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:2.7.1.1 (hexokinase)
5,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein phosphatase 1, comprising the regulatory subunit Reg1 and the catalytic subunit Glc7, has a role in glucose repression in Saccharomyces cerevisiae. Previous studies showed that Reg1 regulates the Snf1 protein kinase in response to glucose. Here, we explore the functional relationships between Reg1, Glc7, and Snf1. We show that different sequences of Reg1 interact with Glc7 and Snf1. We use a mutant Reg1 altered in the Glc7-binding motif to demonstrate that Reg1 facilitates the return of the activated Snf1 kinase complex to the autoinhibited state by targeting Glc7 to the complex. Genetic evidence indicated that the catalytic activity of Snf1 negatively regulates its interaction with Reg1. We show that Reg1 is phosphorylated in response to glucose limitation and that this phosphorylation requires Snf1; moreover, Reg1 is dephosphorylated by Glc7 when glucose is added. Finally, we show that hexokinase PII (Hxk2) has a role in regulating the phosphorylation state of Reg1, which may account for the effect of Hxk2 on Snf1 function. These findings suggest that the phosphorylation of Reg1 by Snf1 is required for the release of Reg1-Glc7 from the kinase complex and also stimulates the activity of Glc7 in promoting closure of the complex.
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PMID:Regulatory interactions between the Reg1-Glc7 protein phosphatase and the Snf1 protein kinase. 1064 18

Exercise acutely stimulates muscle glucose transport and also brings about an adaptive increase in the capacity of muscle for glucose uptake by inducing increases in GLUT-4 and hexokinase.(1) Recent studies have provided evidence that activation of AMP protein kinase (AMPK) is involved in the stimulation of glucose transport by exercise. The purpose of this study was to determine whether activation of AMPK is also involved in mediating the adaptive increases in GLUT-4 and hexokinase. To this end, we examined the effect of incubating rat epitrochlearis muscles in culture medium for 18 h in the presence or absence of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), which enters cells and is converted to the AMP analog ZMP, thus activating AMPK. Exposure of muscles to 0.5 mM AICAR in vitro for 18 h resulted in an approximately 50% increase in GLUT-4 protein and an approximately 80% increase in hexokinase. This finding provides strong evidence in support of the hypothesis that the activation of AMPK that occurs in muscle during exercise is involved in mediating the adaptive increases in GLUT-4 and hexokinase.
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PMID:Increased expression of GLUT-4 and hexokinase in rat epitrochlearis muscles exposed to AICAR in vitro. 1071 Apr 5

We have identified many dark-inducible (din) genes that are expressed in Arabidopsis leaves kept in the dark. In the present study we addressed the question of how plant cells sense the depletion of sugars, and how sugar starvation triggers din gene expression in suspension-cultured cells of Arabidopsis. Depletion of sucrose in the medium triggered marked accumulation of din transcripts. Suppression of din gene expression by 2-deoxy-Glc, and a non-suppressive effect exerted by 3-O-methyl-Glc, suggested that sugar-repressible expression of din genes is mediated through the phosphorylation of hexose by hexokinase, as exemplified in the repression of photosynthetic genes by sugars. We have further shown that the signaling triggered by sugar starvation involves protein phosphorylation and dephosphorylation events, and have provided the first evidence that multiple pathways of protein dephosphorylation exist in sugar starvation-induced gene expression. An inhibitor of serine/threonine protein kinase, K-252a, inhibited din gene expression in sugar-depleted cells. Okadaic acid, which may preferentially inhibit type 2A protein phosphatases over type 1, enhanced the transcript levels of all din genes, except din6 and din10, under sugar starvation. Conversely, a more potent inhibitor of type 1 and 2A protein phosphatases, calyculin A, increased transcripts from din2 and din9, but decreased those from other din genes, in sugar-depleted cells. On the other hand, calyculin A, but not okadaic acid, completely inhibited the gene expression of chlorophyll a/b-binding protein under sugar starvation. These results indicate that multiple signaling pathways, mediated by different types of protein phosphatases, regulate gene expression during sugar starvation.
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PMID:Multiple signaling pathways in gene expression during sugar starvation. Pharmacological analysis of din gene expression in suspension-cultured cells of Arabidopsis. 1108 Feb 91

POP2 protein of Saccharomyces cerevisiae is a component of a protein complex that regulates the transcription of many genes. We found that the 97th threonine residue (Thr 97) of Pop2p was phosphorylated upon glucose limitation. The Thr 97 phosphorylation occurred within 2 min after removing glucose and was reversed within 1 min after the readdition of glucose. The effects of hexokinase mutations and glucose analogs indicate that this phosphorylation is dependent on glucose phosphorylating activity. We purified a protein kinase that phosphorylates a peptide containing Thr 97 of Pop2p and identified it as Yak1p, a DYRK family kinase. Phosphorylation of Pop2p was barely detectable in a yak1Delta strain. We found that Yak1p interacted with Bmh1p and Bmh2p only in the presence of glucose. A GFP-Yak1p fusion protein shuttled rapidly between the nucleus and the cytoplasm in response to glucose. A strain with alanine substituted for Thr 97 in Pop2p showed overgrowth in the postdiauxic transition and failed to stop the cell cycle at G(1) phase in response to glucose deprivation. Thus, Yak1p and Pop2p are part of a novel glucose-sensing system in yeast that is involved in growth control in response to glucose availability.
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PMID:Yak1p, a DYRK family kinase, translocates to the nucleus and phosphorylates yeast Pop2p in response to a glucose signal. 1135 66

