Glycogen Metabolism Carmen Sato­Bigbee, Ph.D. Objectives: 1) To understand the pathways involved in glycogen synthesis and degradation. 2) To discuss the regulation of glycogen metabolism by hormones and other effectors and the role of these mechanisms in different tissues. 3) To discuss the etiology of the common glycogen storage diseases Resources: Lehninger et al, Principles of Biochemistry 2005 ; Marks et al., Medical Biochemistry, 2005. Glycogen is synthesized when there is an excess of glucose (after eating a meal containing carbohydrates). In between meals or in situations that require high ATP consumption (muscle contraction, stress), glycogen is degraded to maintain adequate glucose levels. Why store glucose as glycogen? 1) Glycogen allows to store a large number of glucose residues in a relatively small space and without significantly increasing the osmotic pressure. Osmotic pressures depend only on numbers of molecules. Therefore the osmotic pressure is greatly reduced by formation of fewer glycogen molecules out of thousands or even millions of individual glucose molecules. 2) The branched structure of glycogen allows its very rapid synthesis and degradation. Several branches can be elongated or degraded simultaneously according to the glucose requirement of the cells. This would not be possible if glycogen were a linear molecule. 3) Several steps along glycogen synthesis and degradation are subjected to a very stringent regulation. These regulatory mechanisms allow the cells to only store or release glucose according to the energy needs and not just in a random way.
Figure 1­ Taken from Marks et al. Glycogen plays very different roles in muscle and liver cells Liver and skeletal muscle contain the largest glycogen stores. In skeletal muscle, glycogen degradation provides glucose­6­phosphate that can be directly used by the muscle cells to produce ATP by glycolysis. Liver glycogen is used to maintain blood glucose levels. This ensures that tissues that have low glycogen content can have a continuous supply of glucose. This is particularly important for the brain which does not contain too much glycogen but requires about 75% of the total glucose consumed daily. Glycogen synthesis Glycogen synthesis is carried out by addition of glucose residues to a preexisting glycogen molecule or glycogen primer. The first sugar residue is linked to a protein called glycogenin.
Each new glucose residue is added from UDP­glucose (activated, high energy­content form of glucose) to the non­reducing end of a growing glycogen chain to form a newa­1,4 linkage. This reaction is catalyzed by the enzyme glycogen synthase. When a chain reaches 11 residues in length, a 6­8 glucose chain is cleaved by the branching enzyme. This same branching enzyme then transfers the cleaved chain to another chain creating a new a­1,6 branching point. The new branch is then elongated by the enzyme glycogen synthase and then cleaved as described above by the branching enzyme. This continuous process of elongation, cleavage and reattachment produces the highly branched glycogen molecules. As we will see later, the key enzyme that controls glycogen synthesis is glycogen synthase. Glycogen degradation Glycogen degradation also requires the action of two different enzymes. The enzyme glycogen phosphorylase cleaves, one by one, a­1,4 bonds starting at the end of the chains. Each glucose molecule is released as glucose­1­phosphate. However, glycogen phosphorylase does not "fit well" between branching chains and therefore cannot release the last 4 glucose residues closest to a branching point. Glycogen phosphorylase's helper is the debrancher enzyme. This enzyme removes a 3 glucose unit and transfers it to the end of a longer chain. The debrancher enzyme also hydrolyzes the a­ 1,6 linkage at the branching point releasing the last glucose residue (in this case the residue is simply released as glucose, not glucose­1­phosphate as in the case of glycogen phosphorylase).
Glucose­1­phosphate that is released by glycogen phosphorylase is converted by a phosphoglucomutase into glucose­6­phosphate which can be used directly in the glycolytic pathway. In the liver, the phosphate group of glucose­6­phosphate is removed by the enzyme glucose­6­phosphatase producing glucose that can be released into the blood stream and used by other tissues. Glycogen synthesis and degradation are highly regulated processes [The regulation of glycogen levels is carried out by reciprocal regulation of the degradative enzyme glycogen phosphorylase and the synthetic enzyme glycogen synthase]. Liver glycogen: In liver, glycogen stores provide glucose for other tissues. Therefore, glycogen synthesis and degradation in liver are highly dependent on the blood glucose levels. Glycogen is synthesized after a carbohydrate meal, when blood glucose levels are high. Part of that glucose is used to produce ATP but a large proportion is stored as glycogen. [The synthesis of liver glycogen is stimulated by insulin, a hormone that increases when blood glucose levels are high]. On the other hand, liver glycogen is degraded to provide glucose in between meals and during fasting, when glucose levels are low. [The degradation of liver glycogen is stimulated by glucagon, a hormone that increases when blood glucose levels are low]. Important to remember: High blood glucose ­> high insulin and low glucagon ­> glycogen synthesis is stimulated while glycogen degradation is inhibited. The result: glucose is stored as glycogen and blood glucose levels decrease. Low blood glucose ­> low insulin and high glucagon ­> glycogen synthesis is inhibited while glycogen degradation is stimulated.
