Dr.

Baskaran Krishnan
Associate Professor
Anna Medical College
Mauritius
Specific learning objectives
 Describe glycogenesis.

 Describe glycogenolysis.

 Explain regulation of glycogen metabolism.

 List glycogen storage diseases and clinical features.

Introduction
 Glycogen metabolism: both synthesis & degradation.

 Glycogenesis is synthesis of glycogen.

 Glycogenolysis is break down of glycogen.

 Site: Liver and muscle.

 Intracellular location: Cytoplasm.

Introduction…
 Liver glycogen is mainly for blood glucose regulation.

 Muscle glycogen is for supply of G-6-P for contraction.

 Glycogen storage diseases (GSD) are inborn errors in

glycogen metabolism.
Glycogen
 Glycogen is a polymer of glucose.
 It is storage form of carbohydrates in animals.
 It is stored in the liver and muscle.

 Function of liver glycogen is to provide glucose during

fasting.

 After taking food, blood glucose tends to rise, which

causes glycogenesis in liver.
Glycogen…
 When blood glucose level falls, liver glycogen is broken
down to maintain blood glucose level between meals.

 The function of muscle glycogen is to supply as fuel in

the form of G-6-P for muscle contraction.

 Liver glycogen is around 4% (liver wt: 1800 g) while in

muscle it is 0.7% muscle wt: 35 Kg.
Glycogen…
 Total glycogen store comes around 300 grams and this
can supply for less than 24 hours.

 All the enzymes related to glycogen metabolism are

located in cytoplasm.
Glycogenesis
 Synthesis of glycogen from glucose.

 Occurs in cytoplasm of liver and muscle.

 Requires ATP and UTP.

 The key enzyme is glycogen synthase.

 It occurs post meals as glucose being plenty.

 Insulin promotes glycogenesis.

Glycogenesis…*
 Pathway starts with:
 Glucose is phosphorylated to Glu-6-P by hexokinase in
muscle and by glucokinase in liver.
 Glucose HK/GK Glucose-6-phophate.

 Glu-6-P is isomerized to glu-1-P by

phosphoglucomutase.
 Glu-6-P PGM Glu-1-P.
Glycogenesis…*
 UDP glucose is formed from glucose-1-phosphate and
UTP (uridine triphosphate) by the enzyme UDP-
glucose pyrophosphorylase.
UDP-glu pyrophosphorylase
Glucose-1-P + UTP —————————→ UDP-glucose
+ PPi
Glycogenesis…*
 Primer.
 The glucose moiety from UDP-glucose is transferred to a
glycogen primer (glycogenin) molecule.
 The primer is essential as the acceptor of the glycosyl unit.
 The primer is a protein-carbohydrate complex.
 It is a dimeric protein, having two identical monomers.
 An oligosaccharide chain of 7 glucose units is added to
each monomer.
Glycogenesis…
 Glycogen synthase.
 Glycogen synthase transfers glucose from UDP-glu to
primer.
Glycogen synthase
Glycogen primer (n) ————→ Glycogen primer (n+1)
+ UDP-glucose + UDP
 The glucose units are sequentially added to the
nonreducing (outer) end of the growing chain to form
an alpha-1,4 glycosidic linkage and UDP is released.
Glycogenesis…*
 Branching enzyme.
 The glycogen synthase can add glucose units only in
alpha-1,4 linkage.
 A branching enzyme creates the alpha-1,6 linkages.
 When the chain is lengthened to 11 - 12 glucose residues,
the branching enzyme transfers 6 to 8 glucose residues
from this chain to another site on the growing molecule.
 The branching enzymes is amylo α-[1,4]→[1,6]-
transglucosidase forms this alpha-1,6 linkage.
 To this newly created branch, further glucose units can be
added in alpha-1,4 linkage by glycogen synthase.
Glycogenesis…
Glycogenolysis*
 It is a degradation of glycogen in liver and muscle.

 This pathway is not reversal of glycogenesis.

 Enzymes are located in the cytoplasm.

 Key enzyme is glycogen phosphorylase.

 It occurs in fasting state.

 Hormones active are glucagon & epinephrine (adrenaline).

Glycogenolysis…*
 Glycogen phosphorylase.

 Glycogen phosphorylase removes glucose as

glucose-1-phosphate from glycogen (phosphorolysis).

 It contains pyridoxal phosphate (PLP) as prosthetic

group.

 The alpha-1,4 linkages in the glycogen are cleaved.

Glycogenolysis…*
 It removes glucose units one at a time as glu-1-P.

 It hydrolyses alpha-1,4 glycosidic linkages, till it

reaches a glucose residue, 3-4 glucose units away from
a branch point.

 It cannot attack the 1,6 linkage at branch point.

Glycogenolysis…*
 Debranching enzymes.

 Then three glucose residues are transferred from

the branching point to another branch.

 This enzyme is alpha-1,4 → alpha-1,4 glucan

transferase.

 Now the branch point is free.

Glycogenolysis…*
 Then alpha- 1,6- glucosidase (debranching
enzyme) can hydrolyze the remaining glucosyl
unit held in alpha-1,6 linkage at the branch point.

 This glucose residue is released as free glucose.

Glycogenolysis…*
 The transferase and alpha-1,6-glucosidase activities
of debranching (bifunctional) enzyme will
together convert the branch point to a linear one.

 With the removal of the branch point,

phosphorylase can proceed with its action.
Glycogenolysis
Glycogenolysis…*
 Phosphogluco mutase.

