Glycogen MetabolismGlycogen Metabolism

Objectives:

Why do we need to store carbohydrates?

Why carbohydrates are stored as glycogen?

Overview of glycogen synthesis (Glycogenesis)

Overview of glycogen breakdown (Glycogenolysis)

Key elements in regulation of both Glycogenesis

and Glycogenolysis

What do we really need?What do we really need?

A constant source of glucose is A constant source of glucose is mandatory for mandatory for ::

BrainBrainCells with few or no mitochondriaCells with few or no mitochondriaExercising muscles (anaerobic Exercising muscles (anaerobic

glycolysis)glycolysis)

GLycogen

GlycogenGlycogenA storage form of glucoseA storage form of glucose

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Glycogen is stored in granules in the Glycogen is stored in granules in the

cytosolcytosol of primarily the liver and of primarily the liver and skeletal muscles.skeletal muscles.

Stores of GlycogenStores of GlycogenIn liverIn liver : :

10% of the fresh 10% of the fresh weight in the weight in the well-fedwell-fed adult liver (100g)adult liver (100g)

After 12-18 hrs of After 12-18 hrs of fasting ,almost fasting ,almost depleteddepleted

InIn skeletal skeletal musclemuscle : :

1-2 % of fresh weight of 1-2 % of fresh weight of resting muscle ( 400 g)resting muscle ( 400 g)

Depleted after Depleted after prolonged prolonged vigorous exercisevigorous exercise

Moderately decreased Moderately decreased by prolonged fasting by prolonged fasting (weeks)(weeks)

Liver glycogenLiver glycogen :is used to buffer the overall blood glucose levelbuffer the overall blood glucose level; glycogen is degraded (with the resulting glucose released into the blood stream) during the early stages of a fast.

MuscleMuscle :uses its glycogen stores for (ATP) energy during strenuous exercise.

ThusThus

Structure of GlycogenStructure of Glycogen

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– It is a highly branched –chain homopolysaccharidebranched –chain homopolysaccharide made from αα-D glucose-D glucose .

Amylose is the Amylose is the linear unbranchedlinear unbranched molecule molecule of glucosyl residues attached byof glucosyl residues attached by αα(1→4) (1→4) linkageslinkages..Glycogen Glycogen hashas branchesbranches located on average located on average eighteight

glucosyl residues resulting in highly branched glucosyl residues resulting in highly branched moleculemolecule which leads to :which leads to :

More solubleMore soluble Increase rate of degradation Increase rate of degradation Increase rate of synthesisIncrease rate of synthesis

Glycogenesis: Glycogenesis: Synthesis of Glycogen from GlucoseSynthesis of Glycogen from Glucose

Glycogenolysis:Glycogenolysis:Breakdown of Glycogen to Glucose-6-Breakdown of Glycogen to Glucose-6-phosphatephosphate

Metabolism of Glycogen in Skeletal Muscle

Glycogen Synthesis Glycogen Synthesis (Glycogenesis)(Glycogenesis)

Site : cytosolSite : cytosol It requires ATP &UTPIt requires ATP &UTP 1- Building blocks: 1- Building blocks: UDP-GLUCOSEUDP-GLUCOSE 2- 2- Initiation of synthesis Elongation of pre-existing glycogen fragment of pre-existing glycogen fragment OROR The use of a protein The use of a protein glycogen primer glycogen primer

((glycogenin)glycogenin) ((Glycogen synthase Glycogen synthase cannotcannot initiate synthesis but only initiate synthesis but only

elongates pre-existing glycogen fragment or glycogen elongates pre-existing glycogen fragment or glycogen primer (glycogenin)primer (glycogenin)

3- 3- ELONGATION: : Glycogen synthase Glycogen synthase ((for for 1-4 1-4 linkages) linkages)

4- BRANCHING: 4- BRANCHING: Branching enzyme Branching enzyme ((for for 1-6 linkages1-6 linkages

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Glycogen BreakdownGlycogen BreakdownGlycogenolysisGlycogenolysis

1- Shortening of glycogen chain: phosphorylase Cleaving of 1-4) bonds of the glycogen chain producing glucose 1-phosphate Glucose 1-phosphate is converted to glucose 6-phosphate (by mutase enzyme)

Pyridoxal phosphate(vit -B6

2- 2- Removal of branches Removal of branches : : byby debranching debranching enzymesenzymes

Cleaving of Cleaving of (1-6) bonds of the glycogen chain producing (1-6) bonds of the glycogen chain producing free glucose (few)free glucose (few)

3- Fate of glucose 6-phosphate (G-6-P):3- Fate of glucose 6-phosphate (G-6-P):

- G-6-P is - G-6-P is notnot converted to free glucose converted to free glucose - It is used as a source of energy for skeletal - It is used as a source of energy for skeletal

muscles during muscular exercise (by anaerobic muscles during muscular exercise (by anaerobic glycolysis starting from G-6-P step)glycolysis starting from G-6-P step)

( in case of liver glucose-6-phosphatase ( in case of liver glucose-6-phosphatase

converts G6P to glucoseconverts G6P to glucose

RegulationRegulation

Synthesis & degradation of glycogen are tightly regulated

In Skeletal Muscles: Glycogen degradation occurs during active exercise Glycogen synthesis begins when the muscle is at rest

Regulation occurs by 2 mechanisms:

Regulation of Glycogen Metabolism

1- Allosteric regulation

2- Hormonal regulation (Covalent modification)

Regulation ofRegulation of Glycogen Metabolism Glycogen Metabolism 1. Allosteric Regulation1. Allosteric Regulation

Regulation ofRegulation of Glycogen Glycogen Metabolism Metabolism

Increase of calcium during muscle contraction

Formation of Ca2+ -calmodulin complex

Activation of Ca2+ -dependent enzymes, e.g., glycogen phosphorylase

Regulation of Glycogen Metabolism: 2. Hormonal Regulation by Epinephrine

Muscle contractionEpinephrine release

Skeletal muscle: Epinephrine/receptor bindingSecond messenger: cAMP

Response: Enzyme phosphorylation

Glycogen synthase(Inactive form)

Inhibition of glycogenesis

Glycogen phosphorylase(Active form)

Stimulation of glycogenolysis

P P

Deficiency of skeletal muscle glycogen phosphorylaseDeficiency of skeletal muscle glycogen phosphorylase

Glycogen Storage DiseasesGlycogen Storage DiseasesGSD Type V (Mc Ardle Syndrome)GSD Type V (Mc Ardle Syndrome)

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