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.

2

Glycogen is the storage form of glucose in animals and humans wttich is analogous to the firchin 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 morebranching 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 connectedby 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, thebranches occur at interuals of 8-10 glucose units, while in amylopectin the branches are separatedby 12.20 glucose units.

Glycogen structure

Glycogen structure

The g-cetal links connect

Ci of one glucose to Ca ofthe 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 I\-

glucose glucose-5-phosphate

hexokinase

glucose-1-phosphate

ADP

ATP I\-hexokinase

Synthesis of UDP-glucose

+9c

b€)

glucose-1 -phosphate

+

E|rtr.itUTP

b@[Rl-uracil

\ ribose

Starter Synthesis

The enryme glycogen synthase produces o -1,4-glycosidic bonds, but it can not startcreating 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 issynthesized in the presence of protein glikogenin, which serves as the acceptor Glc residues. Thisreaction is catalyzed by glycogen synfhase stafter. The residue of Glc is combined with -OHgroup of tyrosine, which is built into the struc'ture of this protein. ln this reaction only -OH groupat Cl of Glc takes part, while the C6-OH of Glc is free. Glikogenin can join a few of Glc residuesforming a -1,4-glycosidic bonds. Created a short oligosaccharide chain is combined from severalGlc residues and it becomes the next acceptor Glc residues. This way a synthesis of molecule ofglycogen is started.

9Hz-oH

glucose glucose-6-phosphate

pyrwhoryhorylasa

-/ Elongation of glycogen chain

Energy for glycogen synthesis comes from UTP, which reacts with glucose-l-phosphate, forming UDP-glucose, in reaction catalyzed by enzyme UDP-glucosepyrophosphorylase. Glycogen is synthesized from monomerc of UDP-glucose by the enrymeglycogen synthase, which progressively lengthens the glycogen chain with (o-1+4) bondedglucose.

CHz-OHl_o

/'\,V-@[El-uracir

UDP-glu koza

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

starter: n Glc

gIvcogen

i5T cHzoH

,/3"., , ff",r"Y"Q"QQ,welongation product: (n +1) Glc

Branching chain glycogen

The product of the chain elongation is a line molecule of glycogen, in which glucoseresidues are linked by o-1,t[-bonds. Such glycogen occuls only in plants (amylose) and has onlyone non-reducing end. Breakdown of linear glukogen to glucose would be a very slow process. ltcan 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 splittedfrom the non-reducing end of line molecule. This fragment is attached to the linear chain byforming cr-1,6 -bond with -OH at C6 of Glc built into line molecule. This waythe second non-reductive end of molecule areases, which can be further elongated by glycogen synfhase. Thiscycle 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 thedistribution of glycogen.

o,-114

linear chainl, * 1 6 tranrylucosl'dase

branched chain

10

Breakdown of glycogen

Breakdown of glycogen in liver and muscle requires other enrymes than its biosynthesis. ln thisprocess 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.

of a-7,4 bonds of a-1,6 bonds

glucose-l -phosphate

Removal glycogen's branches

11

%Ss

glucose-l-phoshate *N

debranchingenzwe

The special debranching enzyme

operates on a 4-Glc branch of glycogen and

removes 3Glc unit and adds it to the llort-

reducing end of another chain extending it bythis 3Glc unit. Since a molecule of thisenzyme 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 glycogenphosphorylase. Summary effect action ofabove 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

S **S **S *

GLYCOGEN

glucose

l2

The conversion of glucose-1-phosphate

Glucose.l.phosphate is converted to glucose-G-phosphate under the action ofphosphoglucomutase. 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-1 -phosphateglucose-6-phosphate

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. 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 fromgluconeogenesis. 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.

2. 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

13

9Hz-o-C

glucose

L4

3.

Glycogen storage disease (cont.)

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 isalso 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 furtherdescribed the features of the disorder, or limit dextrinosis.Glycogen is a molecule the bodyuses to store carbohydrate energy. Symptoms of GSD-lll are caused by a deficiency of theenzyme 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 DorothyHansine 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 Theprobable 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.

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 isalso known as McArdle's disease or muscle phosphorylase (myophosphorylase)

deficiency. The onset of this disease is usually noticed in childhood but often notdiagnosed 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 cellsbreakdown, sending their contenb into the bloodstream. Patients may exhibit a "seccr;<l

wind" phenomenon. This is characterized by the patient's befter tolerance for aerobicexercise such as walking and cycling after approximabely 10 minutes. This is attributed tothe combination of increased blood flow and the ability of the body to find alternativesources 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 .

4.

15

t6

f Glycogen storage disease (cont.)

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.

6.

t7