Assoc. Prof. Dr.

Atif Amin Baig ,

Faculty of Medical Sciences,
University Sultan Zainal Abidin.
atifamin@unisza.edu.my

Glycogen Metabolism
LEARNING OUTCOMES:

1. WHAT IS GLYCOGEN?
2. WHAT IS A NEED OF GLYCOGEN?
3. STRUCTURE OF GLYCOGEN?
4. WHAT IS UDP-GLUCOSE?
5. WHAT IS GLYCOGENIN?
6. STEPS IN GLYCOGEN SYNTHESIS AND GLUCOSE RELEASE?
7. GLYCOGEN REGULATION CYCLE AND ITS TYPES?
8. GLYCOGEN BALANCE AND ROLE OF LIVER AND MUSCLE GLYCOGEN?
9. FIGHT AND FLIGHT THEORY
10. GLYCOGEN STORAGE DISEASES.

Level C1 to C2
 AS AN ENERGY MOLECULE:
GLYCOGEN IS A GLUCOSE RESERVE
IN MAMMALS

What is Glycogen?
IMPORTANT TO MAINTAIN BLOOD
GLUCOSE LEVEL

What is the importance of Glycogen?

 AS A BIOMOLECULE:
GLYCOGEN IS A POLYMER OF GLUCOSE,
FROM WHICH; GLUCOSE PHOSPHATES
AND GLUCOSE CAN BE RELEASED WHEN
NEEDED.

What is Glycogen?
GLUCOSE STORAGE ITSELF WOULD NOT BE USEFUL,
AS HIGH CONCENTRATIONS WITHIN CELLS WOULD
MAKE THEM STRONGLY HYPERTONIC AND WOULD
THEREFORE CAUSE AN INFLUX OF WATER. BY
CONTRAST, INSOLUBLE GLYCOGEN HAS ONLY LOW
OSMOTIC ACTIVITY.

What is the need of storing glucose as glycogen?

THE GLUCOSE RESIDUES ARE LINKED BY AN ΑLPHA 1-4-GLYCO- SIDIC BOND.
EVERY TENTH OR SO GLUCOSE RESIDUE HAS AN ADDITIONAL ΑLPHA 1-6
BOND TO ANOTHER GLUCOSE. THESE BRANCHES ARE EXTENDED BY
ADDITIONAL ΑLPHA 1-4-LINKED GLUCOSE RESIDUES. THIS STRUCTURE
PRODUCES TREE-SHAPED MOLECULES CONSISTING OF UP TO 50000
RESIDUES (M > 1 107 DA).

Structure of Glycogen
 CH2OH CH2OH
H O O
glycogen
H H H
H H
OH H OH H 1
O
OH
O
H OH H OH

CH 2OH CH 2OH 6 CH2 CH2OH CH 2OH

H O H H O H H 5 O H H O H H O H
H H H H H
OH H OH H OH H 1 4 OH H OH H
4 O O
O O OH
OH
3 2
H OH H OH H OH H OH H OH

• Glycogen is a polymer of glucose residues linked by

• a(14) glycosidic bonds, mainly
• a(16) glycosidic bonds, at branch points.
Uracil-diphosphate glucose
involved in
glycosyltransferase reactions
in metabolism.
What is UDP-Glucose?
Uridine diphosphate glucose (UDP-glucose) is the
immediate precursor for glycogen synthesis.
As glucose residues are added to glycogen, UDP-
glucose is the substrate and UDP is released as a
reaction product.
Nucleotide diphosphate sugars are precursors also
for synthesis of other complex carbohydrates,
including oligosaccharide chains of glycoproteins,
etc.
 O
UDP-Glucose Pyrophosphorylase
CH2OH HN

H O H
H O N
OH H O O O O

OH O P O + 
O P O P O P O CH2 UDP-Glucose
O
O O O O
Pyrophosphoryase
H OH H H

glucose-1-phosphate UTP H
OH OH
H
They catalyze the transfer of
PPi O saccharide moieties from an
activated nucleotide sugar (also
CH2OH HN known as the "glycosyl donor")
H O H to a nucleophilic glycosyl
H O N
OH H O O acceptor molecule
OH O P O P O CH2
O
H OH O O H H
H H
UDP-glucose OH OH
HEPATIC GLYCOGEN IS NEVER COMPLETELY DEGRADED.

