7 glycogen metabolism

Glycogen Metabolism

Glycogenesis and glycogenolysis occur in the cytoplasm of cells

P~Pi

UDP-glucose pyrophosphorylase

Glycogen synthase

Branching enzyme

Glycogenesis &

Glycogenolysis

Step 2

Step 3

Step 4

Glycogen Structure

Activation of Glucose

UTP

Glucose

Activation

of Glucose

Glycogen synthase enzyme catalyses the transfer of

glucose units of UDPG to a pre–existing glycogen

molecule or primer

C1 of UDPG forms a glycosidic bond with C4 of a

terminal glucose residue of glycogen, liberating UDP

When the chain has been lengthened to between 8 and

12 glucose residues, the branching enzyme transfers a

part of the 1,4–chain to a neighboring chain to form a

1,6–linkage, thus establishing a branching point in the

molecule

Glycogen Synthase Enzyme

& Branching Enzyme

Glycogenin (Glycogen primer)

Glycogen primer synthase

autocatalysis

Glycogen primer

Glycogen primer synthase

Regulation of Glycogenesis Glycogen synthase is the key enzyme of glycogenesis

It is present in two inter-convertible forms:

Synthase D, inactive (Dependent), phosphorylated

It is dependent on the presence of G6P

Synthase I, active (Independent), which is

dephosphorylated and independent on the

presence of glucose 6–phosphate

Synthase I is converted to the inactive synthase D by

phosphorylation by protein kinase enzyme, with ATP

as phosphate donor

The protein kinase only acts in the presence of cAMP

Glycogenesis

Stimulated after carbohydrate meal, due to

increased insulin

Glycogen synthase activated allosterically

by Glucose–6–phosphate & ATP

Inhibited during fasting, due to increased

secretion of adrenaline & glucagon

Inhibited also by thyroxin

cAMP (3', 5'-cylic AMP) is

sterically constrained by having

a phosphate with ester linkages

to 2 hydroxyls of the same ribose.

Hydrolysis of one of these

linkages (in red), converting

cAMP to 5'-AMP is highly

spontaneous.

The lability of cAMP to

hydrolysis makes it an excellent

transient signal.

Explore cAMP with Chime.

N

N N

N

NH2

O

OHO

HH

H

H2C

HO

PO

O-

1'

3'

5' 4'

2'

cAMP 3',5'–Cyclic AMP ( )

The conversion of ATP to cyclic

AMP releases pyrophosphate

((P~Pi

3′,5′-cAMP

+

Adrenaline

&/or

Glucagon

Insulin Decomposes cAMP

3′-

+Insulin

Activation of cAMP-dependent

protein kinase A (PKA)

Glucagon activates it's cell-surface receptor

This activation is coupled to the activation of a

receptor-coupled G–protein (GTP–binding and

hydrolyzing protein)

G–protein is composed of 3 subunits (, , )

Upon activation the alpha subunit dissociates

and binds to and activates adenylate cyclase

Adenylate cyclase then converts ATP to cAMP

PKA is cAMP-dependent protein kinase

PKA is composed of 2 catalytic & 2 regulatory subunits

The cAMP binds to the regulatory subunits of PKA

leading to dissociation of the catalytic subunits, so the

catalytic subunits become active

The dissociated catalytic subunits phosphorylate

numerous substrate using ATP as phosphate donor

Activation of cAMP-dependent

protein kinase A (PKA)

2 Catalytic & 2 Regulatory subunits

RC

CR

Activation of

Protein kinase A

R

CC

R

cAMP

Structural formulas of four common

intracellular Second messengers

cAMP cGMP DAG IP3

Regulation of Glycogen Synthesis

Briefly, glycogen synthase I (active form)

when phosphorylated, becomes much less

active and requires glucose–6–phosphate to

restore its activity

PKA also phosphorylates glycogen synthase

directly

Regulation of Glycogen Synthesis

Glycogen synthase is directly phosphorylated by:

Protein kinase A (PKA), which activated by cAMP

Protein kinase C (PKC) or Calmodulin–dependent

protein kinase, which activated by Ca2+ ions or DAG

DAG is formed by receptor–mediated hydrolysis of

membrane phosphatidylinositol disphosphate (PIP2)

• Phosphorylation of Glycogen Synthase

leads to:

1. Decreased affinity of synthase for UDP–glucose

2. Decreased affinity of synthase for glucose–6–

phosphate

3. Increased affinity of synthase for ATP and Pi

Glycogenolysis It is the breakdown of glycogen into glucose in

liver or into lactic acid in muscles

In liver, glycogenolysis maintains the blood

glucose level during fasting for less then 18

hours

In muscles, glycogenolysis followed by

glycolysis supply the contracting muscle with

energy during muscular exercise

Site: Cytoplasm of cells

Glycogen Catabolism (Breakdown)

