Control Analysis of Muscle Glycogen Metabolism

Schulz, Arthur R.

doi:10.1006/abbi.1998.0643

Cited by 18 publications

(10 citation statements)

References 33 publications

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“…This is explained by the unique compartmentation of glucokinase that involves glucose-dependent partitioning of the enzyme between a free active state and an inactive state bound to its regulatory protein (12,14). The stimulation of glycogenic flux by an increase in glucokinase activity by either translocation (19) or enzyme overexpression (27) is at least in part explained by the increase in glucose 6-P concentration (11), the product of the glucokinase-catalyzed reaction, which is a potent activator of glycogen synthase (28). Glucose 6-phosphatase, which lowers the concentration of glucose 6-P in hepatocytes, has a negative control coefficient on glycogen synthesis (13).…”

Section: Discussionmentioning

confidence: 99%

Hepatic Glycogen Synthesis Is Highly Sensitive to Phosphorylase Activity

Aiston

Hampson

Gómèz-Foix

et al. 2001

Journal of Biological Chemistry

107

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We used metabolic control analysis to determine the flux control coefficient of phosphorylase on glycogen synthesis in hepatocytes by titration with a specific phosphorylase inhibitor (CP-91149) or by expression of muscle phosphorylase using recombinant adenovirus. The muscle isoform was used because it is catalytically active in the b-state. CP-91149 inactivated phosphorylase with sequential activation of glycogen synthase. It increased glycogen synthesis by 7-fold at 5 mM glucose and by 2-fold at 20 mM glucose with a decrease in the concentration of glucose causing half-maximal rate (S 0.5 ) from 26 to 19 mM. Muscle phosphorylase was expressed in hepatocytes mainly in the b-state. Low levels of phosphorylase expression inhibited glycogen synthesis by 50%, with little further inhibition at higher enzyme expression, and caused inactivation of glycogen synthase that was reversed by CP-91149. At endogenous activity, phosphorylase has a very high (greater than unity) negative control coefficient on glycogen synthesis, regardless of whether it is determined by enzyme inactivation or overexpression. This high control is attenuated by glucokinase overexpression, indicating dependence on other enzymes with high control. The high control coefficient of phosphorylase on glycogen synthesis affirms that phosphorylase is a strong candidate target for controlling hyperglycemia in type 2 diabetes in both the absorptive and postabsorptive states.

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Section: Discussionmentioning

confidence: 99%

Hepatic Glycogen Synthesis Is Highly Sensitive to Phosphorylase Activity

Aiston

Hampson

Gómèz-Foix

et al. 2001

Journal of Biological Chemistry

107

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“…However, due to its tight and complex regulation (174), study of glycogen metabolism in vivo may require an analysis with mathematical models including a more complete representation of the regulatory network, as has been done for other organs with metabolic control analysis [e.g., Ref. (175)].…”

Section: Glycogen Metabolismmentioning

confidence: 99%

Metabolic Flux and Compartmentation Analysis in the Brain In vivo

2013

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Through significant developments and progresses in the last two decades, in vivo localized nuclear magnetic resonance spectroscopy (MRS) became a method of choice to probe brain metabolic pathways in a non-invasive way. Beside the measurement of the total concentration of more than 20 metabolites, 1H MRS can be used to quantify the dynamics of substrate transport across the blood-brain barrier by varying the plasma substrate level. On the other hand, 13C MRS with the infusion of 13C-enriched substrates enables the characterization of brain oxidative metabolism and neurotransmission by incorporation of 13C in the different carbon positions of amino acid neurotransmitters. The quantitative determination of the biochemical reactions involved in these processes requires the use of appropriate metabolic models, whose level of details is strongly related to the amount of data accessible with in vivo MRS. In the present work, we present the different steps involved in the elaboration of a mathematical model of a given brain metabolic process and its application to the experimental data in order to extract quantitative brain metabolic rates. We review the recent advances in the localized measurement of brain glucose transport and compartmentalized brain energy metabolism, and how these reveal mechanistic details on glial support to glutamatergic and GABAergic neurons.

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“…G-6-P facilitates glycogen synthesis by reciprocally activating glycogen synthase (GS) and inhibiting glycogen phosphorylase (GP) [6], [7], and possibly by stimulating translocation of HK from mitochondria to the cytoplasm. In liver cells where glycogen synthesis is driven by glucokinase (GK or HKIV) rather than HKI, G-6-P stimulates glycogen synthesis by causing a redistribution of GK and GS to the cell periphery [8].…”

Section: Introductionmentioning

confidence: 99%

Subcellular Localization of Hexokinases I and II Directs the Metabolic Fate of Glucose

2011

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BackgroundThe first step in glucose metabolism is conversion of glucose to glucose 6-phosphate (G-6-P) by hexokinases (HKs), a family with 4 isoforms. The two most common isoforms, HKI and HKII, have overlapping tissue expression, but different subcellular distributions, with HKI associated mainly with mitochondria and HKII associated with both mitochondrial and cytoplasmic compartments. Here we tested the hypothesis that these different subcellular distributions are associated with different metabolic roles, with mitochondrially-bound HK's channeling G-6-P towards glycolysis (catabolic use), and cytoplasmic HKII regulating glycogen formation (anabolic use).Methodology/Principal FindingsTo study subcellular translocation of HKs in living cells, we expressed HKI and HKII linked to YFP in CHO cells. We concomitantly recorded the effects on glucose handling using the FRET based intracellular glucose biosensor, FLIPglu-600 mM, and glycogen formation using a glycogen-associated protein, PTG, tagged with GFP. Our results demonstrate that HKI remains strongly bound to mitochondria, whereas HKII translocates between mitochondria and the cytosol in response to glucose, G-6-P and Akt, but not ATP. Metabolic measurements suggest that HKI exclusively promotes glycolysis, whereas HKII has a more complex role, promoting glycolysis when bound to mitochondria and glycogen synthesis when located in the cytosol. Glycogen breakdown upon glucose removal leads to HKII inhibition and dissociation from mitochondria, probably mediated by increases in glycogen-derived G-6-P.Conclusions/SignificanceThese findings show that the catabolic versus anabolic fate of glucose is dynamically regulated by extracellular glucose via signaling molecules such as intracellular glucose, G-6-P and Akt through regulation and subcellular translocation of HKII. In contrast, HKI, which activity and regulation is much less sensitive to these factors, is mainly committed to glycolysis. This may be an important mechanism by which HK's allow cells to adapt to changing metabolic conditions to maintain energy balance and avoid injury.

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Control Analysis of Muscle Glycogen Metabolism

Cited by 18 publications

References 33 publications

Hepatic Glycogen Synthesis Is Highly Sensitive to Phosphorylase Activity

Hepatic Glycogen Synthesis Is Highly Sensitive to Phosphorylase Activity

Metabolic Flux and Compartmentation Analysis in the Brain In vivo

Subcellular Localization of Hexokinases I and II Directs the Metabolic Fate of Glucose

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