Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Muscle malonyl-CoA decreases during exercise or electrical stimulation, the exercise-induced decline being accompanied by changes in the kinetic properties [maximal velocity (Vmax), activation constant (Ka), and citrate concentration required to produce 50% Vmax (K0.5)] of acetyl-CoAcarboxylase (ACC) and by an increase in the AMP-activated protein kinase activity (AMPK). This study was designed to ascertain whether the exercise-induced changes are contraction mediated and, if so, to follow the time course of these changes. The left sciatic nerve of rats was stimulated at 1 Hz for 0, 2, 5, 10, 20, or 30 min, and the gastrocnemius-plantaris muscle group was then excised, frozen in liquid nitrogen, and later analyzed for malonyl-CoA and other metabolites. ACC and AMPK activities were quantitated in ammonium sulfate precipitates from homogenates prepared from the frozen muscles. The Vmax and Ka of ACC for citrate decreased and increased, respectively, over the first 10 min of stimulation, but significantly increased AMPK activity was not observed until 10 to 20 min of stimulation (P < 0.05). Stimulation increased estimated free AMP (P < 0.05). Thus exercise-induced changes in functional properties of ACC appear to be contraction mediated and are accompanied by increased AMPK activity and an increase in the estimated free AMP.
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PMID:Electrical stimulation inactivates muscle acetyl-CoA carboxylase and increases AMP-activated protein kinase. 912 33

Malonyl-CoA is synthesized by acetyl-CoA carboxylase (ACC) and is an inhibitor of fatty acid oxidation. Exercise induces a decline in skeletal muscle malonyl-CoA, which is accompanied by inactivation of ACC and increased activity of AMP-activated protein kinase (AMPK). This study was designed to determine the effect of exercise intensity on the enzyme kinetics of ACC, malonyl-CoA levels, and AMPK activity in skeletal muscle. Male Sprague-Dawley rats were killed (pentobarbital sodium anesthesia) at rest or after 5 min of exercise (10, 20, 30, or 40 m/min at 5% grade). The fast-twitch red and white regions of the quadriceps muscle were excised and frozen in liquid nitrogen. A progressive decrease in red quadriceps ACC maximal velocity (from 28.6 +/- 1.5 to 14.3 +/- 0.7 nmol . g-1 . min-1, P < 0.05), an increase in activation constant for citrate, and a decrease in malonyl-CoA (from 1.9 +/- 0.2 to 0.9 +/- 0.1 nmol/g, P < 0.05) were seen with the increase in exercise intensity from rest to 40 m/min. AMPK activity increased more than twofold. White quadriceps ACC activity decreased only during intense exercise. We conclude that the extent of ACC inactivation during short-term exercise is dependent on exercise intensity.
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PMID:Effect of exercise intensity on skeletal muscle malonyl-CoA and acetyl-CoA carboxylase. 933 17

We resolved from spinach (Spinacia oleracea) leaf extracts four Ca2+-independent protein kinase activities that phosphorylate the AMARAASAAALARRR (AMARA) and HMRSAMSGLHLVKRR (SAMS) peptides, originally designed as specific substrates for mammalian AMP-activated protein kinase and its yeast homolog, SNF1. The two major activities, HRK-A and HRK-C (3-hydroxy-3-methylglutaryl-coenzyme A reductase kinase A and C) were extensively purified and shown to be members of the plant SnRK1 (SNF1-related protein kinase 1) family using the following criteria: (a) They contain 58-kD polypeptides that cross-react with an antibody against a peptide sequence characteristic of the SnRK1 family; (b) they have similar native molecular masses and specificity for peptide substrates to mammalian AMP-activated protein kinase and the cauliflower homolog; (c) they are inactivated by homogeneous protein phosphatases and can be reactivated using the mammalian upstream kinase; and (d) they phosphorylate 3-hydroxy-3-methylglutaryl-coenzyme A reductase from Arabidopsis at the inactivating site, serine (Ser)-577. We propose that HRK-A and HRK-C represent either distinct SnRK1 isoforms or the same catalytic subunit complexed with different regulatory subunits. Both kinases also rapidly phosphorylate nitrate reductase purified from spinach, which is associated with inactivation of the enzyme that is observed only in the presence of 14-3-3 protein, a characteristic of phosphorylation at Ser-543. Both kinases also inactivate spinach sucrose phosphate synthase via phosphorylation at Ser-158. The SNF1-related kinases therefore potentially regulate several major biosynthetic pathways in plants: isoprenoid synthesis, sucrose synthesis, and nitrogen assimilation for the synthesis of amino acids and nucleotides.
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PMID:Two SNF1-related protein kinases from spinach leaf phosphorylate and inactivate 3-hydroxy-3-methylglutaryl-coenzyme A reductase, nitrate reductase, and sucrose phosphate synthase in vitro. 1031 3

