Glycogen metabolism and its clinical significance

Dr. Rohini C Sane

Structure of Glycogen molecule

Functions of GlycogensGlycogen is stored in Liver and skeletal muscles as energy reserve.

Muscle Glycogen is to provide energy for prolonged muscles contraction

Liver Glycogen is to maintain blood sugar levels in human body.

Glycogen is the storage form of Glucose in animals. It is stored in cytosol of cells of Liver (6-8% )and muscles (1-2%) in a granular

form.

Glycogen Metabolism

Stored Glycogen serves as a fuel reserve

Stored Glycogen serves as a fuel reserve for following reasons

a) Glycogen can be rapidly metabolized.

b) Glycogen can generate energy in absence of oxygen.

c) Brain depends on continuous glucose supply

Fat mobilization is slow and depends on oxygen for energy generation and cannot produce glucose ( to significant extent) in human body .

• Fat = fixed deposit of bank

• Glycogen = saving /current account of bank

GlycogenesisGlycogenesis : Synthesis of Glycogen from Glucose

a) Site of Glycogenesis : cytosol of Muscle (250gms/day),Liver (75gm/day) cells

b) Initiation of glycogen synthesis by Glycogenin :A protein can accept glucose from UDPG in absence of Glycogen primer initiation of Glycogen synthesis

c) Glycogen synthase : uses UDP-glucose as a substrate for Glycogenesis ,adding one residue of Glucose at a time to non reducing end of Glycogen .It forms α1 4 bonds between neighboring glucosyl residues.

d) Branching enzyme of Glycogenesis : Glucosyl α 4,6 transferase/ Amylo α1,4 1,6 transglucosidase).This enzyme transfers a small fragment of 5-8 residues from non reducing end of Glycogen chain (by breaking α1,4 linkages) to another glucose residue where it is linked by α1,6 bond

e) Cofactors required in Glycogenesis : ATP and UDP

f) Glycogen elongation & branching :by repeated action of Glycogen synthase and Glucosyl α 4,6 transferase

g) Reaction involved in Glycogenesis

Glycogenesis

Reaction involved in Glycogenesis

( Glucose )n + Glucose + 2ATP ( Glucose )n+1 + 2ADP + 2 Pi

Of 2 ATP utilized one required for the phosphorylation of Glucose while other is needed for conversion of UDP to UTP.

Initiation of glycogen synthesis by Glycogenin

The hydroxyl group of the amino acid Tyrosine of Glycogenin is siteat which the initial glucose residuegets attached. The enzyme Glycogen synthase transfers

the first Glucose molecule to Glycogenin.

Glycogenin, itself takes up glucose molecules subsequently to form a glycogen primer.

Glycogenesis

Glycogenesis

Glycogenolysis

Glycogenolysis : is a degradation of stored Glycogen

Site of Glycogenolysis : cytosol of Muscle & Liver cells

Enzymes involved in Glycogenolysis: Glycogen Phosphorylase and debranching enzymes

Liver Glycogenolysis

1. Glycogen Phosphorylase : Glycogen Glucose1-P

2. Phosphoglucomutase: Glucose 1-P + Mg2+ Glucose 6-P

3. Glucose 6 Phosphatase : Glucose 6-P Glucose

Muscle Glycogenolysis

I. Glycogen Phosphorylase : Glycogen Glucose 1-p

II. Phosphoglucomutase : Glucose 1-P + Mg2+ Glucose 6-P

III. Glycolysis :Glucose 6-P Lactate

Muscle lacks enzyme –Glucose 6 phosphatase

Glycogen Phosphorylase• Glycogen Phosphorylase :

• It removes glucose residues sequentially from non reducing ends of Glycogen molecule ,producing Glucose 1 phosphate as the first product of Glycogenolysis.

• It breaks α 1 4 glycosidic bonds and cannot break α 1 6 glycosidic branch points/bonds .

Glycogenesis and Glycogenolysis are not reversible & regulated by regulatory enzymes.

Glycogenesis and Glycogenolysis

GLYCOGENOLYSIS IN LIVER

GLYCOGENOLYSIS IN MUSCLES

Glycogen Metabolism in cytosol of Liver & Muscle cells

Fates of Glucose 6-phosphate as an intermediate of Glycogenolysis

Glucose 6-phosphate enters Glycolysis and is oxidized to yield energy for muscle contraction

The ratio of Glucose 1-phosphate toGlucose 6-phosphate is 8:1

Glycogenolysis

Regulation of Glycogenesis and Glycogenolysis

Regulation of Glycogenesis and Glycogenolysis and their good coordination is essential to maintain blood glucose levels .