The induction of fructosylsucrose-synthesizing activity (FSS) by sugars was tested using detached primary leaf blades of several wheat (Triticum aestivum L.) cultivars, immersed in different sugars solutions for 24 h in the dark. The highest induction was brought about by sucrose, while glucose, fructose and maltose also caused significant induction. 5-Ketofructose, 3-methylglucose and 6-deoxyglucose, which cannot be metabolized by plants, produced no induction at all. The fact that mannose also failed to induce FSS and that mannoheptulose did not inhibit the induction by sucrose suggests that the hexokinase-sensing system may not be involved. The protein phosphatase inhibitor okadaic acid and the calmodulin-dependent protein kinase antagonist W7 inhibited FSS induction while some types of protein kinase inhibitors, such as staurosporine and genistein, had less or no effect, respectively. Cycloheximide and cordycepin completely inhibited the induction response, indicating that transcription and translation are necessary for the FSS induction. Northern blot experiments using a sucrose:fructan-6-fructosyl transferase probe gave a clear indication that the mRNA for this enzyme, which is almost absent in control leaves, is dramatically increased after a 24-h treatment with 500 mM sucrose, and confirmed the inhibition produced by protein kinase and protein phosphatase inhibitors. Our data indicate that protein kinase and protein phosphatase activities take part in the chain of events that intervenes in the induction of fructan synthesis by sugars.
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PMID:Protein kinase and phosphatase activities are involved in fructan synthesis initiation mediated by sugars. 1155 97

Mitogenic effects of the extracellular nucleotides ATP and UTP are mediated by P2Y(1), P2Y(2), and P2Y(4) receptors. However, it has not been possible to examine the highly expressed UDP-sensitive P2Y(6) receptor because of the lack of stable, selective agonists. In rat aorta smooth muscle cells (vascular smooth muscle cells; VSMC), UDP and UTP stimulated (3)H-labeled thymidine incorporation with similar pEC(50) values (5.96 and 5.69). Addition of hexokinase did not reduce the mitogenic effect of UDP. In cells transfected with P2Y receptors the stable pyrimidine agonist uridine 5'-O-(2-thiodiphosphate) (UDPbetaS) was specific for P2Y(6) with no effect on P2Y(1), P2Y(2), or P2Y(4) receptors. UDPbetaS stimulated [(3)H]thymidine and [(3)H]leucine incorporation and increased cell number in VSMC. Flow cytometry demonstrated that UDP stimulated cell cycle progression to both the S and G(2) phases. The intracellular signal pathways were dependent on phospholipase C, possibly protein kinase C-delta, and a tyrosine kinase pathway but independent of G(i) proteins, eicosanoids, and protein kinase A. The half-life of P2Y(6) receptor mRNA was <1 h by competitive RT-PCR. The mitogen-activated protein kinase kinase inhibitor PD-098059 significantly suppressed, whereas ATP and interleukin-1beta upregulated, expression of P2Y(6) receptor mRNA. The results demonstrate that UDP stimulates mitogenesis through activation of P2Y(6) receptors and that the receptor is regulated by factors important in the development of vascular disease.
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PMID:UDP acts as a growth factor for vascular smooth muscle cells by activation of P2Y(6) receptors. 1178 30

The cAMP-dependent protein kinase anchoring protein, d-AKAP1, has two N-terminal splice variants. The shorter forms (N0, d-AKAP1a, and -1c) target to mitochondria, and the longer forms (N1, d-AKAP1b, and -1d) with 33 additional residues N-terminal to N0 target to the endoplasmic reticulum (ER) (Huang, L. J., Wang, L., Ma, Y., Durick, K., Perkins, G., Deerinck, T. J., Ellisman, M. H., and Taylor, S. S. (1999) J. Cell Biol. 145, 951-959). In d-AKAP1a, translation may initiate from both Met-34 or Met-49 producing two molecules both targeted to mitochondria. The shorter molecule contains the 15-residue targeting motif, homologous to the N-terminal mitochondrial targeting motif of hexokinase I. Extensive mutagenesis showed that one hydrophobic surface of the 15-residue hexokinase-homologous segment contained the key elements for mitochondrial targeting. The same 15 residues are also part of the ER-targeting signal, but for ER targeting multiple hydrophobic residues are required that encompass both surfaces of the helix. The different involvement of the same helical motif for targeting to the two organelles appears to reflect different modes of interaction with the two organelles. This is the first example of a bifunctional helical element that is required for both ER and mitochondrion targeting.
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PMID:A 15-residue bifunctional element in D-AKAP1 is required for both endoplasmic reticulum and mitochondrial targeting. 1199 83