Acetyl-CoA carboxylase (ACC) catalyzes the formation of malonyl-CoA, an essential substrate for fatty acid biosynthesis and a potent inhibitor of fatty acid oxidation. Here, we provide evidence that glutamate may be a physiologically relevant activator of ACC. Glutamate induced the activation of both major isoforms of ACC, prepared from rat liver, heart, or white adipose tissue. In agreement with previous studies, a type 2A protein phosphatase contributed to the effects of glutamate on ACC. However, the protein phosphatase inhibitor microcystin LR did not abolish the effects of glutamate on ACC activity. Moreover, glutamate directly activated purified preparations of ACC when protein phosphatase activity was excluded. Phosphatase-independent ACC activation by glutamate was also reflected by polymerization of the enzyme as judged by size-exclusion chromatography. The sensitivity of ACC to direct activation by glutamate was diminished by treatment in vitro with AMP-activated protein kinase or cAMP-dependent protein kinase or by beta-adrenergic stimulation of intact adipose tissue. We conclude that glutamate, an abundant intracellular amino acid, induces ACC activation through complementary actions as a phosphatase activator and as a direct allosteric ligand for dephosphorylated ACC. This study supports the general hypothesis that amino acids fulfill important roles as signal molecules as well as intermediates in carbon and nitrogen metabolism.
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PMID:Bimodal activation of acetyl-CoA carboxylase by glutamate. 1075 75

Metformin, one of the most commonly used drugs for the treatment of type II diabetes, was recently found to exert its therapeutic effects, at least in part, by activating the AMP-activated protein kinase (AMPK). However, the site of its action, as well as the mechanism to activate AMPK, remains elusive. Here we report how metformin activates AMPK. In cultured bovine aortic endothelial cells, metformin dose-dependently activated AMPK in parallel with increased detection of reactive nitrogen species (RNS). Further, either depletion of mitochondria or adenoviral overexpression of superoxide dismutases, as well as inhibition of nitric-oxide synthase, abolished the metformin-enhanced phosphorylations and activities of AMPK, implicating that activation of AMPK by metformin might be mediated by the mitochondria-derived RNS. Furthermore, administration of metformin, which increased 3-nitrotyrosine staining in hearts of C57BL6, resulted in parallel activation of AMPK in the aorta and hearts of C57BL6 mice but not in those of endothelial nitric-oxide synthase (eNOS) knockout mice in which metformin had no effect on 3-nitrotyrosine staining. Because the eNOS knockout mice expressed normal levels of AMPK-alpha that was activated by 5-aminoimidazole-4-carboxamide riboside, an AMPK agonist, these data indicate that RNS generated by metformin is required for AMPK activation in vivo. In addition, metformin significantly increased the co-immunoprecipitation of AMPK and its upstream kinase, LKB1, in C57BL6 mice administered to metformin in vivo. Using pharmacological and genetic inhibitors, we found that inhibition of either c-Src or PI3K abolished AMPK that was enhanced by metformin. We conclude that activation of AMPK by metformin might be mediated by mitochondria-derived RNS, and activation of the c-Src/PI3K pathway might generate a metabolite or other molecule inside the cell to promote AMPK activation by the LKB1 complex.
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PMID:Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. 3149 33

In the yeast Saccharomyces cerevisiae, the Snf1 protein kinase of the Snf1/AMP-activated protein kinase (AMPK) family regulates a wide range of responses to stress caused by glucose deprivation. The stress signal is relayed via upregulation of Snf1, which depends on phosphorylation of its activation loop Thr210 residue by upstream kinases. Although Snf1 is also required for coping with various stresses unrelated to glucose deprivation, some evidence suggests a role for low-level basal activity of unphosphorylated Snf1, rather than a specific signaling function. We previously found that Snf1 is required for diploid pseudohyphal differentiation, a developmental response to nitrogen limitation. Here, we present evidence that Snf1 is directly involved in nitrogen signaling. First, genetic analyses suggest that pseudohyphal differentiation depends on the stimulatory phosphorylation of Snf1 at Thr210. Second, immunochemical data indicate that nitrogen limitation improves Thr210 phosphorylation. Analyses of pseudohyphal differentiation in cells with catalytically inactive and hyperactive Snf1 support the role of Snf1 activity. Finally, we show that Snf1 is negatively regulated by the rapamycin-sensitive TOR kinase which plays essential roles in signaling nitrogen and amino acid availability. This and other evidence implicate Snf1 in the integration of signals regarding nitrogen and carbon stress. TOR and Snf1/AMPK are highly conserved in evolution, and their novel functional interaction in yeast suggests similar mechanisms in other eukaryotes.
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PMID:Nitrogen availability and TOR regulate the Snf1 protein kinase in Saccharomyces cerevisiae. 1698 Apr 5