Glycogen synthase regulates Glycogenesis.

Glycogen phosphorylase regulates Glycogenolysis.

Regulation of Glycogenesis and Glycogenolysis

Regulation of Glycogenesis and Glycogenolysis and their good coordination is accomplished by three mechanisms.

a) Hormonal regulation

b) Allosteric regulation

c) Influence of Calcium

Hormonal Regulation of Glycogenesis / Glycogenolysis

The hormones through complex series of reactions bring about covalent modifications ,namely phosphorylation and dephosphorylation of enzymes which ultimately control Glycogen synthesis (Glycogenesis)and or its degradation (Glycogenolysis).

Hormonal Regulation of Glycogenesis / Glycogenolysis by Epinephrine and Insulin

Cyclic AMP ( c AMP)

acts as a second messenger during hormonal regulation of Glycogenesis / Glycogenolysis by Epinephrine , nonepinephrine ,Glucagon and Insulin.

binds to cell membrane and brings changes inside the cell.

Regulates activities of Glycogen synthase and phosphorylase ( involved in Glycogenesis / Glycogenolysis respectively ).

Hormones like epinephrine and nonepinephrine and Glucagon ( in Liver) activate adenylate cyclase to increase the production of Cyclic AMP ( c AMP) .

Insulin increases phosphodiesterase activity in liver and lowers C-AMP levels.(Enzyme phosphodiesterase breaks down C-AMP).

Hormonal Regulation of Glycogenesis / Glycogenolysis by Epinephrine and Insulin

Cyclic AMP ( c AMP) during Starvation

High levels of Cyclic AMP ( c AMP) causes activation of inactive Glycogen phosphorylase enhancing Glycogenolysis ( through protein kinases ).

High levels of Cyclic AMP ( c AMP) inactivates an active Glycogen synthase leading to inhibition of Glycogenesis .

Glucagon and Adrenalin(Epinephrine )stimulate Glycogenolysisthrough High levels of Cyclic AMP

Regulation of Glycogenolysis by Epinephrine, Norepinephrine and Glucagon -through C-Amp

Glycogenolysis is regulated by a enzyme Glycogen Phosphorylase

Glycogen Phosphorylase exist in two forms :

1) a form of Glycogen Phosphorylase ( Phosphorylated and most active )

2) b form of Glycogen Phosphorylase ( dephosphorylated and inactive )

C-Amp is formed due to hormonal (Epinephrine and Glucagon ) stimulation

C-Amp activates dependent on protein Kinase

Conversion of b form(inactive ) to a form (active ) of Glycogen Phosphorylase kinase : phosphorylation catalyzed by active form of protein Kinase

Conversion of b form(inactive ) to a form (active ) of Glycogen Phosphorylase : phosphorylation catalyzed by a form (active ) of Glycogen Phosphorylase kinase.

a form (active ) of Glycogen Phosphorylase degrades Glycogen ( Glycogenolysis )

Conversion of a form to b form of Glycogen Phosphorylase kinase : de phosphorylation by protein phosphatase . (removes phosphate for inactivation of Glycogen Phosphorylase kinase )

Conversion of a form to b form of Glycogen Phosphorylase : de phosphorylation by protein phosphatase I. (removes phosphate for inactivation of Glycogen Phosphorylase )

Inhibition of Glycogenolysis (Glycogen Phosphorylase ) : by epinephrine , norepinephrine and Glucagon by Conversion of a form(active ) to b form (inactive ) of Glycogen Phosphorylase - De phosphorylation

Regulation of Glycogenesis by Epinephrine, Norepinephrine and Glucagon -through C-Amp

Glycogenesis is regulated by Glycogen synthase

Glycogen synthase exist in two forms :

1) a form of Glycogen synthase ( Not Phosphorylated and most active )

2) b form of Glycogen synthase( Phosphorylated and inactive )

Conversion of a form(active ) to b form (inactive ) of Glycogen synthase : phosphorylation catalyzed by C-Amp dependent on protein Kinase

Conversion of b form to a form of Glycogen synthase : de phosphorylation by protein phosphatase I.

