AMPK kinase kinases

Figure 21-6. Regulation of acetyl-CoA carboxylase by phosphorylation/dephosphorylation.The enzyme is inactivated by phosphorylation by AMP-activated protein kinase (AMPK), which in turn is phosphorylated and activated by AMP-activated protein kinase kinase (AMPKK). Glucagon (and epinephrine), after increasing cAMP, activate this latter enzyme via cAMP-dependent protein kinase. The kinase kinase enzyme is also believed to be activated by acyl-CoA. Insulin activates acetyl-CoA carboxylase, probably through an "activator" protein and an insulin-stimulated protein kinase.

Hamilton, S. R., O Donnell, J. B., Jr., Hammet, A., Stapleton, D., Habinowski, S. A., Means, A. R., Kemp, B. E. and Witters, L. A., 2002, AMP-activated protein kinase kinase detection with recombinant AMPK alphal subunit, Biochem Biophys Res Commun, 293, pp 892—8. 

Woods, A., Vertommen, D., Neumann, D., Turk, R., Bayliss, J., Schlattner, U., Wallimann, T., Carling, D., and Rider, M. H. 2003b. Identification of phosphorylation sites in AMP-activated protein kinase (AMPK) for upstream AMPK kinases and study of their roles by site-directed mutagenesis. J Biol Chem 278 28434-28442. 

Alanine-TR, [3-alanine transporter ALDH, aldehyde dehydrogenase ALDO-R, aldosterone receptor Aik Pase, alkaline phosphatase ALL-DB, alloxan-induced diabetic AMCV, artichoke mottled crinkle virus AMP, adenosine 5 -monophosphate 5 -AMP, adenosine 5 -monophosphate AMPA-R, AMPA-receptor AMPK, AMP-dependent protein kinase AMPKK, AMP-dependent protein kinase kinase... 

At the molecular level, precise target recep-tor(U)ave not been identified. Metformin has been reported to activate the AMP-activated protein kinase system (AMPK) in primary hepatocytes (131). AMPK has been proposed as a key regulatory enzyme of carbohydrate and fat metabolism (132). This kinase is activated through an allosteric mechanism by binding 5 -AMP and also by phosphorylation. Activation of AMPK by phosphorylation is 5 -AMP dependent because the binding of AMP to the enzyme makes it a better substrate for AMPK kinase, which phosphorylates AMPK, and a poorer substrate for protein phosphatase 2C, which dephosphorylates it. AMPK kinase is also activated by 5 -AMP. These actions of 5 -AMP are antagonized by high concentrations of ATP, and thus the system... 

Fig. 9. Reciprocal regulation of fatty acid synthesis and oxidation. Malonyl-CoA, the product of the ACC reaction, inhibits CPT-1, which is localized at the outer mitochondrial membrane and catalyzes the conversion of fatty acyl-CoA to fatty acyl-camitine for mitochondrial fatty acid import and oxidation. At the inner mitochondrial membrane, fatty acyl moieties are converted to CoA thioesters by CPT-II before undergoing -oxidation. ACC is activated by citrate and inhibited by fatty acyl-CoA. AMPK is activated by AMP and the high AMP level reflects the low energy state of the cell. Activation of AMPK in response to increases in AMP involves phosphorylation by an upstream AMPK kinase (AMPKK), the tumor suppressor LKB1, and AMPK is inactivated/dephosphory-lated by protein phosphatase 2A (PP2A), which is first activated by insulin via PI3K/Akt pathway. ACC is dephosphorylated/activated by PP2A and is inactivated upon phosphorylation by AMPK. ACC can also be phos-phorylated/inactivated by PKA. TAG, triacylglycerol FA, fatty acid.

De novo fatty acid synthesis is, in part, negatively regulated by the AMP-activated protein kinase (AMPK). When the adipocyte is in an energy deficient state due to the lack of available glucose or other cellular stresses, ATP levels decrease and AMP levels increase. This causes the AMPrATP ratio in the adipocyte to increase and thus AMP binds and activates AMPK kinase, LKB. AMP also binds to AMPK, which allows LKB to recognize AMPK as a substrate and results in the phosphorylation and activation of AMPK. 

AMPK 5 -adenosine monophosphate-activated protein kinase, LKBl upstream serine/threonine AMPK kinase, AgRP agouti-related peptide, NPY neuropeptide Y, CRH corticotrophin-releasing hormone, POMC proopiomelanocortin, FAS fatty acid synthase mRNA levels normalized to 18s rRNA level Bars, within a gene, with a different letter differ significantly (P<0.05). 

Aminoimidazole-4-carboxamide ribonucleoside (also known as AICA riboside or AICAR). An adenosine analogue that is taken up into cells by adenosine transporters and converted by adenosine kinase to the monophosphorylated nucleotide form, ZMP. ZMP is an analogue of AMP that activates the AMP-activated protein kinase (AMPK), for which acadesine or AICAR can be used as a pharmacological activator. 

AMP-activated protein kinase, AMPK SNF1 complex (fungi) SNF1-related kinase-1 (higher plants)... 

AMPK can also be activated by a Ca2+-mediated pathway involving phosphorylation at Thr-172 by the Ca2+/calmodulin-dependent protein kinase, CaMKK 3. CaMKKa and CaMKK 3 were discovered as the upstream kinase for the calmodulin-dependent protein kinases-1 and -IV they both activate AMPK in a Ca2+/ calmodulin-dependent manner in cell-free assays, although CaMKK 3 appears to much more active against AMPK in intact cells. Expression of CaMKKa and CaMKK(3 primarily occurs in neural tissues, but CaMKKp is also expressed in some other cell types. Thus, the Ca2+-mediated pathway for AMPK activation has now been shown to occur in response to depolarization in rat neuronal tissue, in response to thrombin (acting via a Gq-coupled receptor) in endothelial cells, and in response to activation of the T cell receptor in T cells. 

The first pharmacological agent shown to activate AMPK was 5-aminoimidazole-4-carboxamide (AICA) riboside, also known as acadesine. This adenosine analogue is taken up into cells by adenosine transporters and phosphoiylated by adenosine kinase to the mono-phosphorylated form, AICA ribotide or ZMP. ZMP accumulates inside cells to higher concentrations than the concentration of AICA riboside present in the medium, and it mimics both effects of AMP on AMPK system (allosteric activation and inhibition of... 

AMP-activated Protein Kinase. Table 2 Metabolic effects of AMPK activation. In cases marked with an asterisk, there is evidence that AMPK mediates its effects by modulating the target named, although it is not yet clear whether the protein is directly phosphorylated by AMPK... 

---