IN GENERAL, ONLY THE NONREDUCING ENDS OF THE “TREE” ARE

SHORTENED

OR—WHEN GLUCOSE IS ABUNDANT—ELONGATED.

THE REDUCING END OF THE TREE IS LINKED TO A SPECIAL PROTEIN,

GLYCOGENIN (37 KD ENZYME)

What is Glycogenin?
Glycogenin carries out autocatalytic covalent
bonding of the first glucose at one of its
tyrosine residues and elongation of this by up
to seven additional glucose residues.

It is only at this point that glycogen synthase

becomes active to supply further elongation.
 6 CH
2OH tyrosine residue
UDP-glucose
H
5 O H of Glycogenin
H O O C O
4 OH H 1
OH O P O P O Uridine HO C CH
3 2 H2
H OH O O NH

6 CH
2OH
O-linked 5 O
glucose H H
H
C O
residue 4 OH H 1
OH O C CH + UDP
3 2 H2
H OH NH

CH2OH CH2OH
• A glycosidic bond
O is formed between the anomeric
O H
C1 of the glucose moiety derived from UDP-
H H H
glucose
H and the hydroxyl oxygen ofHa tyrosine side-chain of Glycogenin. C O
• releasedHas a product.
UDP isOH OH H
OH O O C CH
H2
H OH H OH NH
 H H
H O O C O
4 OH H 1
OH O P O P O Uridine HO C CH
3 2 H2
H OH O O NH

6 CH
2OH
O-linked 5 O
glucose H H
H
C O
residue 4 OH H 1
OH O C CH + UDP
3 2 H2
H OH NH
UDP-glucose
CH2OH CH2OH

H O H H O H
H H C O
OH H OH H
OH O O C CH + UDP
H2
H OH a(14) H OH NH
linkage

• Glycogenin then catalyzes glucosylation at C4 of the attached glucose (UDP-glucose again

the donor), to yield an O-linked disaccharide with a(14) glycosidic linkage.
• This is repeated until a short linear glucose polymer with a(14) glycosidic linkages is
built up on Glycogenin.
 glycogen(n residues) + Pi 
glycogen (n–1 residues) +
glucose-1-phosphate ?
THE FORMATION OF GLYCOSIDIC
BONDS BETWEEN SUGARS IS
ENDERGONIC. INITIALLY,
THEREFORE, THE ACTIVATED
FORM—UDP-GLUCOSE—IS
SYNTHESIZED BY REACTION OF
GLUCOSE 1-PHOSPHATE WITH UTP

Making the glucose ready?

GLYCOGEN SYNTHASE NOW
TRANSFERS GLUCOSE RESIDUES
ONE BY ONE FROM UDP-GLUCOSE
TO THE NON-REDUCING ENDS OF
THE AVAILABLE “BRANCHES.”

Start of branch?
ONCE THE GROWING CHAIN HAS
REACHED A SPECIFIC LENGTH (> 11
RESIDUES), THE BRANCHING ENZYME
CLEAVES AN OLIGOSACCHARIDE
CONSISTING OF 6–7 RESIDUES FROM THE
END OF IT, AND ADDS THIS INTO THE
INTERIOR OF THE SAME CHAIN OR A
NEIGHBORING ONE WITH ΑLPHA 1-6
LINKAGE. THESE BRANCHES ARE THEN
FURTHER EXTENDED BY GLYCOGEN
SYNTHASE.

Branching of Chain?
• THE BRANCHED STRUCTURE OF GLYCOGEN
ALLOWS RAPID RELEASE OF SUGAR RESIDUES.

THE MOST IMPORTANT DEGRADATIVE ENZYME,

GLYCOGEN PHOSPHORYLASE, CLEAVES
RESIDUES FROM A NON- REDUCING END ONE
AFTER ANOTHER AS GLUCOSE 1-PHOSPHATE.

THE LARGER THE NUMBER OF THESE ENDS, THE

MORE PHOSPHORYLASE MOLECULES CAN
ATTACK SIMULTANEOUSLY.