The result: blood glucose levels increase and more glucose is available to the cells. The degradation of liver glycogen is also stimulated by epinephrine, a hormone that increases in response to exercise and stress situations. (Glucagon and epinephrine regulate glycogen metabolism in the same direction). How do hormones control liver glycogen metabolism? [Glycogen phosphorylase, the key enzyme of glycogen degradation, is activated by phosphorylation by phosphorylase kinase]. This kinase transforms the inactive glycogen phosphorylase b into active glycogen phosphorylase a. Phosphorylase a can be transformed into inactive phosphorylase b by dephosphorylation by protein phosphatase­1. phosphorylase kinase glycogen phosphorylase b glycogen phosphorylase a (inactive) (active) protein phosphatase­1 [Glycogen synthase, the key enzyme of glycogen synthesis, is inactivated by phosphorylation by PKA]. Phosphorylation transforms the active glycogen synthase into inactive glycogen synthase. On the other hand, the inactive synthase b can be transformed into active synthase a by dephosphorylation by protein phosphatase­1. (Notice that the same protein phosphatase­1 inactivates glycogen phosphorylase and activates glycogen synthase). PKA active glycogen synthase inactive glycogen synthase protein phosphatase­1
These phosphorylation/dephosphorylation reactions mediate the regulation of glycogen metabolism by glucagon, epinephrine and insulin. In the liver, binding of glucagon or epinephrine to their membrane receptors, results in activation of the enzyme adenylate cyclase. Adenylate cyclase synthesizes cyclic AMP (cAMP) which in turn activates protein kinase A (cAMP­dependent kinase). Protein kinase A phosphorylates and activates the enzyme phosphorylase kinase. Phosphorylase kinase phosphorylates the inactive glycogen phosphorylase b transforming this enzyme into active glycogen phosphorylase a. This results in stimulation of glycogen degradation. At the same time, we have seen before that protein kinase A inactivates glycogen synthase. Insulin activates the phosphodiesterase that degrades cAMP into AMP. At the same time, insulin initiates a series of phosphorylation reactions that activate protein phosphatase­1. [These actions of insulin reverse the action of glucagon] Figure 2­ Original
[In summary, glucagon and epinephrine increase the levels of cAMP resulting in stimulation of glycogen degradation and inhibition of glycogen synthesis. Therefore liver glycogen levels decrease and blood glucose levels increase]. On the other hand, insulin decreases cAMP levels and activates protein phosphatase­1 resulting in inhibition of glycogen degradation and stimulation of stimulation of glycogen synthesis. Therefore liver glycogen levels increase and blood glucose levels decrease]. Regulation of glycogen metabolism in skeletal muscle The regulation of muscle glycogen metabolism differs from that in liver in several important aspects: 1) Muscle does not have glucagon receptors, thus glucagon has no effect on muscle glycogen metabolism. On the other hand, insulin and epinephrine have similar effects to the ones described above for liver glycogen. 2) In muscle, glycogen phosphorylase is allosterically activated by AMP. (Remember that AMP levels increase when ATP levels decrease. Muscle contraction needs energy which is provided by hydrolysis of ATP to ADP. ADP is transformed into AMP by the enzyme adenylate kinase. The more ATP is used the more AMP is produced signaling the cell a need for more glucose). 3) Ca 2+ released from the sarcoplasmic reticulum during muscle contraction activates phosphorylase kinase. This results in transformation of inactive glycogen phosphorylase b into active phosphorylase a and stimulation of glycogen degradation.
Figure 3­ Taken from Marks et al.
Table 1­ Taken from Marks et al. The deficiency of different enzymes of glycogen metabolism produces several glycogen storage diseases (most autosomal recessive) that can result in hypoglycemia, growth failure, acidosis, lipemia, muscle and liver dysfunction, cardiac failure. Review questions 1) Why do cells store glucose as glycogen? 2) What is the function of glycogen in liver and skeletal muscle? 3) What are the key enzymes in the synthesis and degradation of glycogen?
4) Which are the hormones that regulate glycogen metabolism? 5) How do these hormones regulate glycogen metabolism in liver? 6) How do glucagon and insulin affect glucose levels by regulating liver glycogen metabolism? 7) Is glycogen metabolism in muscle regulated by the same mechanisms operating in liver?