Sir David Cuthbertson was the first to define metabolic alterations in post-aggression syndrome (PAS). From basic measurements of nitrogen loss and total protein synthesis/degradation, the current research has moved to genomics, proteomics and metabolomics. In this respect, first evidence was accumulated for the influence of acute catabolism, immobilisation by bed rest and sarcopenia of old age on the muscle-cell genome and proteome. Moreover, in post-aggression syndrome specific amino acids such as glutamine, arginine, glycine, taurine, tryptophan and cysteine are used for cell and immune modulation. Our laboratory has focused on the regulative capacity of glutamine. Glutamine deficiency as found in post-aggression syndrome reduces lymphocyte proliferation, alters monocyte/macrophage activity, decreases the formation of heat-shock proteins, stimulates cell apoptosis, shifts the cellular redox potential by altering the glutathione synthesis and increases the activity of the AMPK system. Investigating the molecular effect of glutamine on Hsp 70 induction, we tested the glutamine dependence on the formation of transfer-RNA and of heat-shock factor 1 (HSF 1), and on transcription and translation of Hsp 70. We could demonstrate that glutamine stabilises the mRNA of Hsp 70 thereby prolonging its half-life. The lecture also discusses the principal molecular targets of administered arginine, glycine, cysteine, taurine and tryptophan.
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PMID:Immune and cell modulation by amino acids. 1759 24

Copper (Cu) deficiency impairs cerebellar development including biosynthetic processes like myelination and synaptogenesis. The activity of cerebellar mitochondrial cuproenzyme cytochrome c oxidase is markedly lower in Cu deficient rat pups and is accompanied by higher lactate levels indicating mitochondrial inhibition. Cu deficiency impaired energy metabolism is thought to contribute to developmental delays, but specific mechanisms linking these phenomena have remained unexplored. AMP-activated protein kinase (AMPK) is a cellular energy sensor that is activated during mitochondrial inhibition and shuts down biosynthetic processes to help conserve cellular ATP levels. Activated AMPK phosphorylates and inhibits acetylCoA carboxylase (ACC), the first enzyme in fatty acid biosynthesis. We hypothesize that AMPK is activated and ACC inhibited in Cu deficient cerebella. Perinatal copper deficiency was studied in young rats in rapidly frozen cerebella. Compared to copper-adequate (Cu+) pups, copper-deficient (Cu-) pups were hypothermic, had lower brain copper levels and markedly higher cerebellar lactate. Concentration of phosphorylated AMPK (pAMPK), indicating AMPK activation, was robustly higher in Cu- cerebella of rat pups at two ages and in two separate experiments. Compared to Cu+ cerebella, pACC content was significantly higher in all Cu- samples. Mechanisms leading to AMPK activation remain elusive. Higher AMP/ATP ratios and increased reactive nitrogen species (RNS) can lead to AMPK activation. ATP and AMP concentrations were unaltered and nitric oxide metabolites and 3-nitrotyrosine peptide levels remained unchanged in Cu- cerebella. AMPK activation may explain how ATP levels can be maintained even with a severe mitochondrial loss of CCO function.
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PMID:Copper deficiency results in AMP-activated protein kinase activation and acetylCoA carboxylase phosphorylation in rat cerebellum. 1833 63

Metformin is one of the most commonly prescribed oral antidiabetic agents worldwide. However, its mechanism of action remains unknown. The Diabetes Prevention Program Research Group studies have shown that metformin administration and lifestyle-intervention (diet and exercise) reduce the incidence of Diabetes Mellitus type 2 (DM2). A possible biochemical connection between both therapies may be the AMP-activated protein kinase (AMPK). This enzyme was originally described as a sensor of cellular energy status, being activated in exercise. On the other hand, several experimental evidences indicate that AMPK may be an important target of metformin action. This paper discusses various ways for AMPK regulation, suggesting a possible mechanism for its activation by metformin that involves the production of reactive nitrogen species. AMPK activation determines a wide variety of physiological effects, including enhanced glucose uptake by skeletal muscle and enhanced lipid catabolism. Thus, it may be a key player not only in the prevention and treatment of DM2, but also in the development of new treatments for obesity and the metabolic syndrome. The finding of AMPK activation by metformin draws attention to this enzyme as an important pharmacological target.
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PMID:[Metformin and AMPK: an old drug and a new enzyme in the context of metabolic syndrome]. 1834 5

In higher plants, light is crucial for regulation of nitrate uptake, translocation and assimilation into organic compounds. Part of this metabolism is tightly coupled to photosynthesis because the enzymes involved, nitrite reductase and glutamate synthase, are localized to the chloroplasts and receive reducing power from photosynthetic electron transport. However, important enzymes in nitrate acquisition and reduction are localized to cellular compartments other than chloroplasts and are also up-regulated by light, i.e. transporters in cell and organellar membranes and nitrate reductase in the cytosol. This review describes the different light-dependent signalling cascades regulating nitrate metabolism at the transcriptional as well as post-transcriptional level, and how reactions in different compartments of the cell are co-ordinated. Essential players in this network are phytochrome and HY5 (long hypocotyls 5)/HYH (HY5 homologue)-dependent signalling pathways, the energy-related AMPK (AMP-activated protein kinase) protein kinase homologue SNRK1 (sucrose non-fermenting kinase 1-related kinase), chloroplastic thioredoxins and the prokaryotically originated PII protein. A complex light-dependent network of regulation emerges, which appears to be necessary for optimal nitrogen assimilation and for avoiding the accumulation of toxic intermediates and side products, such as nitrite and reactive oxygen compounds.
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PMID:Signalling cascades integrating light-enhanced nitrate metabolism. 1877 47


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