Dr. S.Chakravarty MD
Points to be covered-
Introduction
 Biomedical importance
Glycogen Synthesis- Glycogenesis
 Regulation of glycogenesis
Glycogen Breakdown- Glycogenolysis
 Regulation of glycogenolysis
Reciprocal regulation of Glycogen Metabolism
Glycogen Storage Diseases
INTRODUCTION
 Glycogen - storage form of glucose
- stored in the liver and the skeletal muscles
- energy reserve.
 A homopolysaccharide - linear chain of 
(1→4) linked glucosyl residues with
branches joined by  (1→6) linkages.
Glycogen in liver (6-8%) is higher than
that in the muscles (1-2%).
 Liver glycogen - first line of defense
against declining blood glucose levels
especially between meals.
Tissue
Weight
1.8 kg
Body Content
Liver glycogen
Percentage of Tissue
Weight
5.0
Muscle glycogen
Extracellular glucose
0.7
0.1
35 kg
10 L
245 g
10 g
90 g
USMLE
Biomedical Importance:
1. In health, liver glycogen maintain blood glucose level
particularly between meals whereas muscle glycogen
is a readily available source of glucose in the
exercising muscles.
2. Deficient mobilization and abnormal accumulation of
glycogen leads to certain disorders called as
GLYCOGEN STORAGE diseases which can lead to
muscular weakness and even death in the affected
individual.
REM-Glucose 6-phosphatase is absent in muscle-so NO contribution to plasma glucose level by
muscle glycogen-only locally available glucose 6-P for glycolysis and HMP shunt
GLYCOGEN SYNTHESIS(GLYCOGENESIS):
 Glycogen - synthesized from glucose.
 Site : Liver,
Skeletal Muscles
 Subcellular site: cytosol
Steps: 1.Synthesis of UDP-Glucose
2.Synthesis of Primer to initiate Glycogen synthesis
3.Elongation of chain
4.Formation of branches in Glycogen
1. Synthesis of UDP-Glucose
Glucose
ATP
Glucokinase
Hexokinase
ADP
Glucose-6-phosphate
Phosphoglucomutase
Glucose-1-phosphate
UTP
UDP-Glucose pyrophosphorylase
PPi
UDP- Glucose
Pyrophosphate - is hydrolyzed to inorganic phosphate by
Pyrophosphatase and thus ensures the IRREVERSIBILITY
of this reaction.
2.Synthesis of PRIMER to initiate Glycogen synthesis:
 Primer is a preexisting  (1→4) glucosyl chain with Glycogenin which
will accept the glucosyl residues donated by UDPG.
 Normally a fragment of glycogen serves as a primer.
 When glycogen stores are depleted, a specific protein known as
GLYCOGENIN provides the site at which the primer is built.
Tyrosyl-OH + UDPG
UDPG + glycogen primer
(n residue)
Tyrosyl-o-glucose + UDP
UDP + Glycogen
(n+1residues)
3. Elongation of the chain:
UDP Glucose
Glycogen synthase
+ UDP
4. Formation of Branches in Glycogen:
 The branch points - created by the action of BRANCHING enzyme. Also
called as glucosyl 4:6 transferase OR amylo [14] [1-6]transglucosidase
 When the the chain is minimum 11 glucose residues long , branching
enzyme removes a block of 6-8 glucosyl units from the non reducing end of
the chain and attaches it via an  (1→6) linkage to a glucose residue of the
same or other chain.
Branching enzyme
New branch point
created ( (1→6)
linkage )
Regulation of glycogenesis:
Rate limiting enzyme - GLYCOGEN SYNTHASE
Regulated by-
1. Allosteric regulation: +ve modifiers- Glucose-6-phosphate
in the liver and muscles.