Inhibition of Glycogenesis (Glycogen synthase ) : by epinephrine , norepinephrine and Glucagon through C-Amp (Conversion of a form(active ) to b form (inactive ) of Glycogen synthase by phosphorylation

Hormonal regulation of Glycogenolysis by Epinephrine/Glucagon through ,C-AMP and Protein kinase

a form of Glycogen

synthase ( Not

Phosphorylated and most

active )

b form of Glycogen synthase

( Phosphorylated and inactive )

Conversion of a form to b form by phosphorylation

catalyzed by C-Amp dependent on protein Kinase

Hormonal regulation of Glycogenolysis by Epinephrine through C-AMP and Protein kinase

Hormonal regulation of Glycogenolysis by Epinephrine/Glucagon through G –protein ,C-AMP and Protein kinase

Signal transduction

Allosteric regulation of Glycogen Metabolism

Allosteric regulation of Glycogen Metabolism by Metabolites that allosterically regulate the activities of Glycogen Synthase and Glycogen phosphorylase .

Glycogen synthesis is increased when substrate availability and energy levels are high.

Glycogen breakdown is increased Glucose concentration is low.

Well fed state

Availability of Glucose6-phosphate high

Allosteric activation of Glycogen synthase

More Glycogen synthesis

Allosteric regulation of Glycogen Metabolism

Starvation /fasting state

Availability of Glucose6-phosphate and ATP low

Allosteric activation of Glycogen phosphorylase by C- Amp

More Glycogen breakdown

Allosteric regulation of Glycogen Metabolism

Allosteric regulation of Glycogen Metabolism

ACTIVATORS INHIBITORS

Glycogen synthase ATP, Glucose 6 P (well fed- concentration increases )Glycogenesis ON

C –AMP (starvation concentration increases)Glycogenesis OFF

ACTIVATORS INHIBITORS

Glycogen phosphorylase

C—AMP(concentration increases during starvation) Glycogenolysis ON In muscles ionic Calcium,C-Amp act as activators

ATP, liver free Glucose,Glucose 6- P(concentration increases in well fed ) Glycogeniolysis OFF

STARVATION WELL FED

Glucose ,ATP Decreases glucose ,ATP INCREASES

Glycogenolysis ON Glycogenolysis OFF

Glycogen synthesis OFF Glycogen synthesis ON

Allosteric regulation of Glycogen Metabolism

Glycogenesis/Glycogenolysis during starvation and well fed conditions

WELL FED NUTRITIOUS STATUS STARVATION NUTRITIOUS STATUS

1. HIGH LEVELS OF GLUCOSE CONCENTRATION 1. LOW LEVELS OF GLUCOSE CONCENTRATION

2. HIGH LEVELS OF INSULIN CONCENTRATION (induced by Glucose ) 2. LOW LEVELS OF INSULIN CONCENTRATION

3. LOW LEVELS OF GLUCAGON (inhibited by high levels of Glucose )

4. HIGH LEVELS OF ATP

5. LOW LEVELS OF C-AMP

6. INACTIVATION OF GLYCOGEN PHOSPHORYLASE

7. INHIBITION OF GLYCOGENOLYSIS

8. STIMULATION OF GLYCOGEN SYNTHESIS TILL GLUCOSE CONCENTRATION BROUGHT BACK TO NORMAL

3. HIGH LEVELS OF GLUCAGON (INCREASES )

4. LOW LEVELS OF ATP

5. HIGH LEVELS OF C-AMP

6. ACTIVATION OF GLYCOGEN PHOSPHORYLASE

7. STIMULATION OF GLYCOGENOLYSIS

8. INHIBITION OF IN GLYCOGEN SYNTHESIS TILL GLUCOSE CONCENTRATION BROUGHT BACK TO NORMAL

REGULATION OF GLYCOGEN METABOLISM

WELL FED NUTRITIOUS STATUS STARVATION NUTRITIOUS STATUS

INCREASE IN GLUCOSE CONCINCREASE IN INSULIN DE CREASE IN GLUCOSE CONCDECREASE IN INSULIN

ATP CONC INCREASES ATP CONC DECREASES

C –AMP LOW C –AMP HIGH

GLYCOGENOLYSIS DECREASES--OFF GLYCOGENOLYSIS INCREASES--ON

GLYCOGEN SYNTHESIS INCREASES --ON GLYCOGEN SYNTHESIS DECREASES --OFF

DEPHOSPHORYLATION OF GLYCOGEN SYNTHASE (ACTIVE)

GLYCOGEN SYNTHESIS CONTINUES TILL GLUCOSE CONC BROUGHT BACK TO NORMAL

PHOSPHORYLATION OF GLYCOGEN SYNTHASE (INACTIVE)

