness and tenderness of skeletal muscle revealed findings characteristic of McArdle's disease. The dark urine was attributable to the excretion of myoglobin, and an ischemic exercise test failed to demonstrate the usual rise and fall in blood lactate and pyruvate. Enzyme assays of skeletal muscle showed an absence of phosphorylase, a slight increase in phosphorylase b kinase and a slight decrease in phosphoglucomutase. Chemical and histochemical analyses demonstrated an increase in the skeletal muscle glycogen content and an enlargement of the muscle cells. No abnormality of liver glycogen metabolism was found. In the absence of specific therapy, an effective and practical form of treatment is reduction of exercise below the threshold of symptoms.

Adult↗
PubMed2003

Ubiquitin-negative mini-pick-like bodies in the dentate gyrus in p301l tauopathy.

Neuropathological and biochemical findings are reported in a patient who had suffered from frontotemporal dementia associated with a P310L mutation in the tau gene and included in the H1 haplotype. Tau accumulation, as revealed with phospho-specific anti-tau antibodies Thr181, Ser199, Ser202, Ser214, Ser262, Ser396, Ser422 and AT8 (Ser202 and Thr205), was found in neurons with pre-tangles, and astrocytes and oligodendrocytes through the brain. The most characteristic feature was tau immunoreactivity decorating the perinuclear region and small cytoplasmic aggregates designed as mini-Pick-like bodies, mainly in the dentate gyrus. Inclusions were not stained with anti-ubiquitin antibodies and did not recruit tubulins. Tau accumulation in individual cells was associated with increased expression of kinases linked with tau phosphorylation, mainly active (phosphorylated) stress kinases SAPK/JNK and p38 (SAPK/JNK-P and p38-P). Phosphorylated GSK-3 beta at Ser9 (GSK-3 beta-P), that inactivates the kinase, was particularly abundant in mini-Pick-like bodies, thus suggesting alternative roles of GSK-3 probably involved in cell survival. Western blots of sarkosyl-insoluble fractions revealed a double band pattern of phospho-tau of 68/66 kDa and 64 kDa in the hippocampus and white matter in the P310L mutation. Sarkosyl-insoluble fractions of the hippocampus were enriched in p38-P and GSK-3 beta-P in Alzheimer's disease (AD) cases, processed in parallel for comparative purposes, but not in the P310L mutation. In addition, no bands of high molecular weight were found in P310L in contrast with AD in these fractions. These findings indicate that the major sites of tau phosphorylation, and the expression of kinases involved in tau phosphorylation are active in P310L mutation as in AD and other tauopathies. Yet the P310L mutation has particular phospho-tau inclusions that are not tag with ubiquitin and appear to be rather soluble when compared with AD.

Antibodies, Anti-Idiotypic↗
PubMed1992

Oral, anti-inflammatory activity of a potent, selective, protein kinase C inhibitor.

The protein kinase C family of enzymes is thought to be important in mediating signal transduction. Ro 31-8830 is a novel, potent inhibitor of protein kinase C, derived from the non-selective protein kinase inhibitor staurosporine. In this paper we demonstrate the selectivity of Ro 31-8830 for protein kinase C over other protein kinases and its ability to inhibit protein kinase-C-mediated events in platelets and lymphocytes. In addition, we describe a novel system for the in vivo evaluation of inhibitors of protein kinase C, and we demonstrate the oral anti-inflammatory activity of Ro 31-8830. This finding has implications for the treatment of inflammatory disorders in the clinic.

Administration, Oral↗
PubMed1997

Enhanced phosphorylation of the postsynaptic protein kinase C substrate RC3/neurogranin during long-term potentiation.

Long-term potentiation (LTP) is a sustained strengthening of synaptic connections that occurs in the mammalian hippocampus, and is a cellular mechanism likely to contribute to memory formation. One question of current interest is whether the biochemical mechanisms responsible for the maintenance of LTP have a presynaptic or postsynaptic locus. We have determined that the phosphorylation of the postsynaptic protein kinase (PKC) substrate RC3/neurogranin is increased in the maintenance phase of LTP, and that the induction of this effect is dependent on activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. The sustained increase in RC3/neurogranin phosphorylation requires ongoing protein kinase activity, as application of the protein kinase inhibitor H-7 after LTP induction can reverse the increased RC3/neurogranin phosphorylation. Overall, these data are evidence for postsynaptic biochemical changes in the maintenance of LTP. They also implicate RC3/neurogranin as a downstream effector of PKC activity in LTP that could contribute to physiologic expression of LTP.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1999

A qualitative process system for modeling NF-kappaB and AP-1 gene regulation in immune cell biology research.