2. Covalent modification: By phosphorylation &
dephosphorylation
Protein Kinase
Glycogen synthase
Glycogen synthase
(Dephosphorylated)
(active)
Protein phosphatase
(Phosphorylated)
(Inactive)
Hormonal regulation
Glucagon/Epinephrine
Insulin
+
Adenylate cyclase
Phosphodiesterase
ATP
cAMP
Inactive protein kinase
5’AMP
Active protein kinase
Protein Kinase
Glycogen synthase
Glycogen synthase
(Dephosphorylated)
(active)
(Phosphorylated)
Protein phosphatase
(Inactive)
+
Glycogenesis
stimulated
Glycogenesis inhibited
GLYCOGEN BREAKDOWN (GLYCOGENOLYSIS)
 The principal enzyme of glycogenolysis - GLYCOGEN PHOSPHORYLASE.
Glycogen + Pi
Glycogen + Glucose – 1-P
( n residues) Phosphorylase (n-1 residues)
 glucosyl 4:4 transferase activity transfers the 3 of the 4 glucosyl units
and involves cleaving of an  (1→4)linkage at one site and formation
of new  (1→4)bond elsewhere.
 The key enzyme for removing branch points is the debranching
enzyme -  (1→6) glucosidase activity – free glucose released.
Glycogenolysis:
+
Phosphorylase
Glucan
Transferase
Debranching
enzyme
(Glucosidase or
1,6 glycosidase)
Glucose molecules are removed sequentially by PHOSPHORYLASE until approximately
4 glucose remain on either side of a 16branch point
Glucan transferase removes a trisaccharide from one branch to the other.
Glucosidase removes the remaining glucose
Regulation of Glycogenolysis:
The rate limiting enzyme of glycogenolysis is glycogen phosphorylase
which is regulated by1. Allosteric regulation - +ve modifiers- AMP
-ve modifiers- ATP in liver and muscles
Glucose in liver
Glucose-6-phosphate in muscles
2.Covalent modification-Phosphorylated form is active.
Phosphorylase kinase
Glycogen phosphorylase
Glycogen phosphorylase
(dephosphorylated)
(phosphorylated)
(inactive)
Protein phosphatase
(active)
3.Ca ions- activates phosphorylase kinase
Hormonal regulation
Glucagon/Epinephrine
Insulin
+
Adenylate cyclase
Phosphodiesterase
ATP
cAMP
Inactive protein kinase
5’AMP
Active protein kinase
Phosphorylase Kinase
Glycogen phosphorylase
Glycogen phosphorylase
(Dephosphorylated)
(Inactive)
(Phosphorylated)
Protein phosphatase
(active)
+
Glycogenolysis
stimulated
Reciprocal
regulation
Regulation of Glycogenolysis in
muscle:
Glucose loading in Sports!!
• i.v glucose loading( CARBO-LOADING ) for 1-2
days prior to sports event has been
extensively used by athletes to build up stores
of glycogen to enhance performance later on
during the contest.
Glycogen storage diseases
Abnormalities in metabolism of glycogen leads to a group
of disorders called Glycogen storage diseases.
Types- Hepatic (I III,IV,VI,and VIII)
Myopathic(V and VII)
General features – Hypoglycemia , poor exercise tolerance , lactic
acidosis
Muscle weakness in myopathic forms
Hepatic fibrosis and hepatomegaly(due to accumulation of
glycogen in liver)
Glycogen Storage Diseases
USMLE
Type Name
Enzyme Deficiency
Clinical Features
0
—
Glycogen synthase
Hypoglycemia; hyperketonemia; early death
Ia
Von Gierke's disease Glucose 6phosphatase
Ib
—
II
Pompe's disease
IIIa
Limit dextrinosis,
Forbe's or Cori's
disease
Liver and muscle
Fasting hypoglycemia; hepatomegaly in infancy;
debranching enzyme accumulation of characteristic branched
polysaccharide (limit dextrin); muscle weakness
IIIb
Limit dextrinosis
Liver debranching
enzyme
Glycogen accumulation in liver and renal tubule
cells; hypoglycemia; lactic acidemia; ketosis;
hyperlipemia, hyperuricemia
Endoplasmic
As type Ia; neutropenia and impaired
reticulum glucose 6- neutrophil function leading to recurrent
phosphate
infections
transporter
Accumulation of glycogen in lysosomes:
Lysosomal α 14
juvenile onset variant, muscle hypotonia, death
and α16
glucosidase (acid
from heart failure by age 2; adult onset variant,
