Chapter 11

Metabolism of glycogen

Glycogen is the analogue of starch, a less branched glucose polymer in plants, and is
commonly referred to as animalstarch, having a similar structure to amylopectin.
Glycogen is found in the form of granules in the cytosol in many cell types, and plays
an important role in the glucose cycle. Glycogen forms an energy reserve that can be
quickly mobilized to meet a sudden need for glucose, but one that is less compact
than the energy reserves of triglycerides (lipids). ln the liver hepatocy{es glycogen
can compose up to 8% of the fresh weight (100-120 g in an adult) soon after a meal.
After a meal has been digested and glucose levels begin to fall, insulin
secretion is reduced, and glycogen synthesis stops. When it is needed for energy,
glycogen is broken down and converted again to glucose. Glycogen phosphorylase
is the primary enzyme of glycogen breakdown. For the next 8-12 houts, glucose
derived from liver glycogen will be the primary source of blood glucose to be used by
the rest of the body for fuel.

Glycogen is the storage form of glucose in animals and humans wttich is analogous to the firch
in plants. Glycogen is synthesized and stored mainly in the liver and the muscles. Structurally,
glycogen is very similar to amylopectin with o- acetal linkages, horvever, it has even more
branching and more glucose units are present than in amylopectin. Various samples of glycogen
have been measured at 1,700-600,000 units of glucose.
The structure of glycogen consists of long polymer chains of glucose units connected
by an o-acetal linkage. The graphic on the bottom shows a very small portion of a glycogen chain.
All of the monomer units are o- -D-glucose, and all the a- acetal links connect Cl of one glucose
to Ca of the next glucose.
The branches are formed by linking Cr to a C6 through an acetal linkages. ln glycogen, the
branches occur at interuals of 8-10 glucose units, while in amylopectin the branches are separated
by 12.20 glucose units.

Glycogen structure

Glycogen structure

The g-cetal links connect

Ci of one glucose to Ca of

the next glucose.

The branches are formed
by linking Ci to a C5
through an o- acetal
linkages

Glycogenesis
Glycogen is synthesized in cytosol from o-D{lucose. ln first step glucose is
phosphorytated to glucose-1-phosphate. The energy for this step comes from ATP.
Glycogen synthesis is, unlike its breakdown, endergonic. This means that glycogen
synthesis requires the input of energy. Energy for glycogen synthesis comes from UTP, which
reacts with glucose.l.phosphate (see next slide), forming UDP-glucose, in readion catalyzed
by ttDP-gtucose pyrophosphorylase. Glycogen is synthesized from monomers of UDP-glucose
by the enzyme glycogen synthase, which progressively lengthens the glycogen chain with (q'
1-+4) bonded glucose. As glycogen synthase can lengthen only an existing chain, the protein
glycogenin is needed to initiate the synthesis of glycogen.'

ArP
\-

hexokinase

glucose

glucose-5-phosphate

glucose-1-phosphate

Synthesis of UDP-glucose

9Hz-oH

ADP

ATP

\-

b)

hexokinase

glucose

glucose-6-phosphate

glucose-1 -phosphate

E|rtr.it

+9c

b@[Rl-uracil
\

UTP

pyrwhoryhorylasa

ribose

Starter Synthesis
The enryme glycogen synthase produces o -1,4-glycosidic bonds, but it can not start
creating a chain of glycogen from the free glucose (Glc) by joining the rest of Glc to UDP-glucose.
It can only prolong the existing chain. By the beginning of new molecule of glycogen synthesis,
the part of glycogen chain is needed. ln the case of its absence the short glycogen chain is
synthesized in the presence of protein glikogenin, which serves as the acceptor Glc residues. This
reaction is catalyzed by glycogen synfhase stafter. The residue of Glc is combined with -OH
group of tyrosine, which is built into the struc'ture of this protein. ln this reaction only -OH group
at Cl of Glc takes part, while the C6-OH of Glc is free. Glikogenin can join a few of Glc residues
forming a -1,4-glycosidic bonds. Created a short oligosaccharide chain is combined from several
Glc residues and it becomes the next acceptor Glc residues. This way a synthesis of molecule of
glycogen is started.

