Regulation of glycogen synthase from mammalian skeletal muscle – a unifying view of allosteric and covalent regulation

@article{Palm2013RegulationOG,
  title={Regulation of glycogen synthase from mammalian skeletal muscle – a unifying view of allosteric and covalent regulation},
  author={Daniel C. Palm and Johann M. Rohwer and Jan-Hendrik S. Hofmeyr},
  journal={The FEBS Journal},
  year={2013},
  volume={280}
}
It is widely accepted that insufficient insulin‐stimulated activation of muscle glycogen synthesis is one of the major components of non‐insulin‐dependent (type 2) diabetes mellitus. Glycogen synthase, a key enzyme in muscle glycogen synthesis, is extensively regulated, both allosterically (by glucose‐6‐phosphate, ATP, and others) and covalently (by phosphorylation). Although glycogen synthase has been a topic of intense study for more than 50 years, its kinetic characterization has been… Expand
Incorporating covalent and allosteric effects into rate equations: the case of muscle glycogen synthase.
TLDR
This study shows, using non-linear parameter optimization with robust weight estimation, that a Monod-Wyman-Changeux model in which phosphorylation favours the inactive T conformation provides a satisfactory description of muscle glycogen synthase kinetics. Expand
Molecular basis for the regulation of human glycogen synthase by phosphorylation and glucose-6-phosphate
TLDR
These structures reveal how phosphorylations of specific N- and C- terminal residues are sensed by different arginine clusters that lock the GYS1 tetramer complex in an inhibited state via inter-subunit interactions and provide the first mechanistic insights into human glycogen synthase regulation. Expand
Progresses of the Past Decade on Factors Contributing to Skeletal MuscleGlycogen Synthase Regulation
Glycogen is the primary storage form of glucose, which is metabolized actively in the liver and skeletal muscle of mammals. The skeletal muscle glycogen is used intracellularly to provide startingExpand
Structural basis for the recruitment of glycogen synthase by glycogenin
TLDR
The crystal structure of Caenorhabditis elegans GS in complex with a minimal GS targeting sequence in GN is described and a 34-residue region of GN binds to a conserved surface on GS that is distinct from previously characterized allosteric and binding surfaces on the enzyme. Expand
Characterization of Muscle Glycogen Synthase and its Association with RNA in Sertoli Cells
The metabolism of Sertoli cells is highly active to maintain nutritional needs of germ cells. After glucose incorporation, only 1-3% is converted to glycogen suggesting low levels of glycogenExpand
Metabolic control analysis of hepatic glycogen synthesis in vivo
TLDR
It is demonstrated that glucokinase (GCK)-mediated glucose phosphorylation is the rate-controlling step in insulin-stimulated hepatic glycogen synthesis in vivo, by use of the somatostatin pancreatic clamp technique using GCK translocation with metabolic control analysis (MCA). Expand
Beyond energy storage: roles of glycogen metabolism in health and disease
TLDR
This review highlights the essential role of the gluconeogenesis‐glycogenesis‐ glycogenolysis‐PPP metabolic chain in redox homeostasis, thus providing insights into potential therapeutic strategies against major chronic diseases including cancer. Expand
Integration of flux measurements to resolve changes in anabolic and catabolic metabolism in cardiac myocytes
TLDR
It is suggested that a major portion of intracellular glucose in cardiac myocytes is apportioned for ancillary biosynthetic reactions and that PFK co-ordinates the activities of the pentose phosphate, hexosamine biosynthetics, and glycerolipid synthesis pathways by directly modulating glycolytic intermediate entry into auxiliary glucose metabolism pathways and by indirectly regulating mitochondrial cataplerosis. Expand
Up-Regulation of Glycogen Synthesis and Degradation Enzyme Level Maintained Myocardial Glycogen in Huddling Brandt’s Voles Under Cool Environments
TLDR
The results indicate that the reduced glycogen degradation enzyme level and enhanced glucose transport may lead to an increase in myocardial glycogen content of the separated voles under cool environment; while the up-regulation of glycogen synthesis and degradation enzymes level maintained myocardian glycogencontent in the huddling vole. Expand
A Modular Mathematical Model of Exercise-Induced Changes in Metabolism, Signaling, and Gene Expression in Human Skeletal Muscle
TLDR
A physiologically based computational model of skeletal muscle comprising energy metabolism, Ca2+, and AMPK (AMP-dependent protein kinase) signaling pathways and the expression regulation of genes with early and delayed responses was developed based on a modular modeling approach and included 171 differential equations and more than 640 parameters. Expand
...
1
2
3
...

