Glycogen Metabolism: A Comprehensive Analysis of Breakdown, Synthesis, and Regulation, Schemes and Mind Maps of Enzymes and Metabolism

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Glycogen Metabolism

Glycogen Breakdown Glycogen Synthesis

Control of Glycogen Metabolism

Glycogen Storage Diseases

Glycogen

Glycogen - animal storage glucan

100- to 400-Å-diameter cytosolic granules

up to 120,000 glucose units

α(1 → 6) branches every 8 to 12 residues

muscle has 1-2% (max) by weight

liver has 10% (max) by weight

~12 hour supply

Although metabolism of fat provides more energy:

1. Muscle mobilize glycogen faster than fat
2. Fatty acids of fat cannot be metabolized anaerobically
3. Animals cannot convert fatty acid to glucose (glycerol can be converted to glucose)

Glycogen Breakdown

Glycogen debranching enzyme - possesses two activities

α(1 → 4) transglycosylase (glycosyl transferase) 90% glycogen → glucose-1-phosphate

transfers trisaccharide unit from "limit branch" to nonreducing end of another branch

α(1 → 6) glucosidase 10% glycogen → glucose

Debranching activity < phosphorylase activity

Glycogen Breakdown

Phosphoglucomutase - a phosphoenzyme (Ser)

reaction similar to that of phosphoglycerate mutase

formation of glucose-1,6-bisphosphate (required for full activity)

phosphoglucokinase - provides product

glucose-1-phosphate + ATP → glucose-1,6-bisphosphate

Glycogen Synthesis

Three enzymes: UDP-glucose pyrophosphorylase glycogen synthase glycogen branching enzyme

UDP-glucose pyrophosphorylase - phosphoanhydride exchange

Glucose-1-phosphate + UTP UDP-glucose + PP (^) i ∆G˚' = 0 kJ.^ mol- H 2 O + PPi → 2P (^) i ∆G˚' = -33.5 kJ.mol-

Common biosynthetic strategy generates:

glucose-1-phosphate + UTP → UDP-glucose + 2P (^) i ∆G˚' = -33.5 kJ.mol-

Glycogen Synthesis

Glycogen synthase - adds glycosyl unit from UDP-glucose to form α(1 → 4) glycosidic bonds

Glycogen Primer:

glycogenin - protein to which glucose is added to Tyr residue by tyrosine glucosyltransferase

autocatalytically extends chain up to 7 glucose residues by UDP-glucose

glycosyl oxonium ion intermediate (similar to phosphorylase and lysozyme mechanisms)

Note:

glycogen breakdown (∆G˚' = -5 to -8 kJ.^ mol-1)

and

glycogen synthesis (∆G˚' = -13.4 kJ.mol-1)

are thermodynamically favorable processes

The cost of controlling both is the hydrolysis of UTP (similar to ATP)!

Control of Glycogen Metabolism

Glycogen phosphorylase and glycogen synthase: allosteric control substate cycling covalent modification of activity (under hormonal control)

Direct allosteric control of glycogen phosphorylase and glycogen synthase

Precise flux control by having two opposing enzymes at a control step (far from equilibrium) in a pathway

Glycogen phosphorylase activated by AMP inhibited by ATP and glucose-6-phosphate

Glycogen synthase activated by glucose-6-phosphate

High demand for ATP: glycogen breakdown low [ATP], low [G6P], high [AMP] glycogen phosphorylase stimulated glycogen synthase inhibited

Low demand for ATP: glycogen synthesis high [ATP], high [G6P], low [AMP] glycogen phosphorylase inhibited glycogen synthase stimulated

Control of Glycogen Metabolism

Covalent modification of enzymes by cyclic cascades

Features:

1. Respond to greater number of stimuli
2. Greater flexibility in control patterns
3. Amplification potential in response to effector concentrations

Small change in [allosteric effector] of a modifying enzyme → large change in [active, modified target enzyme]

Cyclic cascades nomenclature:

a - more active target enzyme b - less active target enzyme m - modified enzyme form o - original (unmodified) enzyme form

Recall that the rate of reaction = k[E (^) active][S]

Using a mathematical model (beyond the scope of this course) we could show quantitatively how changes in [effectors] modulate [E (^) active]

so a cyclic cascade allows an effector signal to be amplified

Control of Glycogen Metabolism

Glycogen synthase bicyclic cascade

Not as well understood

Two forms of enzyme:

m -glycogen synthase b (inactive)

allosterically controlled - inhibited by ATP, ADP, P (^) i overcome by [glucose-6-phosphate] > 10 mM (rare)

o -glycogen synthase a (active)

deactivated by calmodulin-dependent protein kinase, protein kinase C, glycogen synthase kinase-

Control of Glycogen Metabolism (What the book does not illustrate)

Integration of glycogen metabolism control mechanisms

Maintenance of blood glucose levels - liver buffers [glucose] ~ 5 mM

The Cast

Hormones Glucagon - polypeptide (liver) Insulin - polypeptide (muscle, other tissues) Epinephrine - adrenal

Second messengers Ca 2+ Inositol-1,4,5-triphosphate (IP 3 ) - lipid-derived Diacylglycerol (DAG) - lipid-derived

Phospholipase C - cleaves membrane lipid (phosphatidylinositol-4,5-bisphosphate, PIP 2 ) to generate IP 3 and DAG

Receptors β-Adrenergic - binds adrenal hormones α-Adrenergic - binds adrenal hormones Glucagon Insulin

Control of Glycogen Metabolism

Maintenance of blood glucose levels

Hexokinase:

Michaelis-Menten kinetics

high glucose affinity (Km ~ 0.1 mM)

inhibited by glucose-6-phosphate

Glucokinase:

monomeric

Sigmoidal kinetics (Hill constant of 1.5)

lower glucose affinity (K0.5 ~5 mM)

not inhibited by physiological [glucose-6-phosphate]

inhibited by glucokinase regulatory protein + fructose-6- phosphate

Control of Glycogen Metabolism

Maintenance of blood glucose levels

Flux control by substrate cycle and covalent modification system

Phosphofructokinase-1 (PFK-1) - allosterically activated by fructose-2,6-bisphosphate

Fructose-1,6-bisphosphatase-1 (FBPase-1) - allosterically inhibited by fructose-2,6-bisphosphate

Phosphofructokinase-2 (PFK-2)/fructose-2,6- bisphosphatase-2 (FBPase-2):

Bifunctional homodimeric protein phosphorylated (inactive)/dephosphorylated (active)

In liver - breakdown glycogen, release glucose into blood or take up glucose, synthesize glycogen

In heart - glycogen breakdown, increase glycolysis (different PFK-2/FBPase-2 gene)

In muscle - no phosphorylation site on enzyme, no cAMP- dependent phosphorylation control

Control of Glycogen Metabolism

Epinephrine

cAMP

Liver cell

ββββ

Glucagon^ Insulin

fructose-6-phosphate

Protein kinase A

fructose-2,6-bisphosphate glucose

fructose-6-phosphate

fructose-1,6-bisphosphate pyruvate

FBPase-1 PFK-

PFK-2 b FBPase-2 a

PFK-2 a FBPase-2 b

Phosphoprotein phosphatase

- +

AMP

Control of Glycogen Metabolism

Epinephrine

cAMP

Heart tissue

ββββ

Glucagon Insulin

fructose-6-phosphate

Protein kinase A

fructose-2,6-bisphosphate

glucose

fructose-6-phosphate

fructose-1,6-bisphosphate

pyruvate

FBPase-1 PFK-

PFK-2 a FBPase-2 b

PFK-2 b FBPase-2 a

Phosphoprotein phosphatase