Elongation

-/

of

glycogen chain

Energy for glycogen synthesis comes from UTP, which reacts with glucose-lphosphate, forming UDP-glucose,
reaction catalyzed by enzyme UDP-glucose
pyrophosphorylase. Glycogen is synthesized from monomerc of UDP-glucose by the enryme
glycogen synthase, which progressively lengthens the glycogen chain with (o-1+4) bonded

in

glucose.

[s"\
,F
f"
+,ffi"qq,

CHz-OH

l_o
/'\

,V-@[El-uracir

OH
UDP-glu koza

starter: n Glc

g
e

cHzoH

,r"Y"Q"QQ,
w
i5T

,/3".,

ff"

elongation product: (n +1) Glc

Branching chain glycogen

The product of the chain elongation is a line molecule of glycogen, in which glucose
residues are linked by o-1,t[-bonds. Such glycogen occuls only in plants (amylose) and has only
one non-reducing end. Breakdown of linear glukogen to glucose would be a very slow process. lt
can occur faster in the case of branched molecules, where there are several hundred glucosidic
ends. So nature took care of a creating a branched glycogen.
Underthe action of enryme 1,*l,fifiansglucosidase, a 5-8 glucose residue is splitted
from the non-reducing end of line molecule. This fragment is attached to the linear chain by
forming cr-1,6 -bond with -OH at C6 of Glc built into line molecule. This waythe second nonreductive end of molecule areases, which can be further elongated by glycogen synfhase. This
cycle repeated several times leads to multiplication of non-reducing ends. As result a glycogen
molecule is formed similar to the "bush" . A multitude of non-reducing end facilitates the
distribution of glycogen.
o,-114

l,

linear chain

* 1 6 tranrylucosl'dase
branched chain
10

Breakdown of glycogen
Breakdown of glycogen in liver and muscle requires other enrymes than its biosynthesis. ln this
process dominates phosphorolysis of c.l,4 bonds. Decay a-1,6 bonds occurs in the chain branching points.
Product of phosphorolysis is glucose.l.phosphate, and hydrolysis - glucose molecule.

GLYCOGEN

of a-7,4 bonds

of a-1,6 bonds

glucose

glucose-l -phosphate

11

Removal glycogen's branches

The special debranching enzyme
operates on a 4-Glc branch of glycogen and
removes 3Glc unit and adds it to the llort-

%Ss

debranching

enzwe

../

reducing end of another chain extending it by

this 3Glc unit. Since a molecule of this
enzyme has two activities: glucosr'dasfc and
transferasic, that makes that the one a -1 4
bond is created, and the second o -1.4 bond
is broken- The last rest of Glc of branch is
removed by enzym e *7,6-glucosidase.
Linear fragment of the molecule is
breakdowns by enryme glycogen
phosphorylase. Summary effect action of
above enzymes is the breakdown of glycogen
to glucose-l-phosphate and a small amount
of free glucose.

l,6
I pr,o+r, oryte
I

glucose-l-phoshate

*N S

**S **S

l2

The conversion of glucose-1-phosphate

is

to

glucose-G-phosphate under the action of

phosphoglucomutase. This product in the liver is transformed to free glucose by the enzyme
glucosed-ptrosphafase. Free glucose enters the blood and is directed to other tissues.
Skeletal muscle cells have not glucose6-pfiospfiafase, and therefore glucose-G-phosphate
must be used in these cells (manly in glicolysis) because the cell membrane is impenetrable
to phosphate esters of sugars.

Glucose.l.phosphate

converted

9Hz-o-C

glucose-1 -phosphate

glucose-6-phosphate

glucose

13

Glycogen storage disease

Glycogen storage disease (GSD, also glycogenosis and dextrinosis) is the result of defects in
the processing of glycogen synthesis or breakdown within muscles, liver, and other cell
types. GSD has two classes of cause: genetic and acquired. Genetic GSD is caused by
any inborn error of metabolism (genetically defective enrymes) involved in these
processes.

1.

