Control of glycogen synthase

Figure 18-7. Control of glycogen synthase in muscle (n = number of glucose residues). The sequence of reactions arranged in a cascade causes amplification at each step, allowing only nanomole quantities of hormone to cause major changes in glycogen concentration. (GSK, glycogen synthase kinase-3, -4, and -5 G6P, glucose 6-phosphate.)...

Glycogen synthase forms the O -1,4 glycosidic bond found in the linear glucose chains of the granule. Table 1-14-1 shows the control of glycogen synthase in liver and skeletal muscle. 

C. Villar-Palasi and J. J. Guinovart The role of glucose-6-phosphate in the control of glycogen synthase. FASEB Journal 11,544 (1997). 

Fig. 3.7. Control of glycogen synthase and phosphorylase. PPase, phosphorylase GS, glycogen synthase.

The relations between hormonal action, the phosphorylation of proteins, and the kinetic properties of the enzymes involved in the synthesis and degradation of glycogen have been reviewed. The control of glycogen synthase has also been discussed. ... 

Figure 6.40 Reciprocal control of glycogen phosphorylase and glycogen synthase...

FIGURE 15-36 Control of glycogen synthesis from blood glucose in myocytes. Insulin affects three of the five steps in this pathway, but it is the effects on transport and hexokinase activity, not the change in glycogen synthase activity, that increase the flux toward glycogen. 

Shulinan, R.G., Block, G., Rothman, D.L. (1995) In vivo regulation of muscle glycogen synthase and the control of glycogen synthesis. Proc. Natl. Acad. Sci. USA 92, 8535-8542. 

Two key regulatory enzymes involved in the control of glycogen metabolism were first recognized as targets of cAMP and cAMP-dependent protein kinase in liver and skeletal muscle. These are phosphorylase b kinase and glycogen synthase. The molecular details of the phosphorylation and regulation of these enzymes are better understood in muscle than in liver since the liver enzymes have only recently been purified to homogeneity in the native form. However, it appears that they share many key features in common. 

How is the enzyme dephosphorylated and activated Insulin stimulates the carboxylase by causing its dephospkorylation. It is not clear which of the phosphatases activates the carboxylase in response to insulin. The hormonal control of acetyl CoA carboxylase is reminiscent of that of glycogen synthase (Section 21.5.2). 

Other proteins involved in glyeogen synthase control are calmodulin, inhibitor-1, and inhibitor-2. Troponin C, when complexed with Ca " ", can activate phosphorylase kinase, but phosphorylase kinase may have little or no role in the inactivation of glycogen synthase in vivo. Inhibitor-1 (M.W. 18,600), when phosphorylated on threonine 35 by cAMP-dependent protein kinase, binds to and inhibits protein phosphatase-1. The concentration of protein phosphatase-1 is lower than that of inhibitors, and its activity is sensitive to the latter, suggesting that inhibitor-1 phosphorylation may be an important regulatory mechanism for this phosphatase. Inhibitor-2 (M.W. 30,500) appears to be an integral part of protein phosphatase-1, forming an inactive 1 1 complex, called Mg +/ATP-dependent phosphatase, with the catalytic subunit of this enzyme. Phosphorylation of inhibitor-2 (also at a threonine residue) activates protein phosphatase-1. This phosphorylation, which requires Mg -ATP, is catalyzed by an activating factor (Fa), GSK-3. 

Whether glycogen synthase is a substrate for phosphorylase kinase in vivo is unclear. [Modified and reproduced with permission from P. Cohen, Protein phosphorylation and the control of glycogen metabolism in skeletal muscle. Philos. Trans. R. Soc. Land. (Biol.) 302, 13 (1983).]... 

Hepatic glycogen synthesis after a meal. The permeability of the liver to glucose provides the substrate for hepatic glycogen synthesis. This synthesis is controlled by (1) activation of glycogen synthase by insulin,... 

Figure 21.17 Coordinate control of glycogen metabolism. Glycogen metabolism is regulated, in part, by hormone triggered cyclic AMP cascades. The sequence of reactions leading to the activation of protein kinase A ultimately activates glycogen degradalion. At the same time, protein kinase A also inactivates glycogen synthase, shutting down glycogen synthesis.

Figure 16.12 Regulation of glycogen synthase activity through cAMP-mediated control of phosphoprotein phosphatase (PP-1) activity. 

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