4.

Metabolism of Glycogen
BIOMEDICAL IMPORTANCE
Glycogen is the major storage carbohydrate in animals,corresponding to
starch in plants; it is a branched polymer of α-D-glucose. It occurs mainly
in liver (up to 6%)and muscle, where it rarely exceeds 1%. However,
because of its greater mass, muscle contains about three to four times as
much glycogen as does liver .Muscle glycogen is a readily available
source of glucose for glycolysis within the muscle itself. Liver glycogen
functions to store and export glucose to maintain blood glucose between
meals. After 12–18 hours of fasting, the liver glycogen is almost totally
depleted.Glycogen storage diseases are a group of inherited disorders
characterized by deficient mobilization of glycogen or deposition of
abnormal forms of glycogen, leading to muscular weakness or even
death.

GLYCOGENESIS OCCURS MAINLY IN MUSCLE & LIVER

The Pathway of Glycogen Biosynthesis Involves a Special Nucleotide

of Glucose
As in glycolysis, glucose is phosphorylated to glucose 6-phosphate,
catalyzed by hexokinase in muscle and glucokinase in liver. Glucose 6-
phosphateis isomerized to glucose 1-phosphate by phosphoglucomutase.
The enzyme itself is phosphorylated, and the phosphogroup takes part in
a reversible reaction in which glucose 1,6-bisphosphate is an
intermediate. Next, glucose 1-phosphate reacts with uridine triphosphate
(UTP) to form the active nucleotide uridine diphosphate glucose
(UDPGlc)* and pyrophosphate, catalyzed by UDPGlc
pyrophosphorylase. Pyrophos-18phatase catalyzes hydrolysis of

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pyrophosphate to 2 mol of inorganic phosphate, shifting the equilibrium
of the main reaction by removing one of its products.Glycogen synthase
catalyzes the formation of a glycoside bond between C1 of the activated
glucose of UDPGlc and C4 of a terminal glucose residue of glycogen,
liberating uridine diphosphate (UDP). A preexisting glycogen molecule,
or “glycogen primer,” must be present to initiate this reaction. The
glycogen primer may in turn be formed on a primer known as
glycogenin,which is a 37-kDa protein that is glycosylated on a specific
tyrosine residue by UDPGlc. Further glucose residues are attached in the
1→4 position to make a short chain that is a substrate for glycogen
synthase.In skeletal muscle, glycogenin remains attached in the center of
the glycogen molecule ,whereas in liver the number of glycogen
molecules is greater than the number of glycogenin molecules.

Branching Involves Detachment of Existing Glycogen Chains

The addition of a glucose residue to a preexisting glycogen chain, or
“primer,” occurs at the nonreducing,outer end of the molecule so that the
“branches” of the glycogen “tree” become elongated as successive 1→4
linkages are formed . When the chain has been lengthened to at least 11
glucose residues, branching enzyme transfers a part of the 1→4 chain (at
least six glucose residues) to a neighboring chain to form a 1→6 linkage,
establishing a branch point. The branches grow by further additions of
1→4-glucosyl units and further branching.

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 - GLYCOGENOLYSIS IS NOT THE REVERSE OF
GLYCOGENESIS BUT IS A SEPARATE PATHWAY .
Glycogen phosphorylase catalyzes the rate-limiting step in
glycogenolysis by promoting the phosphorylytic cleavage by inorganic
phosphate (phosphorylysis; cf hych18drolysis) of the 1→4 linkages of
glycogen to yield glucose 1-phosphate. The terminal glucosyl residues
from the outermost chains of the glycogen molecule are removed
sequentially until approximately four glucose residues remain on either
side of a 1→6 branch . Another enzyme (_-[1v4]v_-[1v4] glucan
transferase) transfers a trisaccharide unit from one branch to the other,
exposing the 1→6 branch point.Hydrolysis of the 1→6 linkages requires
the debranching enzyme. Further phosphorylase action can then
proceed. The combined action of phosphorylase and these other enzymes
leads to the complete breakdown of glycogen. The reaction catalyzed by
phosphoglucomutase is reversible, so that glucose 6-phosphate can be
formed from glucose 1-phosphate. In liver (and kidney), but not in
muscle, there is a specific enzyme,glucose-6-phosphatase, that
hydrolyzes glucose 6-phosphate, yielding glucose that is exported,
leading to an increase in the blood glucose concentration.