The effects of systemic administration of rolipram, a selective phosphodiesterase type 4 inhibitor, on [(3)H]2-deoxyglucose (DG) uptake in brain and peripheral tissues were examined. Rolipram significantly and dose-dependently decreased [(3)H]DG uptake in brain, heart and skeletal muscle. In contrast, the radioactivity concentrations in the plasma of rolipram-treated mice were significantly higher than those of control mice at all times after injection of the tracer. In the kinetic study, the initial uptake of [(3)H]DG in brain was decreased by rolipram, whereas no significant differences were observed in the uptake in heart and skeletal muscle. However, radioactivity concentrations in the brain, heart and skeletal muscle 30 min after the injection of [(3)H]DG were significantly lowered by rolipram to about 60%, 10% and 10% of control values, respectively. The uptake of [(13)N]ammonia in brain and heart of rolipram-treated mice was slightly decreased, which indicated that rolipram diminished both cerebral and cardiac blood flow. These results indicate that the phosphorylation process via hexokinase rather than the transport of [(3)H]DG might be depressed by rolipram. Together with the previous observations that inhibition of protein kinase A (PKA) markedly enhanced [(14)C]DG uptake in rat brain, these results indicate an important role of the cAMP/PKA systems in the regulation of glucose metabolism in the living brain as well as in peripheral tissues such as the heart and skeletal muscle.
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PMID:Rolipram depresses [(3)H]2-deoxyglucose uptake in mouse brain and heart in vivo. 1219 68

Both purinergic stimulation and activation of cystic fibrosis transmembrane conductance regulator (CFTR) increases Cl(-) secretion and inhibit amiloride-sensitive Na(+) transport. CFTR has been suggested to conduct adenosine 5'-triphosphate (ATP) or to control ATP release to the luminal side of epithelial tissues. Therefore, a possible mechanism on how CFTR controls the activity of epithelial Na(+) channels (ENaC) could be by release of ATP or uridine 5'-triphosphate (UTP), which would then bind to P2Y receptors and inhibit ENaC. We examined this question in native tissues from airways and colon and in Xenopus oocytes. Inhibition of amiloride-sensitive transport by both CFTR and extracellular nucleotides was observed in colon and trachea. However, nucleotides did not inhibit ENaC in Xenopus oocytes, even after coexpression of P2Y(2) receptors. Using different tools such as hexokinase, the P2Y inhibitor suramin or the Cl(-) channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), we did not detect any role of a putative ATP secretion in activation of Cl(-) transport or inhibition of amiloride sensitive short circuit currents by CFTR. In addition, N(2),2'-O-dibutyrylguanosine 3',5'-cyclic monophosphate (cGMP) and protein kinase G (PKG)-dependent phosphorylation or the nucleoside diphosphate kinase (NDPK) do not seem to play a role for the inhibition of ENaC by CFTR, which, however, requires the presence of extracellular Cl(-).
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PMID:No evidence for inhibition of ENaC through CFTR-mediated release of ATP. 1222 48

Insulin resistance is a principal feature of type 2 diabetes and precedes the clinical development of the disease by 10 to 20 years. Insulin resistance is caused by the decreased ability of peripheral target tissues (especially muscle) to respond properly to normal circulating concentrations of insulin. Defects in muscle glycogen synthesis play a significant role in insulin resistance, and 3 potentially rate-controlling steps in muscle glucose metabolism have been implicated in its pathogenesis: glycogen synthase, hexokinase, and GLUT4 (the major insulin-stimulated glucose transporter). Results from recent studies using nuclear magnetic resonance (NMR) spectroscopy implicate intracellular defects in glucose transport as the rate-controlling step for insulin-mediated glucose uptake in muscle. These alterations in glucose transport activity are likely the result of dysregulation of intramyocellular fatty acid metabolism, whereby fatty acids cause insulin resistance by activation of a serine kinase cascade, leading to decreased insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and decreased IRS-1-associated phosphatidylinositol 3-kinase activity, a required step in insulin-stimulated glucose transport into muscle. The thiazolidinedione class of antidiabetic agents directly targets insulin resistance in skeletal muscle by improving glucose transport activity and insulin-stimulated muscle glycogen synthesis. Although the precise mechanism of action is not known, recent NMR studies support the hypothesis that these agents improve insulin action in skeletal muscle and liver by promoting a redistribution of fat out of these tissues and into peripheral adipocytes.
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PMID:Pathogenesis of skeletal muscle insulin resistance in type 2 diabetes mellitus. 1223 Oct 74


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