Allosteric Regulation of Glycogenesis and Glycogenolysis

In addition to hormonal signals, glycogen synthase and glycogen phosphorylase respond to the levels of metabolites and energy needs of the cell. Glycogenesis is stimulated when glucose and energy levels are high, whereas glycogenolysis is increased when glucose and energy levels are low. This allosteric regulation allows a rapid response to the needs of a cell and can override the effects of hormone-mediated covalent regulation.  [Note: The “a” and “b” forms of the allosteric enzymes of glycogen metabolism are each in an equilibrium between the R (relaxed, more active) and T (tense, less active) conformations . The binding of effectors shifts the equilibrium and alters enzymic activity without directly altering the covalent modification.]
1. Regulation in the well-fed state: In the well-fed state, glycogen synthase b in both liver and muscle is allosterically activated by glucose 6- phosphate, which is present in elevated concentrations (Fig.1). In contrast, glycogen phosphorylase a is allosterically inhibited by glucose 6-phosphate, as well as by ATP, a high-energy signal. [Note: In liver, but not muscle, free glucose is also an allosteric inhibitor of glycogen phosphorylase a.]

Figure 1: Allosteric regulation of glycogenesis and glycogenolysis in liver (A) and muscle (B). P = phosphate; AMP = adenosine monophosphate.
2. Glycogenolysis activation by AMP: Muscle glycogen phosphorylase (myophosphorylase), but not the liver isozyme, is active in the presence of the high AMP concentrations that occur under extreme conditions of anoxia and ATP depletion. AMP binds to glycogen phosphorylase b, causing its activation without phosphorylation . [Note: Recall that AMP also activates phosphofructokinase-1 of glycolysis , allowing glucose from glycogenolysis to be oxidized.]

3. Glycogenolysis activation by calcium: Calcium (Ca2+) is released into the sarcoplasm in muscle cells (myocytes) in response to neural stimulation and in the liver in response to epinephrine binding to α1- adrenergic receptors. The Ca2+ binds to calmodulin (CaM), the most widely distributed member of a family of small, Ca2+-binding proteins. The binding of four molecules of Ca2+ to CaM triggers a conformational change such that the activated Ca2+–CaM complex binds to and activates protein molecules, often enzymes, that are inactive in the absence of this complex (Fig. 2). Thus, CaM functions as an essential subunit of many complex proteins. One such protein is the tetrameric phosphorylase kinase, whose “b” form is activated by the binding of Ca2+ to its δ subunit (CaM) without the need for the kinase to be phosphorylated by PKA. [Note: Epinephrine at β-adrenergic receptors signals through a rise in cAMP, not Ca2+ .]

Figure 2: : Calmodulin mediates many effects of intracellular calcium (Ca2+). [Note: Ca2+ activates phosphorylase kinase in liver and muscles.]
a. Muscle phosphorylase kinase activation: During muscle contraction, there is a rapid and urgent need for ATP. It is supplied by the degradation of muscle glycogen to glucose 6-phosphate, which enters glycolysis. Nerve impulses cause membrane depolarization, which promotes Ca2+ release from the sarcoplasmic reticulum into the sarcoplasm of myocytes. The Ca2+ binds the CaM subunit, and the complex activates muscle phosphorylase kinase b .
b. Liver phosphorylase kinase activation: During physiologic stress, epinephrine is released from the adrenal medulla and signals the need for blood glucose. This glucose initially comes from hepatic glycogenolysis. Binding of epinephrine to hepatocyte α1-adrenergic GPCR activates a phospholipid-dependent cascade (see p. 205) that results in movement of Ca2+ from the ER into the cytoplasm. A Ca2+– CaM complex forms and activates hepatic phosphorylase kinase b. [Note: The released Ca2+ also helps to activate protein kinase C that can phosphorylate (therefore, inactivate) glycogen synthase a.]