Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucose performs key functions as a signaling molecule in the yeast Saccharomyces cerevisiae. Glucose depletion is known to regulate gene expression via pathways that lead to derepression of genes at the transcriptional level. In this study, we have investigated the effect of glucose depletion on protein synthesis. We discovered that glucose withdrawal from the growth medium led to a rapid inhibition of protein synthesis and that this effect was readily reversed upon readdition of glucose. Neither the inhibition nor the reactivation of translation required new transcription. This inhibition also did not require activation of the amino acid starvation pathway or inactivation of the TOR kinase pathway. However, mutants in the glucose repression (reg1, glc7, hxk2, and ssn6), hexose transporter induction (snf3 rgt2), and cAMP-dependent protein kinase (tpk1(w) and tpk2(w)) pathways were resistant to the inhibitory effects of glucose withdrawal on translation. These findings highlight the intimate connection between the nutrient status of the cell and its translational capacity. They also help to define a new area of posttranscriptional regulation in yeast.
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PMID:Glucose depletion rapidly inhibits translation initiation in yeast. 1071 3

The mammalian TOR (mTOR) pathway is a key regulator of cell growth and proliferation and increasing evidence suggests that its deregulation is associated with human diseases, including cancer and diabetes. The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism. Recent work identifying two structurally and functionally distinct mTOR-containing multiprotein complexes and TSC1/2, rheb, and AMPK as upstream regulators of mTOR is beginning to reveal how mTOR can sense diverse signals and produce a myriad of responses.
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PMID:Growing roles for the mTOR pathway. 1622 44

Autophagy is inhibited by TOR-dependent signaling. Interruption of signalling by rapamycin is known to stimulate autophagy, both in mammalian cells and in yeast. However, inactivation of TOR by AMPK has yielded controversial results in the literature with regard to its effect on autophagy: activation of autophagy in yeast but inhibition in hepatocytes. In a recent study, carried out with hepatocytes, HT-29 cells, and HeLa cells, the possible role of AMPK in the control of mammalian autophagy was reexamined. The data suggest that in mammalian cells, as in yeast, AMPK is required for autophagy.
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PMID:AMP-activated protein kinase and autophagy. 1722 23

Metabolic disorders, such as diabetes and obesity, are fundamentally caused by cellular energy imbalance and dysregulation. Therefore, understanding the regulation of cellular fuel and energy metabolism is of great importance to develop effective therapies for metabolic disease. The cellular nutrient and energy sensors, AMPK and TOR, play a key role in maintaining cellular energy homeostasis. Like AMPK and TOR, PAS kinase (PASK) is also a nutrient responsive protein kinase. In yeast, PAS kinase phosphorylates the enzyme Ugp1 and thereby shifts glucose partitioning toward cell wall glucan synthesis at the expense of glycogen synthesis. Consistent with this function, yeast PAS kinase is activated by both cell integrity stress and growth in non-fermentative carbon sources. PASK is also important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular level. In cultured pancreatic beta-cells, PASK is activated by elevated glucose concentrations and is required for glucose-stimulated transcription of the insulin gene. PASK knockdown in cultured myoblasts causes increased glucose oxidation and elevated cellular ATP levels. Mice lacking PASK exhibit increased metabolic rate and resistance to diet-induced obesity. Interestingly, PGC-1 expression and AMPK and TOR activity were not affected in PASK deficient mice, suggesting PASK may exert its metabolic effects through a new mechanism. We propose that PASK plays a significant role in nutrient sensing, metabolic regulation, and energy homeostasis, and is a potential therapeutic target for metabolic disease.
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PMID:The role of PAS kinase in regulating energy metabolism. 1834 4

Caloric restriction (CR), reduced protein, methionine, or tryptophan diets; and reduced insulin and/or IGFI intracellular signaling can extend mean and/or maximum lifespan and delay deleterious age-related physiological changes in animals. Mice and flies can shift readily between the control and CR physiological states, even at older ages. Many health benefits are induced by even brief periods of CR in flies, rodents, monkeys, and humans. In humans and nonhuman primates, CR produces most of the physiologic, hematologic, hormonal, and biochemical changes it produces in other animals. In primates, CR provides protection from type 2 diabetes, cardiovascular and cerebral vascular diseases, immunological decline, malignancy, hepatotoxicity, liver fibrosis and failure, sarcopenia, inflammation, and DNA damage. It also enhances muscle mitochondrial biogenesis, affords neuroprotection; and extends mean and maximum lifespan. CR rapidly induces antineoplastic effects in mice. Most claims of lifespan extension in rodents by drugs or nutrients are confounded by CR effects. Transcription factors and co-activators involved in the regulation of mitochondrial biogenesis and energy metabolism, including SirT1, PGC-1alpha, AMPK and TOR may be involved in the lifespan effects of CR. Paradoxically, low body weight in middle aged and elderly humans is associated with increased mortality. Thus, enhancement of human longevity may require pharmaceutical interventions.
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PMID:Caloric restriction: from soup to nuts. 1985 62