maltase)
muscle dystrophy
As type IIIa, but no muscle weakness
harper
USMLE
IV Amylopectinosis, Branching enzyme Hepatosplenomegaly; accumulation of
Andersen's
amylopectin like polysaccharide with few branch
disease
points; death from heart or liver failure before
age 5
V Myophosphorlyl Muscle
Poor exercise tolerance; muscle glycogen
ase deficiency, phosphorylase
abnormally high (2.5–4%); blood lactate very low
McArdle's
after exercise
syndrome
VI Hers' disease
Liver
Hepatomegaly; accumulation of glycogen in liver;
phosphorylase
mild hypoglycemia; generally good prognosis
VII Tarui's disease Muscle and
Poor exercise tolerance; muscle glycogen
erythrocyte
abnormally high (2.5–4%); blood lactate very low
phosphofructokin after exercise; also hemolytic anemia
ase 1
VIII
Liver
Hepatomegaly; accumulation of glycogen in liver;
phosphorylase
mild hypoglycemia; generally good prognosis
kinase
IX
Liver and muscle Hepatomegaly; accumulation of glycogen in liver
phosphorylase
and muscle; mild hypoglycemia; generally good
kinase
prognosis
X
cAMP-dependent Hepatomegaly; accumulation of glycogen in liver
protein kinase A
harper
• Glucose 6 phosphatase deficiency
• Hypoglycemia not responding even to i.v
glucagon/epinephrine .
• Lactic acidosis – Impairment of gluconeogenesis.
•
Accumulation of G6P inhibits conversion of lactate to pyruvate.
The lactic acid level rises during fasting as glucose falls. In people with
GSD I, it may not fall entirely to normal even when normal glucose levels
are restored.
• Hepatomegaly – progressing to cirrhosis
• Hyperuricemia ??
---- increased glucose 6 P  increased influx into HMP
shunt increased Ribose 5P INCREASED DENOVO
BIOSYNTHESIS OF Nucleic acids.
Pompe’s disease:
• Type II – Glycogen storage disease:
• Lysosomal α 14 and α16 glucosidase (acid
maltase) deficiency.
• Affects - liver , muscle and heart.
• Accumulation of glycogen in vacuoles
• Death due to cardiac failure
• Massive cardiomegaly.
• Normal blood glucose levels.
Anderson Disease:
• Def of Branching enzyme –
• Accumulation of poorly branched polysaccharide –
with minimal branching
• Amylopectin like appearance of glycogen molecules
• Normal blood glucose levels
• Death in first year of life
Cori disease/Forbes disease:
• Def. of enzyme – Debranching enzyme
• Accumulation of abnormal small dextrin like
polysaccharides in liver.
• Hypoglycemia seen.
6-month-old who is failing to thrive is brought to your clinic.
Tests reveal hepatosplenomegaly, muscle weakness and
atrophy, hypotonia, and decreased deep tendon reflexes. Blood
tests reveal that the infant has normal glucose levels. Biopsy of
the liver reveals initial stages of cirrhosis due to the
accumulation of an abnormal glycogen with few branch points,
whose structure resembles amylopectin. The clinical and
laboratory results presented are indicative of which glycogen
storage disease?
•Von Gierke disease
•Tarui disease
•Andersen disease
•Cori or Forbes disease
•McArdle disease
Branching enzyme
An infant with growth retardation, hepatomegaly and
hypoglycemia demonstrate hepatic fibrosis without fat
accumulation on liver biopsy. There is also accumulation of small
chain dextrin- like material within the cytosol of the hepatocytes.
Which of the following enzymes is most likely deficient in this
patient?
•Glucose -6-phosphate
•Glycogen phosphorylase
•Debranching enzyme
•Amylo-α (1,6) –glucosidase
•Pyruvate kinase.
Cori’s or Forbe’s or Limit Dextrinosis
After a meal, blood glucose enters cells and is stored
as glycogen, particularly in the liver. Which of the
following is the donor of new glucose molecules in
glycogen?
•
•
•
•
•
UDP-glucose-1-phosphate
UDP-glucose
UDP-glucose-6-phosphate
Glucose-6-phosphate
Glucose-1-phosphate