Glycogen synthase, glucagon

Enzymes of glycogenes Glycogen synthase system is,glycoiy T sis, and py T ruvate oxidation Insulin Insulin Glucose 6-phosphate Glucagon (cAMP) phos-phorylase, glycogen... 

In the fed state when the insulin glucagon ratio is high, would you expect glycogen synthase, PK and PDH to be phosphorylated or de-phosphorylated Give reasons to support your answer. 

The key control enzyme in the pathway is glycogen synthase (GS) which occurs in either a high activity state (GS-a) or a low activity state (GS-b) the switch from one to the other is brought about partly by covalent modification of the enzyme in response to stimulation by glucagon and partly by allosteric effects of key metabolites. Glycogen... 

In contrast to glucagon, the peptide hormone insulin (see p. 76) increases glycogen synthesis and inhibits glycogen breakdown. Via several intermediates, it inhibits protein kinase GSK-3 (bottom right for details, see p. 388) and thereby prevents inactivation of glycogen synthase. In addition, insulin reduces the cAMP level by activating cAMP phosphodiesterase (PDE). 

Correct answer = B. Epinephrine and glucagon both cause increased glycogen degradation in the liver. Therefore, glycogen phosphorylase activity is increased, whereas glycogen synthase activity is decreased. Both cAMP-dependent protein kinase and its substrate, phosphorylase kinase, are also activated. 

The same cAMP-dependent protein kinase that is responsible for phosphorylating phosphorylase kinase also catalyzes the phosphorylation of glycogen synthase. Whereas phosphorylation of glycogen phosphorylase leads to increased activity, the phosphorylation of glycogen synthase decreases its activity. As a result when glycogen breakdown is stimulated in response to glucagon, glycogen synthesis is inhibited. In this way the simultaneous operation of both enzymes associated with pseudocycle la is prevented. 

The same protein kinase that phosphorylates glycogen phosphorylase and glycogen synthase does not phosphorylate the enzymes of pseudocycle II. Rather an enzyme gets phos-phorylated that catalyzes the synthesis of a potent allosteric effector of the two relevant enzymes, phosphofructokinase and fructose bisphosphate phosphatase. In the liver the un-phosphorylated form this enzyme synthesizes fructose-2,6-bisphosphate. Phosphorylation converts it into a degradative enzyme for the same compound. Fructose-2,6-bisphosphate is an activator of phosphofructokinase and an inhibitor of fructose bisphosphate phosphatase. As a result the net effect of glucagon on pseudocycle II is to stimulate fructose bisphosphate phosphatase while inhibiting phosphofructokinase (see table 12.2 and fig. 12.30). 

Fig. 6. Effects of glucagon (1 nM) on the activities of phosphorylase a, glycogen synthase and pyruvate kinase in isolated rat hepatocytes. Reproduced from Ref. 58 by permission of the author and publisher.

Glucagon decreases cholesterol synthesis in isolated hepatocytes [131,132] apparently because it reduces the fraction of hydroxymethylglutaryl-CoA reductase in the active form [131,132], This is due to an increase in reductase kinase activity [133], However, there is no evidence that cAMP-dependent protein kinase phos-phorylates either the reductase, reductase kinase or reductase kinase kinase [134], It has been proposed that the phosphorylation state of these enzymes is indirectly controlled through changes in the activity of protein phosphatase I [132,134], This phosphatase can dephosphorylate and activate the reductase [134,135] and its activity can be controlled by a heat stable inhibitor (inhibitor 1), the activity of which is increased by cAMP-dependent phosphorylation [136,137], Since the phosphorylated forms of acetyl-CoA carboxylase, ATP-citrate lyase, pyruvate kinase, phos-phorylase, phosphorylase kinase and glycogen synthase are also substrates for protein phosphatase I [135], this mechanism could also contribute to their phosphorylation by glucagon. 

FFA, free fatty acid GH, growth hormone GLP-1, glucagon-like protein 1 GS, glycogen synthase GSK3, glycogen synthase kinase 3 HDL, high density lipoprotein HF, heart failure IKK, inhibitor of kappa B kinase INK, c-jun N-terminal kinase EDL, low density lipoprotein Ep(a), lipoprotein little a EV, left ventricular MetS, metabolic syndrome MI, myocardial infarction... 

All known actions of glucagon are mediated by protein kinases that are activated hy cyclic AMP. The activation of the cyclic AMP cascade results in a higher level of phosphorylase a activity and a lower level of glycogen synthase a activity. Glucagon s effect on this cascade is reinforced hy the diminished binding of glucose to phosphorylase a, which makes the enzyme less susceptible to the hydrolytic action of the phosphatase. Instead, the phosphatase remains hound to phosphorylase a, and so the synthase stays in the in-active phosphorylated form. Consequently, there is a rapid mobilization of glycogen. 

---