05 - Glycogen Metabolism

TARGET DECK: MED::I::Signaling Pathways in Health and Disease::Metabolic Biochemistry::05 - Glycogen Metabolism

Overview

Glycogen sits at the crossroads of carbohydrate metabolism:

$\text{Glycogen}\leftrightarrow \text{Glucose}\leftrightarrow \text{Glucose-6-phosphate}$

From glucose-6-phosphate, pathways diverge toward:

• Glycolysis / Gluconeogenesis → Pyruvate → Amino acids, Lactate, Acetyl-CoA
• Pentose phosphate pathway → Ribose-5-phosphate

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Tissue-Specific Regulation

Liver

Controls blood glucose homeostasis

• Insulin (post-meal) → promotes glycogen synthesis
• Glucagon (fasting) → promotes glycogenolysis

Muscle

Responds to local energy demands (within seconds)

• High ATP → glycogen synthesis
• Low ATP / contraction → glycogenolysis

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Glycogen Granule Structure

Glycogen granules in hepatocytes contain:

• Glycogen polymer
• Synthetic and degradative enzymes
• Regulatory machinery (kinases, phosphatases)

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Glycogen Synthesis (Glycogenesis)

Reaction Sequence

$\text{Glucose}+\text{ATP}\to \text{Glucose-6-P}+\text{ADP}$

$\text{Glucose-6-P}\to \text{Glucose-1-P}[\text{phosphoglucomutase}]$

$\text{Glucose-1-P}+\text{UTP}\to \text{UDP-glucose}+{\text{PP}}_i[\text{UDP-glucose pyrophosphorylase}]$

$\text{UDP-glucose}+{\text{Glycogen}}_n\to \text{UDP}+{\text{Glycogen}}_{n+1}[\text{glycogen synthase}]$

$\text{UDP}+\text{ATP}\to \text{UTP}+\text{ADP}[\text{NDPK}]$

${\text{PP}}_i+{\text{H}}_2\text{O}\to 2,{\text{P}}_i[\text{inorganic pyrophosphatase}]\Delta G^{\circ \prime }=-19.2\text{ kJ/mol}$

Why use UDP-glucose?

The anomeric carbon of glucose is activated by attachment to UMP via a phosphodiester bond.

This provides:

1. Irreversibility — PPi hydrolysis drives the reaction forward
2. A good leaving group for nucleophilic attack
3. A molecular tag marking glucose for glycogen synthesis

Why is UDP-glucose used in glycogen synthesis?

It activates glucose, provides a good leaving group, and makes the reaction effectively irreversible.

Nucleotide Interconversion Enzymes

Enzyme	Reaction
Adenylate kinase (myokinase)	$\text{AMP}+\text{ATP}\leftrightarrow 2,\text{ADP}$
Nucleoside monophosphokinase (NMPK)	$\text{NMP}+\text{ATP}\leftrightarrow \text{NDP}+\text{ADP}$
Nucleoside diphosphokinase (NDPK)	$\text{NDP}+\text{ATP}\leftrightarrow \text{NTP}+\text{ADP}$

Glycogen Synthase

Synthase ≠ Synthetase

• Glycogen synthase = glycosyltransferase; transfers glucose from UDP-glucose to glycogen
• Synthetase / Ligase uses ATP to condense two molecules: $A+B+\text{ATP}\to A\text{-}B+\text{ADP}+{\text{P}}_i$ $A+B+\text{ATP}\to A\text{-}B+\text{AMP}+{\text{PP}}_i$

Branching

Branching enzyme (transglycosylase) cleaves an $\alpha (1\to 4)$ bond and reforms it as an $\alpha (1\to 6)$ bond, creating branch points. This increases solubility and the number of non-reducing ends (= more sites for rapid synthesis/breakdown).

Glycogenin — The Primer

Glycogenin Glycogen synthesis requires a protein primer:

1. UDP-glucose forms a glycosidic bond with Tyr194 of glycogenin (self-glucosylation)
2. Seven more UDP-glucose units are added to build an oligosaccharide
3. Glycogen synthase then takes over for chain elongation

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Glycogenolysis

Reaction Sequence

${\text{Glycogen}}_n+{\text{P}}_i\to {\text{Glycogen}}_{n-1}+\text{Glucose-1-P}[\text{glycogen phosphorylase}]$

$\text{Glucose-1-P}\to \text{Glucose-6-P}[\text{phosphoglucomutase}]$

$\text{Glucose-6-P}+{\text{H}}_2\text{O}\to \text{Glucose}+{\text{P}}_i[\text{glucose-6-phosphatase — liver only}]$

De-branching uses a bifunctional debranching enzyme:

• Transferase activity: moves a trisaccharide from the branch to the main chain ($\alpha 1\to 4\to \alpha 1\to 4$)
• Glucosidase activity: hydrolyses the single remaining $\alpha (1\to 6)$ glucose → free glucose

What are the two activities of the glycogen debranching enzyme?

Transferase activity moves a trisaccharide to the main chain, and glucosidase activity removes the remaining α(1→6)-linked glucose.

Phosphorylase limitation

Glycogen phosphorylase can only cleave $\alpha (1\to 4)$ bonds and stalls 4 residues from a branch point. Debranching enzyme must act first.

How far from a branch point does glycogen phosphorylase stall?

Four residues from the branch point.