An experiment-oriented integrated model of the regulation of the biologically ubiquitous NF-kappaB and AP-1 gene transcription promoters was built by extending a previously developed qualitative process system for simulating cell behavior in the immune system. The core knowledge base (KB) implemented a deep biological ontology including molecular, ultrastructural, cytological, histological, and organismic definitions. KB states, relationships, predicates, and heuristics also represented process interactions between reactive oxygen species, growth factors, and a variety of kinases phosphorylating intermediate molecules in the NF-kappaB and AP-1 regulatory signaling pathways. The system successfully simulated the molecular process steps underlying outcomes of eight different molecular genetics laboratory experiments, including those dealing with NF-kappaB and AP-1 regulation in immunodeficiency virus infection and tumor necrosis factor responses.

Antibody Formation↗
PubMed1987

Calmodulin-binding proteins in plasma membranes from adrenocortical cells.

Highly purified plasma membranes from Y-1 mouse adrenal tumor cells and those from bovine fasciculata cells were shown by [125I]iodocalmodulin overlay to contain five calmodulin-binding proteins of 240,000, 150,000, 66,000, 60,000, and 51,000 mol wt (Mr). Three of these proteins were also detected by affinity chromatography on calmodulin-Sepharose. Calmodulin binding was inhibited by competition with unlabeled calmodulin and by an inhibitor of calmodulin (trifluoperazine). Binding to each of the proteins was Ca2+ dependent. The relative proportion of binding to each of the five proteins was very different for Y-1 and bovine membranes. In Y-1 membranes as much as 50% of total binding was to the 51,000 Mr protein, whereas in bovine membranes more than 50% of binding occurred with the 150,000 Mr protein. Three of the five proteins were tentatively identified as follows: the 240,000 Mr protein is alpha-spectrin, the 60,000 Mr protein is the A subunit of the Ca2+/calmodulin-dependent protein phosphatase called calcineurin and the 51,000 Mr protein is the major subunit of a Ca2+/calmodulin-dependent protein kinase. The kinase was shown to act on specific substrates. It is concluded that calmodulin, by binding to the kinase and phosphatase, is capable of influencing the degree of phosphorylation of specific substrates in the plasma membranes of adrenal cells, and by binding to alpha-spectrin it may influence the cytoskeletons of these cells. These effects of calmodulin are likely to be important in the regulation of steroid synthesis in the adrenal cortex.

Adrenal Cortex↗
PubMed1990

Post mortem glycogenolysis is a combination of phosphorolysis and hydrolysis.

1. Glycogen, glucose, lactate and glycogen phosphorylase concentrations and the activities of glycogen phosphorylase a and acid 1,4-alpha-glucosidase were measured at various times up to 120 min after death in the liver and skeletal muscle of Wistar and gsd/gsd (phosphorylase b kinase deficient) rats and Wistar rats treated with the acid alpha-glucosidase inhibitor acarbose. 2. In all tissues glycogen was degraded rapidly and was accompanied by an increase in tissue glucose and lactate concentrations and a lowering of tissue pH. In the liver of Wistar and acarbose-treated Wistar rats and in the skeletal muscle of all rats glycogen loss proceeded initially very rapidly before slowing. In the gsd/gsd rat liver glycogenolysis proceeded at a linear rate throughout the incubation period. Over 120 min 60, 20 and 50% of the hepatic glycogen store was degraded in the livers of Wistar, gsd/gsd and acarbose-treated Wistar rats, respectively. All 3 types of rat degraded skeletal muscle glycogen at the same rate and to the same extent (82% degraded over 2 hr). 3. In Wistar rat liver and skeletal muscle glycogen phosphorylase was activated soon after death and the activity of phosphorylase a remained well above the zero-time level at all later time points, even when the rate of glycogenolysis had slowed significantly. Liver and skeletal muscle acid alpha-glucosidase activities were unchanged after death. 4. The decreased rate and extent of hepatic glycogenolysis in both the gsd/gsd and acarbose-treated rats suggests that this process is a combination of phosphorolysis and hydrolysis. 5. Glycogen was purified from Wistar liver and skeletal muscle at various times post mortem and its structure investigated. Fine structural analysis revealed progressive shortening of the outer chains of the glycogen from both tissues, indicative of random, lysosomal hydrolysis. Analysis of molecular weight distributions showed inhomogeneity in the glycogen loss; in both tissues high molecular weight glycogen was preferentially degraded. This material is concentrated in lysosomes of both skeletal muscle and liver. These results are consistent with a role for lysosomal hydrolysis in glycogen degradation.

Acarbose↗