CYCLIC AMP INTEGRATES THE REGULATION OF

GLYCOGENOLYSIS & GLYCOGENESIS

The principal enzymes controlling glycogen metabolism—glycogen

phosphorylase and glycogen synthase—are regulated by allosteric
mechanisms and covalent modifications due to reversible
phosphorylation and dephosphorylation of enzyme protein in response to
hormone action .Cyclic AMP (cAMP) (Figure 18–5) is formed from

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ATP by adenylyl cyclase at the inner surface of cell membranes and acts
as an intracellular second messenger in response to hormones such as
epinephrine, norepinephrine,and glucagon. cAMP is hydrolyzed by
phosphodiesterase, so terminating hormone action. In liver, insulin
increases the activity of phosphodiesterase.

Phosphorylase Differs Between Liver & Muscle.

In liver, one of the serine hydroxyl groups of active phosphorylase a

is phosphorylated. It is inactivated by hydrolytic removal of the
phosphate by protein phosphatase-1 to form phosphorylase b.
Reactivation requires rephosphorylation catalyzed by phosphorylase
kinase.Muscle phosphorylase is distinct from that of liver. It is a dimer,
each monomer containing 1 mol of pyridoxal phosphate (vitamin B6). It
is present in two forms: phosphorylase a, which is phosphorylated and
active in either the presence or absence of 5′-AMP (its allosteric
modifier);and phosphorylase b, which is dephosphorylated and active
only in the presence of 5′-AMP. This occurs during exercise when the
level of 5′-AMP rises, providing,by this mechanism, fuel for the muscle.
Phosphorylase a is the normal physiologically active form of the enzyme.

cAMP Activates Muscle Phosphorylase

Phosphorylase in muscle is activated in response to epinephrine

acting via cAMP. Increasing the concentration of cAMP activates cAMP-
dependent protein kinase, which catalyzes the phosphorylation by ATP
of inactive phosphorylase kinase b to active phosphorylase kinase a,
which in turn, by means of a further phosphorylation, activates
phosphorylase b to phosphorylase a.

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Ca2+ Synchronizes the Activation of Phosphorylase With Muscle
Contraction.

Glycogenolysis increases in muscle several hundred-fold

immediately after the onset of contraction. This involves the rapid
activation of phosphorylase by activation of phosphorylase kinase by
Ca2+, the same signal as that which initiates contraction in response to
nerve stimulation. Muscle phosphorylase kinase has four types of
subunits—α, β, γ, and δ—in a structure represented as (αβγδ)4. The α and
β subunits contain serine residues that are phosphorylated by cAMP-
dependent protein kinase. The δ subunit binds four Ca2+ and is identical
to the Ca2+-binding protein calmodulin . The binding of Ca2+ activates
the catalytic site of the γ subunit while the molecule remains in the
dephosphorylated b configuration. However, the phosphorylated a form
is only fully activated in the presence of Ca2+. A second molecule of
calmodulin, or TpC (the structurally similar Ca2+-binding protein in
muscle), can interact with phosphorylase kinase, causing further
activation. Thus, activation of muscle contraction and glycogenolysis are
carried out by the same Ca2+-binding protein, ensuring their
synchronization.

Glycogenolysis in Liver Can Be cAMP-Independent

In addition to the action of glucagon in causing formation of cAMP

and activation of phosphorylase in liver,_1-adrenergic receptors mediate
stimulation of glycogenolysis by epinephrine and norepinephrine. This
involves a cAMP-independent mobilization of Ca2+ from mitochondria
into the cytosol, followed by the stimulation of a Ca2+/calmodulin-
sensitive phosphorylase kinase. cAMP-independent glycogenolysis is

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also caused by vasopressin, oxytocin, and angiotensin II acting through
calcium or the phosphatidylinositol bisphosphate pathway .

