Glycogen metabolism
Glycogenesis - Glycogen synthesis
- Glycogenesis is the process of glycogen synthesis, in which glucose molecules are added to chains
of glycogen for storage. This process is activated during rest periods following the Cori cycle, in the
liver, and also activated by insulin in response to high glucose levels, for example after a
carbohydrate-containing meal.
- The following enzyme reactions occur in glycogen synthesis:
Synthesis:
1. Synthesis of an activated precursor (UDP-glucose) by UTP:glucose-1-phosphate
uridylyltransferase
2. Initiation of glycogen synthesis by glycogenin
3. Introduction of branches by branching enzyme
4. Chain elongation by glycogen synthase
5. Repeat steps 3 and 4
Activation of glucose for glycogen synthesis
- Both glycogenin and glycogen synthase use an activated form of glucose, UDPglucose, which is
formed from glucose-6-phosphate in two steps. Phosphoglucomutase first transforms glucose-6-
phosphate to glucose-1-phosphate (1), which is then converted to UDP-glucose (2). The latter
reaction requires uridine triphosphate (UTP) and releases pyrophosphate (3).
NB: The UDP-glucose that is used in the Leloir pathway of galactose degradation is derived in the
same manner. UDP-glucose is also the precursor of UDP-glucuronic acid, which is used in the
conjugation of bilirubin and of xenobiotics
Overview of Glycogen synthesis
- Glycogenin is a small bifunctional protein that serves both as the starter substrate and the
polymerase that synthesizes the initial linear strand of glucose residues. It begins the synthesis by
attaching the initial glucose residue to a strategic tyrosine side chain of itself, and then successively
adds several more glucose residues to the sugar’s 4′ end. The linear chain synthesized by
glycogenin may contain up to ~12 glucose residues. This chain length would be long enough to
serve as a substrate for branching enzyme, and it seems likely that the next step is indeed the
introduction of the first branch.
- Alternatively, it is possible that the free end is first extended by glycogen synthase before
branching occurs. In any event, after branching has occurred, glycogen synthase extends both of the
two available 4′ ends. The remainder of the molecule is built through the alternating actions of
branching enzyme and glycogen synthase; the cycle repeats until the glycogen reaches its inherent
size limit at approximately 10MDa
- The reactions performed by glycogenin itself and by glycogen synthase are equivalent. It is
interesting to note that the carbon 1 of each glucose subunit is in the α-configuration both in UDP-
glucose and in glycogen. What does this tell us about the mechanism of the reaction?
Glycogenolysis – Glycogen Breakdown
- Glycogenolysis (also known as "Glycogenlysis") is the breakdown of glycogen to glucose-1-
phosphate and glucose. Glycogen branches are catabolized by the sequential removal of glucose
monomers via phosphorolysis, by the enzyme glycogen phosphorylase.
Function - Glycogenolysis takes place in the cells of the muscle and liver tissues in response to
hormonal and neural signals.
- In myocytes (muscle cells), glycogen degradation serves to provide an immediate source of
glucose-6-phosphate for glycolysis, to provide energy for muscle contraction.
- In hepatocytes (liver cells), the main purpose of the breakdown of glycogen is for the release of
glucose into the bloodstream for uptake by other cells. The phosphate group of glucose-6-phosphate
is removed by the enzyme glucose-6-phosphatase, which is not present in myocytes, and the free
glucose exits the cell via GLUT2 facilitated diffusion channels in the hepatocyte cell membrane.