 Phosphorylase reaction produces glucose-1- phosphate

while debranching enzyme releases glucose.

 The glucose-1-phosphate is converted to glucose-6-

phosphate by phosphoglucomutase
Glycogenolysis…
 Glucose-6-phosphatase in liver.
 Hepatic glucose-6-phosphatase hydrolyses glucose-6-
phosphate to glucose.
 Free glucose is released to the blood stream.
 Muscle will not release glucose to the blood stream, as
muscle tissue does not contain glucose-6-phosphatase.
 Instead, in muscle, glucose-6-phosphate undergoes
glycolysis to produce ATP for muscle contraction.
Regulation of glycogen metabolism
 Key enzyme for glycogenesis is glycogen synthase.
 For glycogenolysis is glycogen phosphorylase.
 Hormones: Insulin, glucagon & epinephrine.
 Glycogen synthase is activated by insulin under
hyperglycemia.
 Glycogen phosphorylase is activated by glucagon &
adrenaline under the stimulus of hypoglycemia.
Regulation…
 Regulatory mechanisms: Allosteric control & covalent
modification of enzymes by these hormones.

 Allosteric effectors: ATP, AMP, G-6-P and Ca++.

 Both pathways are reciprocally regulated by regulating the

key enzymes reciprocally to prevent futile cycles.
 This is done by covalent modification of the enzymes-
phosphorylation and dephosphorylation.
Regulation…
 Glycogen phosphorylase is active on phosphorylation.

 Glycogen synthase is inactive on phosphorylation.

 Specific protein kinases bring about phosphorylation

and protein phosphatases cause dephosphorylation.

 Covalent modification of these enzymes is done by a

cyclic AMP (cAMP) mediated cascade.
Regulation…
 Liver & muscle phosphorylases are activated by this.

 Glucagon activates liver glycogen phosphorylase.

 But it has no effect on the muscle.

 Epinephrine acts in both liver and muscle.

 When they bind to their receptors on the cell membrane.

 Adenyl cyclase is activated which converts ATP to cAMP .

Regulation…
 Now cAMP activates a protein kinase.

 The active protein kinase has two actions:

 It phosphorylates glycogen synthase thereby switch off
glycogenesis.
 And it also phosphorylates the phosphorylase kinase to an
active phosphorylated form.
 Now this active phosphorylase kinase phosphorylates glycogen
phosphorylase-b(inactive) to glycogen phosphorylase- a (active).
Regulation…
Regulation…
 Insulin promotes glycogen synthesis by favoring
dephosphorylation.
 It stimulates protein phosphatase-1.
 It brings out the following changes:
 It dephosphorylates glycogen synthase.

 It also dephosphorylates glycogen phophorylase.

 Insulin activates phosphodiesterase which hydrolyzes

cAMP thereby opposing the action of glucagon.
Glycogen storage disease
 Glycogen storage diseases (GSD) are a group of
inherited disorders.
 They are inborn errors in glycogen metabolism.

 Due to deficient or absent of enzymes in glycogen

metabolism.
 They are characterized by deficient mobilization of
glycogen or deposition of abnormal forms of glycogen.
Glycogen storage disease…
 Clinical features include:

 Liver damage.

 Muscle weakness.

 In some GSDs there is an early death.

von Gierke's disease
 It is glycogen storage disease type-I.
 Most common type of glycogen storage disease.
 Incidence is 1 in 100,000 live births.
 Due to glucose-6-phosphatase deficient.
 Glucose not released from liver during over night fasting.
 Fasting hypoglycemia that does not respond to adrenaline.
 Lactic acidosis, hyperlipidemia, and ketosis.
von Gierke's disease…
 G-6-P is channeled to HMP shunt.

 This generates more ribose and more nucleotides.

 Excess uric acid from purine nucleotides causing

hyperuricemia and gout.

 Glycogen gets deposited in liver and massive liver

enlargement may lead to cirrhosis.
von Gierke's disease…
 Children usually die in early childhood.

 Management is to give small quantity of food at

frequent intervals.
Type Name Enzyme Clinical features
I Von Gierke’s disease Glucose-6- Fasting hypoglycemia, hepatomegaly
phosphatase

II Pompe’s disease Lysosomal Glycogen accumulates in liver, muscle

maltase and heart. Death by 2 yrs

III Limit dextrinosis, Debranching Fasting hypoglycemia, hepatomegaly

Cori’s disease enzyme

IV Amylopectinosis, Branching Mild hypoglycemia, hepatosplenomegaly

Anderson’s disease enzyme

V McArdle’s disease Muscle Exercise intolerance

phosphorylase

VI Hers’ disease Liver Mild hypoglycemia, hepatomegaly, better

phosphorylase prognosis

VII Tarui’s disease Muscle PFK Exercise intolerance, hemolytic anemia

Glycogen storage disease…
 Types VIII, IX and X – Are due to deficiencies of
phosphorylase kinase of liver, muscle and protein
kinase A deficiency respectively.

 Mild hypoglycemia, exercise intolerance and

hepatomegaly are the clinical feature.

 They have better prognosis.

Reflection
 How glycogen metabolism is regulated?

 What is the role of hepatic glycogen?

 Which hormone favors glycogenesis?

 Which hormones favors glycogenolysis?

 Reason out : liver can form glucose while muscle can not.

 Reason out for fasting hypoglycemia and lactic acidosis in

von Geirk’s disease.