How is glycogen metabolism controlled?

How is glycogen metabolism controlled?

How does an organism ensure that glycogen synthesis and glycogen breakdown do not operate simultaneously? If this were to occur, the main result would be the hydrolysis of UTP, which would waste chemical energy stored in the phosphoric anhydride bonds. A major controlling factor lies in the behavior of glycogen phosphorylase. This enzyme is subject not only to allosteric control but also to another control feature: covalent modification. In that example, phosphorylation and dephosphorylation of an enzyme determined whether it was active, and a similar effect takes place here.

Figure 18.5 summarizes some of the salient control features that affect glyco-gen phosphorylase activity. The enzyme is a dimer that exists in two forms, the inactive T (taut) form and the active R (relaxed) form. In the T form (and only in the T form), it can be modified by phosphorylation of a specific serine resi-due on each of the two subunits. The esterification of the serines to phosphoric acid is catalyzed by the enzyme phosphorylase kinase; the dephosphorylation is catalyzed by phosphoprotein phosphatase. The phosphorylated form of glycogen phosphorylase is called phosphorylasea, and the dephosphorylated form is called phosphorylaseb. The switch from phosphorylase b to phosphorylase a is the major form of control over the activity of phosphorylase. The response time of the changes is on the order of seconds to minutes. Phosphorylase is also controlled more quickly in times of urgency by allosteric effectors, with a response time of milliseconds.

In liver, glucose is an allosteric inhibitor of phosphorylase a. It binds to the substrate site and favors the transition to the T state. It also exposes the phosphorylated serines so that the phosphatase can hydrolyze them. This shifts the equilibrium to phosphorylase b. In muscle, the primary allosteric effectors are ATP, AMP, and glucose-6-phosphate (G6P). When the muscles use ATP to contract, AMP levels rise. This increase in AMP stimulates formation of the R state of phosphorylase b, which is active. When ATP is plentiful or glucose-6-phosphate builds up, these molecules act as allosteric inhibitors shifting the equilibrium back to the T form. These differences ensure that glycogen will be degraded when there is a need for energy, as is the case with high [AMP], low [G6P], and low [ATP]. When the reverse is true (low [AMP], high [G6P], and high [ATP]), the need for energy, and consequently for glycogen breakdown, is less. “Shutting down” glycogen phosphorylase activity is the appropriate response. The combination of covalent modification and allosteric control of the process allows for a degree of fine-tuning that would not be possible with either mechanism alone. Hormonal control also enters into the picture. When epinephrine is released from the adrenal gland in response to stress, it triggers a series of events, that suppress the activity of glycogen synthase and stimulate that of glycogen phosphorylase.

The activity of glycogen synthase is subject to the same type of covalent modification as glycogen phosphorylase. The difference is that the response is opposite. The inactive form of glycogen synthase is the phosphorylated form. The active form is unphosphorylated. The hormonal signals (glucagon or epi-nephrine) stimulate the phosphorylation of glycogen synthase via an enzyme called cAMP-dependent protein kinase. After the glycogen syn-thase is phosphorylated, it becomes inactive at the same time the hormonal sig-nal is activating phosphorylase. Glycogen synthase can also be phosphorylated by several other enzymes, including phosphorylase kinase and several enzymes called glycogen synthase kinases. Glycogen synthase is dephosphorylated by the same phosphoprotein phosphatase that removes the phosphate from phos-phorylase. The phosphorylation of glycogen synthase is also more complicated in that there are multiple phosphorylation sites. As many as nine different amino acid residues have been found to be phosphorylated. As the progressive level of phosphorylation increases, the activity of the enzyme decreases.

Glycogen synthase is also under allosteric control. It is inhibited by ATP. This inhibition can be overcome by glucose-6-phosphate, which is an activa-tor. However, the two forms of glycogen synthase respond very differently to glucose-6-phosphate. The phosphorylated (inactive) form is called glycogensynthase D (for “glucose-6-phosphate dependent”) because it is active onlyunder very high concentrations of glucose-6-phosphate. In fact, the level necessary to give significant activity would be beyond the physiological range. The nonphosphorylated form is called glycogen synthase I (for “glucose-6-phosphate independent”) because it is active even with low concentrations of glucose-6-phosphate. Thus, even though purified enzymes can be shown to respond to allosteric effectors, the true control over the activity of glycogen syn-thase is by its phosphorylation state, which, in turn, is controlled by hormonal states.

The fact that two target enzymes, glycogen phosphorylase and glycogen syn-thase, are modified in the same way by the same enzymes links the opposing processes of synthesis and breakdown of glycogen even more intimately.

Finally, the modifying enzymes are themselves subject to covalent modifica-tion and allosteric control. This feature complicates the process considerably but adds the possibility of an amplified response to small changes in conditions. A small change in the concentration of an allosteric effector of a modifying enzyme can cause a large change in the concentration of an active, modified target enzyme; this amplification response is due to the fact that the substrate for the modifying enzyme is itself an enzyme. 

At this point, the situation has become very complex indeed, but it is a good example of how opposing pro-cesses of breakdown and synthesis can be controlled to the advantage of an organism.