THE FORMATION OF GLUCOSE 1-PHOSPHATE

INSTEAD OF GLUCOSE HAS THE ADVANTAGE
THAT NO ATP IS NEEDED TO CHANNEL THE
RELEASED RESIDUES INTO GLYCOLYSIS OR THE
PPP.

Degradation of chains
DUE TO THE STRUCTURE OF GLYCOGEN
PHOSPHORYLASE, DEGRADATION COMES TO
A HALT FOUR RESIDUES AWAY FROM EACH
BRANCHING POINT.

TWO MORE ENZYMES OVERCOME THIS

BLOCKAGE.

FIRST, A GLUCANOTRANSFERASE MOVES A

TRISACCHARIDE FROM THE SIDE CHAIN TO
THE END OF THE MAIN CHAIN [5].

A 1,6-GLUCOSIDASE [6] THEN CLEAVES THE

SINGLE REMAINING RESIDUE AS A FREE
GLUCOSE AND LEAVES BEHIND AN
UNBRANCHED CHAIN THAT IS ONCE AGAIN
ACCESSIBLE TO PHOSPHORYLASE.
Glucose relsease?
WHY ARE TWO ADDITIONAL ENZYMES NEEDED FOR GLYCOGEN
BREAKDOWN?
DEBRANCHING

WHAT DOES GLYCOGEN TRANSFERASE DO?

SHIFTS BLOCK OF 3 GLYCOSYL RESIDUES FROM OUTER BRANCH

WHAT DOES a-1,6-GLUCOSIDASE DO?

HYDROLZES 1,6 LINKAGE

Some Questions?
BY TWO MECHANISMS

1. REGULATION BY INTERCONVERSIONS

2. TRANSCRIPTIONAL CONTROL

Regulation of glycogen synthesis

 “ANIMALS REACT TO THREATS WITH A GENERAL DISCHARGE OF
THE SYMPATHETIC NERVOUS SYSTEM, PRIMING THE ANIMAL FOR
FIGHTING OR FLEEING”

MORE SPECIFICALLY, THE ADRENAL MEDULLAPRODUCES A HORMONAL

CASCADE THAT RESULTS IN THE SECRETION OF CATECHOLAMINES,
ESPECIALLY NOR EPINEPHRINEAND EPINEPHRINE

THE HORMONES ESTROGEN, TESTOSTERONE AND CORTISOL, AND THE

NEUROTRANSMITTERS DOPAMINE AND SEROTONIN, ALSO AFFECT HOW
ORGANISMS REACT TO STRESS
Fight or flight response
THE HUMAN ORGANISM CAN STORE UP TO 450 G OF GLYCOGEN—
ONE-THIRD IN THE LIVER AND ALMOST ALL OF THE REMAINDER IN
MUSCLE. THE GLYCOGEN CONTENT OF THE OTHER ORGANS IS LOW

HEPATIC GLYCOGEN IS MAINLY USED TO MAINTAIN THE BLOOD

GLUCOSE LEVEL IN THE POSTRESORPTIVE PHASE

THE GLYCOGEN CONTENT OF THE LIVER THEREFORE VARIES

WIDELY, AND CAN DECLINE TO ALMOST ZERO IN PERIODS OF
EXTENDED HUNGER.

AFTER THIS, GLUCONEOGENESIS TAKES OVER THE GLUCOSE SUPPLY

FOR THE ORGANISM.

Glycogen Balance and Hepatic Glycogen

MUSCLE GLYCOGEN SERVES AS AN ENERGY RESERVE AND IS NOT
INVOLVED IN BLOOD GLUCOSE REGULATION.

MUSCLE DOES NOT CONTAIN ANY GLUCOSE 6-PHOSPHATASE AND

IS THEREFORE UNABLE TO RELEASE GLUCOSE INTO THE BLOOD.

THE GLYCOGEN CONTENT OF MUSCLE THEREFORE DOES NOT

FLUCTUATE AS WIDELY AS THAT OF THE LIVER.

Glycogen Balance and Muscle Glycogen

WHY WE NEED TO STUDY THE GLYCOGEN
METABOLISM?
What’s Your Message?