GLYCOGEN SYNTHESIS DECREASES TILL GLUCOSE CONC BROUGHT BACK TO NORMAL

Regulation of Glycogen Metabolism by Insulin

C-Amp + Phosphodiesterase 5’AMP

Insulin promotes phosphodiesterase decreases C-Amp levels

Insulin converts Glycogen Phosphorylase A (active and phosphorylated form ) GlycogenPhosphorylase B (inactive )THEREFORE INSULIN INHIBITS GLYCOGENOLYSIS

Glycogen Synthase B (dephosphorylated form and inactive) Glycogen Synthase A ( active and phosphorylated )THEREFORE INSULIN ENHANCES GLYCOGENESIS

Mechanism : Insulin decreases C-AMP levels (Glycogen synthase remains in active form)STIMULATES GLYCOGEN SYNTHESIS.

INSULIN PLAYS ANABOLIC ROLE

EFFECT OF CALCIUM IONS ON GLYCOGENOLYSIS

1. Need for ATP increases during Muscle Contraction

2. Muscle Contraction induces release Of Calcium From Sarcoplasmic Reticulum

3. Calcium –Calmodulin Complex formed

4. Direct Activation Of Phosphorylase Kinase without C-amp Dependent Protein Kinase

5. Muscle Activity Of Glycogen Phosphorylase Increases

6. Increase In Concentration Of ATP

Effect of Calcium ions on Glycogenolysis

Muscle Contraction

Need for ATP increases

Release Of Calcium From Sarcoplasmic Reticulum

Calcium –Calmodulin Complex formed

Direct Activation of Phosphorylase Kinase without C-amp Dependent Protein Kinase

Muscle Activity of Glycogen Phosphorylase increases increase In Concentration Of ATP

Calcium –Calmodulin Complex

Effect of Calcium ions on Glycogenolysis

FUTILE CYCLESThe synthesis and degradative pathways of metabolism ( particularly reactions involving phosphorylation and de-phosphorylation utilizing ATP ) are well regulated and subjected to fine tuning to meet body’s demands with minimal wastage of energy. Glycogenolysis and Glycogenesis operate in selective fashion to suit cellular demands.

Glycogen storage diseases

Glycogen storage diseases

VAN GIRKE DISEASE –TYPE I GLYCOGEN STORAGE DISEASE

• GLUCOSE 6 PHOSPATASE MUTATED /ABSENT

• HYPOGLYCEMIA

• GLUCOSE 6P –NOT CONVERTED TO GLUCOSE BT ENTERS GLYCOLYSIS TO FORM LACTIC ACID –(LACTIC ACIDOSIS )

• INNCREASE CONC OF G-6P - HMP SHUNT NADPH HYPERLIPEDEMIA

• INNCREASE CONC OF G-6P - HMP SHUNT RIBOSE SUGAR PURINE SYNTHESIS GOUTY ARTHRITIS

• KETOSIS( LOW GLUCOSE –LOW GLYCOLYSIS – LOW PYRUVATE & OAA __DECREASE TCAKETOSIS )

GLYCOGEN STORAGE DISEASE MUTATION MANIFESTATION

POMPE –TYPE2 LYSOSOMAL 1,4 GLUCOSIDASE OF ALL ORGANS

LYSOSOMAL STORAGE OF GLYCOGEN –LYSOME LYSIS CELL DEATH –LIVER ,HEART ,NEURAL CELLS --HEART FAILURE MENNTAL RETARDATION ,LIVER ENLARGEMENT

CORI’S DISEASE TYPE 3LIMIT DEXTROMINOSIS

AMYLO AILPH 1,6 GLUCOSIDASE DEBRANCHING ENZYME

SAME AS TYPE -1 BUT MILDER

ANDERSON’S DIEASE—TYPE 4 ( AMYLOPECTINOSIS )

GLYCOSYL (4,6 ) TRANSFERASEBRANCHING ENZYME

GLYCOGEN WITH FEW BRANCHES

M C ARDLE DISEASE –TYPE 5 MUSCLE GLYCOGEN PHOSPHORYLASE

MUSCLE CRAMPS –MUSCLE DAMAGE DUE TO INADEQUATE ENERGY SUPPLY

HER’S DISEASE—TYPE 6 LIVER GLYCOGEN PHOSPHORYLASE MILD HYPOGLYCEMIA ,KETOSIS

TAURI’S DISEASE –TYPE 7 PHOSPHO FRUCTOKINASE IN RBC, MUSLE

MUSCLE CRAMPS,HEMOLYSIS

I- VON GIRE DISEASE

V -MC ARDLEVI HER’S