References

SHOWING 1-10 OF 155 REFERENCES
In vivo regulation of muscle glycogen synthase and the control of glycogen synthesis.
TLDR
A quantitative model is proposed in which the glucose transporter/hexokinase steps control the rate of glycogen synthesis in normal humans and rat muscle and preliminary evidence favors the transporter step. Expand
Allosteric regulation of glycogen synthase controls glycogen synthesis in muscle.
TLDR
This study provides genetic evidence that allosteric activation of GS is the primary mechanism by which insulin promotes muscle glycogen accumulation in vivo and demonstrates that knockin mice expressing the G6P-insensitive mutant display an ∼80% reduced Muscle glycogen synthesis by insulin and markedly reduced glycogen levels. Expand
Phosphorylation-dependent Translocation of Glycogen Synthase to a Novel Structure during Glycogen Resynthesis*
TLDR
Evidence is presented of a new regulatory mechanism of skeletal muscle glycogen metabolism based on glycogen enzyme intracellular compartmentalization, and for the first time, a phosphorylation-dependent intrACEllular distribution of GS is shown. Expand
Covalent phosphorylation in the regulation of glycogen synthase activity
TLDR
The nature of several hormonal influences on the interconversion of synthase species led to a functional significance for the phosphorylationdephosphorylation of the enzyme. Expand
Muscle glycogen synthase in vivo state:
TLDR
These experiments indicated a smooth, monotonic dependence of properties on phosphate content and investigated the relationship between enzyme kinetic properties of synthase and the alkali-labile phosphate content of the enzyme. Expand
Enzymatic phosphorylation of muscle glycogen synthase: a mechanism for maintenance of metabolic homeostasis.
  • R. Shulman, D. Rothman
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 1996
TLDR
It is proposed that the phosphorylation of GSase, which alters the sensitivity to allosteric activation by glucose 6-phosphate (G6P), is a mechanism for controlling the concentration of G6P instead of controlling the flux. Expand
Dual Regulation of Muscle Glycogen Synthase during Exercise by Activation and Compartmentalization*
TLDR
The results show that GS intrinsic activity is strongly dependent on glycogen levels and that such regulation involves associated dephosphorylation at sites 2+2a, 3a, and 3a + 3b, and the existence of several glycogen metabolism regulatory mechanisms based on GS intracellular compartmentalization is reported. Expand
Rabbit skeletal muscle glycogen synthase. II. Enzyme phosphorylation state and effector concentrations as interacting control parameters.
TLDR
Changes in the phosphorylation of the enzyme corresponding to changes in the %I activity reported in the literature for studies in vivo were capable of producing large alterations in glycogen synthase activity, and there may be an integration of local cellular control through small molecule effects, with hormonal control, through theosphorylation state of glycogen synthetase. Expand
Glycogen and its metabolism.
  • P. Roach
  • Chemistry, Medicine
  • Current molecular medicine
  • 2002
TLDR
Though the number of enzymes directly involved in the metabolism of glycogen is quite small, many more proteins act indirectly in a regulatory capacity and, with some exceptions, mutations in the regulatory proteins appear to cause a more subtle phenotypic change. Expand
Glycogen and its metabolism: some new developments and old themes.
TLDR
Significant new developments in eukaryotic glycogen metabolism over the last decade or so include: (i) three-dimensional structures of the biosynthetic enzymes glycogenin and glycogen synthase, with associated implications for mechanism and control; (ii) analyses of several genetically engineered mice with altered glycogens metabolism that shed light on the mechanism of control. Expand
...
1
2
3
4
5
...