2.

von Gierke's disease is the most common of the glycogen storage diseases. This genetic
disease results from deficiency of the enryme glucoseO-phosphatase. This deficiency
impairc the ability of the liver to produce free glucose from glycogen and from
gluconeogenesis. Since these are the two principal metabolic mechanisms by which the
liver supplies glucose to the rest of the body during periods of fasting, it causes severe
hypoglycemia. Reduced glycogen breakdown results in increased glycogen storage in
liver and kidneys, causing enlargement of both.
Glycogen storage disease type ll (also called Pompe disease or acid maltase deficiency)
is disorderwhich damages muscle and nerve cells throughout the body. lt is caused by
an accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid
atpha-glucosidase enryme. lt is the only glycogen storage disease with a defect in
lysosomal metabolism. The build-up of glycogen causes progressive muscle weakness
(myopathy) throughout the body and affects various body tissues, particularly in the
heart, skeletal muscles, liver and nelvous system.l4
L4

Glycogen storage disease (cont.)

3.

4.

Glycogen storage disease type lll is an autosomal recessive metabolic disorder and inborn
error of metabolism characterized by a deficiency in glycogen debranching enzymes. lt is
also known as Cori's disease in honor of the 1947 Nobel laureates Carl Cori and Gerty Cori.
Other names include Forbes disease in honor of clinician Gilbert Burnett Forbes who further
described the features of the disorder, or limit dextrinosis.Glycogen is a molecule the body
uses to store carbohydrate energy. Symptoms of GSD-lll are caused by a deficiency of the
enzyme amylo-1,6 glucosrUase, or debrancher enzyme. This causes excess amounts of an
abnormal glycogen to be deposited in the liver, muscles and, in some cases, the heart.
Glycogenosis type lV. The eponym "Andersen's disease" is sometimes used, for Dorothy
Hansine Andersen. lt is a result of the absence of the glycogen branching enzyme amylo-|,*
1,6 transglucosidase, which is critical in the production of glycogen. This leads to very Iong
unbranched glucose chains being stored in glycogen. The long unbranched molecules
(known as amylose) have a low solubility which leads to glycogen precipitation in the liver.
These deposits subsequently build up in the body tissue, especially the heart and liver The
probable end result is cirrhosis and death within 5 years. ln adult polyglucosan body disease
the ac'tivity of the enzyme is higher and symptoms do not appear until later in life.

15

Glycogen storage disease (cont.)

5.

Glycogen storage disease type V (GSD-V) is a metabolic disorder, more specifically a

glycogen storage disease, caused by a deficiency of myophosphorylax. GSD type V is
also known as McArdle's disease or muscle phosphorylase (myophosphorylase)
deficiency. The onset of this disease is usually noticed in childhood but often not
diagnosed until the third or fourth decade of life. Symptoms include exercise intolerance
with myalgia, early fatigue, painful cramps, weakness of exercising muscles and
myoglobinuria. Myoglobinuria, the condition where myoglobin is present in urine, may
result from serious damage to the muscles, or rhabdomyolysis, where muscle cells
breakdown, sending their contenb into the bloodstream. Patients may exhibit a "seccr;<l
wind" phenomenon. This is characterized by the patient's befter tolerance for aerobic
exercise such as walking and cycling after approximabely 10 minutes. This is attributed to
the combination of increased blood flow and the ability of the body to find alternative
sources of energy, Iike fatty acids and proteins. ln the long term, patients may exhibit renal
failure due to the myoglobinuria, and with age, patients may exhibit progressively
increasing weakness and substantial muscle loss .

t6

Glycogen storage disease (cont.)

6.

Glycogen storage disease type Vl (GSD Vl) is a type of glycogen storage disease caused
by a deficiency in liver glycogen phosphorytase or other components of the associated
p-hosphorytase cascade system.lt is also known as "Hers' disease", after Henri G. Hers.
Fatients generally have a benign cour:se, and typically present with hepatomegaly and
growth ietardation early in childhood. Mild hypoglycemia, hyperlipidemia, and
hyperketosis may occur. Lactic acid and uric acid levels are normal.
ihosphofructoffinase deficiency, also known as Glycogen storage disease type Vll or
Taruiis disease, is metabolic disorder with autosomal recessive inheritance. The mutation
impairs the ability of pfrosphofructokinase to phosphorylate fructose.6'phosphate prior to
its cleavage into glyceraldehyde which enters the Krebs cycle, effectively limiting energy
production. Unlike most other glycogen storage diseases, it directly affects glycolysis. The
disease presents with exercise-induced muscle cramps and weakness (sometimes
rhabdomyolysis), myoglobinuria, as well as with haemoly{ic anaemia causing dark urine a
few hours later. Hyperuricemia is common.

t7