Dietary restriction (DR) without malnutrition is widely regarded to be a universal mechanism for prolonging lifespan. It is generally believed that the benefits of DR arise from eating fewer calories (termed caloric restriction, CR). Here we argue that, rather than calories, the key determinant of the relationship between diet and longevity is the balance of protein to non-protein energy ingested. This ratio affects not only lifespan, but also total energy intake, metabolism, immunity and the likelihood of developing obesity and associated metabolic disorders. Among various possible mechanisms linking macronutrient balance to lifespan, the nexus between the TOR and AMPK signaling pathways is emerging as a central coordinator.
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PMID:Macronutrient balance and lifespan. 2015 61

In virtually every cell, neutral lipids are stored in cytoplasmic structures called lipid droplets (LDs) and also referred to as lipid bodies or lipid particles. We developed a rapid high-throughput assay based on the recovery of quenched BODIPY-fluorescence that allows to quantify lipid droplets. The method was validated by monitoring lipid droplet turnover during growth of a yeast culture and by screening a group of strains deleted in genes known to be involved in lipid metabolism. In both tests, the fluorimetric assay showed high sensitivity and good agreement with previously reported data using microscopy. We used this method for high-throughput identification of protein phosphatases involved in lipid droplet metabolism. From 65 yeast knockout strains encoding protein phosphatases and its regulatory subunits, 13 strains revealed to have abnormal levels of lipid droplets, 10 of them having high lipid droplet content. Strains deleted for type I protein phosphatases and related regulators (ppz2, gac1, bni4), type 2A phosphatase and its related regulator (pph21 and sap185), type 2C protein phosphatases (ptc1, ptc4, ptc7) and dual phosphatases (pps1, msg5) were catalogued as high-lipid droplet content strains. Only reg1, a targeting subunit of the type 1 phosphatase Glc7p, and members of the nutrient-sensitive TOR pathway (sit4 and the regulatory subunit sap190) were catalogued as low-lipid droplet content strains, which were studied further. We show that Snf1, the homologue of the mammalian AMP-activated kinase, is constitutively phosphorylated (hyperactive) in sit4 and sap190 strains leading to a reduction of acetyl-CoA carboxylase activity. In conclusion, our fast and highly sensitive method permitted us to catalogue protein phosphatases involved in the regulation of LD metabolism and present evidence indicating that the TOR pathway and the SNF1/AMPK pathway are connected through the Sit4p-Sap190p pair in the control of lipid droplet biogenesis.
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PMID:A new fluorescence-based method identifies protein phosphatases regulating lipid droplet metabolism. 2106 Aug 91

Recent data suggests that PAS kinase acts as a signal integrator to adjust metabolic behavior in response to nutrient conditions. Specifically, PAS kinase controls the partitioning of nutrient resources between the myriad of possible fates. In this capacity, PAS kinase elicits a pro-growth program, which includes both signaling and metabolic control, both in yeast and in mammals. We propose that, like other kinases possessing these properties-AMPK and TOR, PAS kinase might be target for therapy of diabetes, obesity and cancer.
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PMID:PAS kinase: integrating nutrient sensing with nutrient partitioning. 2224 33

The perception of nutrient and energy levels inside and outside the cell is crucial to adjust growth and metabolism to available resources. The signaling pathways centered on the conserved TOR and SnRK1/Snf1/AMPK kinases have crucial and numerous roles in nutrient and energy sensing and in translating this information into metabolic and developmental adaptations. In plants evidence is mounting that, like in other eukaryotes, these signaling pathways have pivotal and antagonistic roles in connecting external or intracellular cues to many biological processes, including ribosome biogenesis, regulation of translation, cell division, accumulation of reserves and autophagy. Data on the plant TOR pathway have been hitherto rather scarce but recent findings have shed new light on its roles in plants. Moreover, the distinctive energy metabolism of photosynthetic organisms may reveal new features of these ancestral eukaryotic signaling elements.
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PMID:Sensing nutrient and energy status by SnRK1 and TOR kinases. 2230 21

Previous studies in two rainbow trout lines divergently selected for lean (L) or fat (F) muscle suggested that they differ in their ability to metabolise glucose. In this context, we investigated whether genetic selection for high muscle fat content led to a better capacity to metabolise dietary carbohydrates. Juvenile trout from the two lines were fed diets with or without gelatinised starch (17.1%) for 10 weeks, after which blood, liver, muscle and adipose tissues were sampled. Growth rate, feed efficiency and protein utilisation were lower in the F line than in the L line. In both lines, intake of carbohydrates was associated with a moderate post-prandial hyperglycaemia, a protein sparing effect, an enhancement of nutrient (TOR-S6) signalling cascade and a decrease of energy-sensing enzyme (AMPK). Gene expression of hepatic glycolytic enzymes was higher in the F line fed carbohydrates compared with the L line, but concurrently transcripts for the gluconeogenic enzymes was also higher in the F line, possibly impairing glucose homeostasis. However, the F line showed a higher gene expression of hepatic enzymes involved in lipogenesis and fatty acid bioconversion, in particular with an increased dietary carbohydrate intake. Enhanced lipogenic potential coupled with higher liver glycogen content in the F line suggests better glucose storage ability than the L line. Overall, the present study demonstrates the changes in hepatic intermediary metabolism resulting from genetic selection for high muscle fat content and dietary carbohydrate intake without, however, any interaction for an improved growth or glucose utilisation in the peripheral tissues.
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PMID:Regulation of metabolism by dietary carbohydrates in two lines of rainbow trout divergently selected for muscle fat content. 2278 33


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