Overview of glycogen degradation
- Glycogen degradation is brought about by phosphorylase and debranching enzyme. All glucose
residues that are joined by α-(1-4) glycosidic bonds i.e. those in the straight segments, are released
by glycogen phosphorylase. Most enzymes that cleave glycosidic bonds simply hydrolyze them;
examples are intestinal amylase and β-galactosidase. In contrast, glycogen phosphorylase employs
phosphate ions instead of water, and so produces glucose-1-phosphate rather than free glucose. - ---
Glucose-1-phosphate is then converted to the mainstream metabolite glucose-6-phosphate by
phosphoglucomutase. ATP not needed in first step because glucose 1-phosphate already formed.
phosphoglucomutase
glucose 1-phosphate --------------------------> glucose 6-phosphate
- In the liver, which stores glycogen for the benefit of the entire body, the lion’s share of glucose-6-
phosphate will be dephosphorylated by glucose-6-phosphatase and then released into the
circulation; overall, this is equivalent to outright hydrolysis.
glucose 6-phosphatase
glucose 6-phosphate -----------------------------> glucose + Pi
- However, muscle uses glycogen largely toward its own energy needs, and therefore glucose-6-
phosphate will usually be funneled straight into glycolysis. In this case, the use of phosphorolysis
instead of hydrolysis bypasses the hexokinase reaction, thereby saving one equivalent of ATP.
- Glycogen phosphorylase only degrades the chain ends to within four residues of a branching
point. Then, debranching enzyme takes over and transplants the strand to another free end, where it
becomes again a substrate for phosphorylase. However, this reaction leaves behind a single residue
attached by a α-1 6-glycosidic bond. This residue is subsequently released by the same enzyme as
free glucose through hydrolysis.
Degradation:
1. Depolymerization of linear strands by glycogen phosphorylase
2. Removal of branches by debranching enzyme
3. Repeat steps 1 and 2
Regulation of glycogen metabolism
Allosteric regulation of glycogen synthase and phosphorylase
- The allosteric regulatory effects exercised by glucose-6-phosphate, ATP and AMP on glycogen
phosphorylase and glycogen synthase make good physiological sense. Depletion of ATP is an
excellent reason to release glucose from the store in order to make some more. On the other hand,
glucose-6-phosphate will be plentiful when glucose itself is abundant, and therefore signals an
opportunity for replenishing the glycogen stores.
- Glycogen synthase –P is the inactive form (b) and Glycogen phosphorylase-P is the active (a).
- When blood glucose is low, protein kinase A is activated through hormonal action of glucagon.
Glycogen synthase is inactivated and phosphorylase kinase is activated which activates glycogen
phosphorylase and glycogen degradation occurs.
- Phosphorylase kinase also activated by increased [Ca2+] during muscle contraction.
- To reverse the same pathway involves protein phosphatases, which remove phosphate groups
from proteins which dephosphorylates phosphorylase kinase and glycogen phosphorylase (both
inactivated), but dephosphorylation of glycogen synthase activates this enzyme.
- Protein phosphatase-1 activated by insulin then dephosphorylates glycogen synthase and glycogen
synthesis occurs.
- In liver, glycogen phosphorylase A inhibits phosphatase-1 and no glycogen synthesis can occur.
- Glucose binding to protein phosphatase-1 activates protein phosphatase-1, dephosphorylates
glycogen phosphorylase resulting in inactivation and no glycogen degradation occurs.
- Protein phosphatase-1 can also dephosphorylate glycogen synthase and active it.
Hormonal control of glycogen metabolism
- Hormonal control of glycogen metabolism is similar to that of gluconeogenesis; the cascade
shown here is identical all the way from the hormones to the activation of protein kinase A. The
activated kinase directly phosphorylates glycogen synthase, which inactivates that enzyme. Protein
kinase A indirectly stimulates glycogen breakdown by phosphorylation of a dedicated regulatory
enzyme, phosphorylase kinase, which in turn phosphorylates glycogen phosphorylase. Note that
glycogen synthase and phosphorylase respond in opposite ways to phosphorylation: The synthase is
inactivated, whereas the phosphorylase is activated.
1. Insulin is a 51 AA protein made by β-cells of pancreas. Secreted when [glucose] high which
increases rate of glucose transport into muscle and fat via GLUT4 glucose transporters. It stimulates
glycogen synthesis in liver.
2. Glucagon is a 29 aa protein secreted by α-cells of pancreas. Operational under low [glucose].
Restores blood sugar levels by stimulating glycogen degradation.