Protein Phosphatase-1 Inactivates Phosphorylase

Both phosphorylase a and phosphorylase kinase a are

dephosphorylated and inactivated by protein phosphatase-1. Protein
phosphatase-1 is inhibited by a protein, inhibitor-1, which is active only
after it has been phosphorylated by cAMP-dependent protein kinase.
Thus, cAMP controls both the activation and inactivation of
phosphorylase . Insulin reinforces this effect by inhibiting the activation
of phosphorylase b. It does this indirectly by increasing uptake of
glucose, leading to increased formation of glucose 6-phosphate, which is
an inhibitor of phosphorylase kinase.

- Glycogen Synthase & Phosphorylase Activity Are Reciprocally

Regulated.

Like phosphorylase, glycogen synthase exists in either a

phosphorylated or nonphosphorylated state. However,unlike
phosphorylase, the active form is dephosphorylated (glycogen synthase
a) and may be inactivated to glycogen synthase b by phosphorylation on
serine residues by no fewer than six different protein kinases.Two of the
protein kinases are Ca2+/calmodulindependent (one of these is
phosphorylase kinase). Another kinase is cAMP-dependent protein
kinase, which allows cAMP-mediated hormonal action to inhibit
glycogen synthesis synchronously with the activation of glycogenolysis.
Insulin also promotes glycogenesis in muscle at the same time as
inhibiting glycogenolysis by raising glucose 6-phosphate concentrations,

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which stimulates the dephosphorylation and activation of glycogen
synthase. Dephosphorylation of glycogen synthase b is carried out by
protein phosphatase-1, which is under the control of cAMP-dependent
protein kinase.
- REGULATION OF GLYCOGEN METABOLISM IS
EFFECTED BY A BALANCE IN ACTIVITIES BETWEEN
GLYCOGEN SYNTHASE & PHOSPHORYLASE.

Not only is phosphorylase activated by a rise in concentration of

cAMP (via phosphorylase kinase), but glycogen synthase is at the same
time converted to the inactive form; both effects are mediated via
cAMPdependent protein kinase. Thus, inhibition of glycogenolysis
enhances net glycogenesis, and inhibition of glycogenesis enhances net
glycogenolysis. Furthermore, the dephosphorylation of phosphorylase a,
phosphorylase kinase a, and glycogen synthase b is catalyzed bya single
enzyme of wide specificity—protein phosphatase-1. In turn, protein
phosphatase-1 is inhibited by cAMP-dependent protein kinase via
inhibitor-1.Thus, glycogenolysis can be terminated and glycogenesis can
be stimulated synchronously, or vice versa, because both processes are
keyed to the activity of cAMP-dependent protein kinase. Both
phosphorylase kinase and glycogen synthase may be reversibly
phosphorylated in more than one site by separate kinases and
phosphatases.These secondary phosphorylations modify the sensitivity of
the primary sites to phosphorylation and dephosphorylation (multisite
phosphorylation). What is more, they allow insulin, via glucose 6-
phosphate elevation,to have effects that act reciprocally to those of cAMP
.

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CLINICAL ASPECTS
Glycogen Storage Diseases Are Inherited
“Glycogen storage disease” is a generic term to describe a group of
inherited disorders characterized by deposition of an abnormal type or
quantity of glycogen in the tissues. The principal glycogenoses are
summarized in Table 1. Deficiencies of adenylyl kinase and cAMP-
dependent protein kinase have also been rech18 ported. Some of the
conditions described have benefited from liver transplantation.

SUMMARY
• Glycogen represents the principal storage form of carbohydrate in the
mammalian body, mainly in the liver and muscle.
• In the liver, its major function is to provide glucose for extrahepatic
tissues. In muscle, it serves mainly as a ready source of metabolic fuel for
use in muscle.
• Glycogen is synthesized from glucose by the pathway of glycogenesis.
It is broken down by a separate pathway known as glycogenolysis.
Glycogenolysis leads to glucose formation in liver and lactate formation
in muscle owing to the respective presence or absence of glucose-6-
phosphatase.
• Cyclic AMP integrates the regulation of glycogenolysis and
glycogenesis by promoting the simultaneous activation of phosphorylase
and inhibition of glycogen synthase. Insulin acts reciprocally by
inhibiting glycogenolysis and stimulating glycogenesis.
• Inherited deficiencies in specific enzymes of glycogen metabolism in
both liver and muscle are the causes of glycogen storage diseases.

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