• Glycogen Phosphorylase

catalyzes phosphorolytic

cleavage of the (1 4)

glycosidic linkages of

glycogen, releasing

glucose-1-phosphate

Glycogen (n) + Pi glycogen (n-1) + glucose-1-phosphate

Glycogenolysis

1. Glycogen phosphorylase acts at the 1,4–glycosidic

linkages yielding glucose–1–P. It stops when there are

only four glucose units away from a branch point

2. Glucan transferase transfers a trisaccharide unit from

one side to the other, thus exposing the 1,6–linkage

(branch point)

3. Debranching enzyme acts on the 1,6–linkage to

liberate a free glucose residue

Glycogenolysis

Glycogenolysis

(Absent in Muscles)

Phosphoglucomutase

Regulation of Glycogenolysis

Phosphorylase is the key enzyme of glycogenolysis

There are 2 types of phosphorylase enzyme

Active form: phosphorylase a, which is

phosphorylated, so known as phospho-

phosphorylase

Inactive form: phosphorylase b, which is

dephosphorylated, so known as dephospho-

phosphorylase

Regulation of Glycogenolysis

Phosphorylase b is converted to phosphorylase a

by the enzyme phosphorylase b kinase, with ATP

as phosphate donor

Phosphorylase b kinase is activated by the enzyme

protein kinase which requires cAMP for its activity

cAMP is increased by glucagon (in liver) and

adrenaline (in liver and muscle)

Regulation of Glycogenolysis

Glycogen phosphorylase is also regulated by

allosteric effectors:

Activation by AMP is seen only in muscle cells

under extreme conditions of anoxia and ATP

depletion

G6P inhibits glycogen phosphorylase by binding

to the AMP allosteric site, to ensure that glycogen

is not wasted if the cells have sufficient energy

Regulation of Glycogenolysis

Activation of glycogen degradation during muscle

contraction by calcium

Rapid need of ATP increases nerve impulses,

leading to membrane depolarization, which

promote Ca release from the sarcoplasmic

reticulum into the sarcoplasm of muscle cells

Regulation of Glycogenolysis

Calcium binds to calmodulin (subunit of

phosphorylase kinase)

So Calcium ions activate phosphorylase kinase

even in the absence of the enzyme phosphorylase

kinase

This allows neuromuscular stimulation by

acetylcholine leading to increased glycogenolysis

in the absence of receptor stimulation

Regulation of Glycogen

Phosphorylase

Regulation of Glycogen Phosphorylase

Glycogen phosphorylase is activated by:

• cAMP

• AMP, allosterically

• Ca2+

• Phospholipase C (PLC)

Glycogen phosphorylase is inhibited by:

• G–6–P

• F–1–P, allosterically

Differences Between Liver & Muscle Glycogen

Muscle GlycogenLiver Glycogen

30 Kg1 – 1.5 KgTissue Weight

300 g100 gGlycogen

Amount

1 %10 %Glycogen

Conc.

Blood Glucose onlyBlood Glucose &

GluconeogenesisSource

Blood LactateBlood GlucoseHydrolysis

Product

Used by muscles onlyUsed by all tissuesEnergy

produced

Source of Energy for

muscles only

Maintenance of Blood

GlucoseFunction

Factors Affecting Liver &

Muscle Glycogen

Muscle

Glycogen

Liver

Glycogen

Less Marked IncreaseIncreases greatlyDiet

Little effectDepletionFasting

DepletionLittle effectMuscular

Exercise

Hormonal Regulation of Liver & Muscle Glycogen

Muscle

Glycogen

Liver

Glycogen

GlycogenesisGlycogenesis Insulin

Little increase due to

hyperglycemiaGluconeogenesisGlucocorticoids

Little increase due to

hyperglycemiaGluconeogenesis

Growth

Hormone

GlycogenolysisGlycogenolysisThyroxine

No EffectGlycogenolysisGlucagon

GlycogenolysisGlycogenolysisAdrenaline

Glycogen Storage Diseases (GSD)

• Glycogen storage diseases are inborn errors of

glycogen metabolism (genetic diseases)

• It is characterized by the storage of abnormal

amounts of glycogen in the body

• There are five different types of these diseases

depending on the enzyme missing

Glycogen Storage Diseases (GSD)

• All people who are born with GSD are unable to

properly metabolize or break down glycogen

• People with GSD have the ability to use sugar

stored as glycogen, but are unable to use the

stores to provide the body with energy during

fasting or exercise

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