3. Epinephrine stimulates glycogen mobilization of glucose 1-phosphate to form glucose 6-
phosphate. It Increases rate of glycolysis in muscle and the amount of glucose in bloodstream.
Occurs in response to fight-or-flight response.
- Binds to β-adrenergic receptors in liver and muscle and α1 receptors in liver cells. Binding of
epinephrine or glucagon to β-receptors activates adenylate cyclase, which is a membrane-traversing
enzyme that converts ATP to cAMP, activates protein kinase A.
- Binding of epinephrine to α1 receptors activates IP3 pathway and protein kinase C resulting in
phosphorylation of insulin receptors thus insulin cannot bind.
Regulatory differences between liver and muscle phosphorylase
Liver enzyme Muscle enzyme
Inhibition by glucose + −
Activation by Ca2+ − +
Activation by AMP even when
Unphosphorylated − +
- There are regulatory differences between glycogen phosphorylase in muscle and liver. Glucose
inhibits the liver enzyme but not the muscle enzyme, and Ca2+ stimulates the muscle enzyme but
not the liver enzyme. Recall that Ca2+ is also the trigger for muscle contraction; the simultaneous
stimulation of glycogen breakdown therefore anticipates an increased demand for ATP. As one
would expect from their regulatory differences, the phosphorylases in liver and muscle are different
molecules. Enzymes that catalyze the same reaction yet are separate molecules are referred to as
isozymes. Although we usually don’t mention it, many other enzymes covered in this text occur as
multiple isozymes, too.
Inter organ relationships in glycogen metabolism
- As stated above, the two tissues that have the most significant pools of glycogen are the liver and
skeletal muscle. Liver glycogen is turned over rapidly; it serves as the major reserve of blood
glucose during short-term fasts. Once liver glycogen is depleted, muscle glycogen can be drawn
down; this, however, requires some roundabout metabolic trickery.
Liver glycogen utilization
- The liver mobilizes glucose from its glycogen store via glycogen phosphorylase and
phosphoglucomutase, which yields glucose-6-phosphate. The latter is transported to the
endoplasmic reticulum, where it is dephosphorylated. Glucose is taken back to the cytosol and
released into the bloodstream. Some of the glucose will be rephosphorylated before making it out of
the cell. However, the dominant glucose phosphorylating enzyme in the liver is glucokinase, which
has fairly low affinity for glucose, therefore, enough glucose will escape rephosphorylation and be
released into the bloodstream.
Muscle glycogen utilization
- Muscle glycogen primarily serves the energy needs of muscle tissue itself; during prolonged
physical exercise, most of it is broken down to glucose-6-phosphate and then consumed via the
usual pathways right within the cells that stored it. As discussed above, this usage is facilitated by
calcium-mediated activation of glycogen phosphorylase.
- Under suitable conditions, namely, prolonged fast without physical exercise, muscle glycogen can
also contribute to the replenishment of blood glucose. However, even though muscle cells have
been shown to express glucose-6-phosphatase and thus are, in principle, able to produce free
glucose, they should find it difficult to release it. This is because muscle contains hexokinase,
which has a much greater substrate affinity than glucokinase and therefore will keep the
intracellular level of free glucose well below the extracellular concentration. The net transport of
glucose should therefore be directed inward at all times; this agrees with all the physiological
evidence.
- The way around this obstacle is to convert glucose-6-phosphate to pyruvate and then lactate. At a
low rate, lactate formation occurs even in resting muscle and under aerobic conditions. This lactate
is derived in various proportions from blood glucose and glycogen, respectively. In animal
experiments, epinephrine promotes glycogen utilization and lactate release, but overall the
hormonal control of this process and the magnitude of its contribution to systemic glucose control
are not well characterized.
Glycogen storage diseases
- Genetic defects have been described for several enzymes of glycogen metabolism. The clinical
syndromes associated with these defects are referred to as glycogen storage diseases. While these
conditions are not particularly common, they do shed some light on the physiological significance
of glycogen metabolism. Some conditions are clinically severe and are the focus of ongoing
therapeutic research. A few examples are briefly discussed below.
Glucose-6-phosphatase deficiency (von Gierke disease)
• Glucose formed in gluconeogenesis or released from glycogen cannot be exported from liver and
kidney cells
• Glycogen builds up in liver and kidneys
• Severe hypoglycemia
• Lactic acidosis, • Hyperlipidemia, • Hyperuricemia
- Gluconeogenesis and glycogen degradation in liver and kidneys produce glucose-6-phosphate,
which must then be dephosphorylated to glucose in order to be exported into the bloodstream. An
enzyme defect for glucose-6-phosphatase prevents glucose release, which causes abnormally low
blood glucose levels (hypoglycemia). Some of the surplus glucose accumulates as glycogen,
whereas the remainder is converted to pyruvate in glycolysis and either emerges as lactate or,
downstream of pyruvate dehydrogenase, is turned into triacylglycerol and cholesterol; the excess
lactate and lipids account for the observed lactic acidosis and hyperlipidemia.
- The causation of hyperuricemia—excess blood levels of uric acid is less obvious. During episodes
of hypoglycemia, the liver will be intensely stimulated by glucagon and epinephrine and make a
forceful but futile attempt to mobilize its stored glycogen. The large amount of glucose-6-phosphate
produced in this attempt, which cannot be converted to glucose, ties up and depletes cellular
phosphate. This impedes the regeneration of ATP and raises the level of AMP, some of which then
enters degradation to uric acid.
- The clinical severity of this disease may vary, presumably due to different levels of residual
enzyme activity. Some cases may be managed with a diet of frequent, starch-rich meals, which
helps to avoid hypoglycemia. In more severe cases, liver transplantation may become necessary.
Acid maltase deficiency (Pompe disease)
- A homozygous deficiency of acid maltase disrupts lysosomal glycogen degradation and results in
glycogen accumulation. Skeletal and heart muscle are more strongly affected than the liver. The
tissue section of diseased muscle tissue shows “white holes,” which represent unstained aggregates
of glycogen particles. Glycogen accumulation interferes with muscle cell function and contraction,
and heart failure — leads to death.
- The condition, which is known as Pompe’s disease, can vary in severity; complete lack of enzyme
activity becomes manifest in infants, whereas mutations that reduce but do not completely
inactivate the enzyme will cause milder disease with onset deferred to later childhood or
adolescence. The disease can be treated with enzyme replacement therapy.
Muscle phosphorylase deficiency (McArdle’s disease)
• Deficient glycogen breakdown inhibits rapid ATP replenishment
• Patients experience rapid exhaustion and muscle pain
• Liver phosphorylase and blood glucose homeostasis remain intact
- Since liver and muscle phosphorylase are distinct isozymes, defects usually affect one and spare
the other. In McArdle’s disease, the muscle isoform is selectively affected. An unexplained
symptom in this disease is the so-called “second wind” phenomenon: during physical activity,
patients initially fatigue rapidly, but then recover to a degree under continued exercise. The lack of
muscle phosphorylase should also inhibit the utilization of muscle glycogen toward blood glucose
stabilization by way of the Cori cycle. One might therefore expect that McArdle’s disease might
involve episodes of hypoglycemia.
Lafora disease
• Deficiency for laforin, a glycogen phosphatase
• Accumulation of hyper-phosphorylated glycogen (Lafora bodies)
• Patients develop epilepsy, dementia
- Laforin is a phosphatase that is associated with glycogen particles and removes phosphate groups
from glycogen itself. The functional significance of glycogen phosphorylation and
dephosphorylation is not clear. However, genetic deficiencies of the phosphatase lead to the
accumulation of Lafora bodies, which consist of phosphorylated, poorly branched glycogen
molecules. The disease becomes manifest through a specific form of epilepsy (myoclonic seizures),
dementia and is fatal. The CNS symptoms—like the involvement of the kidneys in v. Gierke
disease, illustrate that tissues other than liver and muscle contain glycogen as well and may be
damaged by its accumulation.