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Glycogen Phosphorylase

Key Sites

Site	Ligand / Modification	Effect
Active site	Glycogen + ${\text{P}}_i$	Catalysis
Allosteric site	AMP	Activation
Allosteric site	ATP, Glucose	Inhibition
Phosphorylation site (Ser14)	${\text{Ser-OPO}}_3^{2-}$ (form a)	Active
Phosphorylation site (Ser14)	$\text{Ser-OH}$ (form b)	Less active
Cofactor	Pyridoxal-5’-phosphate (PLP)	Required

Tissue-specific regulatory dominance

• Muscle: allosteric regulation (ATP/AMP) dominates → energy sensor
• Liver: phosphorylation dominates → blood glucose control

Interconversion of Forms

$\text{Phosphorylase b (less active)}\underset{\text{2 ATP}}{\overset{\text{phosphorylase kinase}}{\to }}\text{Phosphorylase a (active)}$

$\text{Phosphorylase a}\stackrel{\text{PP1 (phosphoprotein phosphatase-1)}}{\to }\text{Phosphorylase b}$

Glucose feedback in liver

In hepatocytes, glucose binds an allosteric site on phosphorylase a, inducing a conformational change that makes Ser14 more accessible to PP1 → dephosphorylation → inactivation. This auto-brakes glycogenolysis when blood glucose rises.

Hormonal Activation Cascade

$\text{Glucagon / Epinephrine}\to \text{adenylate cyclase}\to \text{ATP}\to \text{cAMP}+{\text{PP}}_i$

$\text{cAMP}\to \text{PKA (active)}$

$\text{PKA}+\text{Phosphorylase b kinase}\to \text{Phosphorylase b kinase-P (active)}$

$\text{Phosphorylase b kinase-P}+\text{Phosphorylase b}\to \text{Phosphorylase a (active)}$

$\text{Phosphorylase a}+{\text{Glycogen}}_n+{\text{P}}_i\to \text{Glucose-1-P}+{\text{Glycogen}}_{n-1}$

Signal amplification

This enzyme cascade provides massive amplification: each step multiplies the number of activated molecules. One glucagon receptor → many cAMP → many PKA → many phosphorylase kinase → many phosphorylase a → rapid glycogen breakdown.

PKA Activation by cAMP

Inactive PKA = $R_2{C}_2$ tetramer (2 regulatory + 2 catalytic subunits).

$R_2{C}_2+4,\text{cAMP}\to R_2(\text{cAMP}{)}_4+2,C_{\text{(active)}}$

cAMP binds regulatory subunits → they dissociate → free catalytic subunits are active.

Termination: cAMP phosphodiesterase (PDE) hydrolyses cAMP → 5’-AMP. PDE itself can be activated by PKA (feedback).

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Glycogen Synthase Regulation

Glycogen synthase (GS) exists in two forms:

Form	Phosphorylation	Activity
GS-a	Unphosphorylated	Active
GS-b	Phosphorylated	Inactive

GSK3 (Glycogen Synthase Kinase 3) phosphorylates → inactivates GS.

Insulin activates PKB (Akt) → PKB phosphorylates and inactivates GSK3 → GS stays active.

PP1 dephosphorylates both GS (activates) and glycogen phosphorylase (inactivates).

Which glycogen synthase form is active?

GS-a, the unphosphorylated form.

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Coordination of Glycogen Metabolism

Liver

Hormone	Phosphorylase	Glycogen Synthase	Net Effect
Insulin	Dephosphorylated → inactive	Dephosphorylated → active	Glycogen synthesis
Glucagon	Phosphorylated → active	Phosphorylated → inactive	Glycogen breakdown

Reciprocal regulation

Phosphorylase and synthase are always regulated in opposite directions— the cell never wastes energy cycling between synthesis and breakdown simultaneously.

What is the logic of reciprocal regulation in glycogen metabolism?

Glycogen synthase and glycogen phosphorylase are regulated in opposite directions so synthesis and breakdown do not occur at the same time.

Downstream Effects of Glucagon

Metabolic effect	Target enzyme
↑ Glycogenolysis	Glycogen phosphorylase
↓ Glycogen synthesis	Glycogen synthase
↓ Glycolysis	PFK-1
↑ Gluconeogenesis	FBPase-2, PEP carboxykinase, pyruvate kinase
↑ Fatty acid mobilization	Hormone-sensitive lipase
↑ Ketogenesis	Acetyl-CoA carboxylase

Glucose as a Direct Signal in Liver

High blood glucose → enters hepatocytes (GLUT2) → glucose-6-P accumulates → allosterically activates GS and inhibits phosphorylase.

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Glycogen Metabolism in Muscle

Key differences from liver

• Glucose uptake via GLUT4 (insulin-dependent)
• Phosphorylation by low-Km hexokinase
• No glucose-6-phosphatase → glucose-6-P cannot leave as free glucose; it feeds glycolysis only
• Regulation dominated by ATP/AMP ratio, not blood glucose

• At rest: high ATP → glycogen synthesis
• During contraction:
  • AMP accumulates → allosterically activates phosphorylase b
  • ${\text{Ca}}^{2+}$ activates phosphorylase b kinase (calmodulin subunit) → phosphorylase a
  • GS is simultaneously phosphorylated → inactive
  • Glucose-6-P flows exclusively into glycolysis

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ATP Production in Skeletal Muscle

Rapid ATP Recovery Systems

$2,\text{ADP}\stackrel{\text{adenylate kinase}}{\to }\text{ATP}+\text{AMP}$

$\text{Phosphocreatine}+\text{ADP}\stackrel{\text{creatine kinase}}{\to }\text{Creatine}+\text{ATP}$

Creatine kinase directionality

At rest (high ATP): $\text{ATP}+\text{Creatine}\to \text{ADP}+\text{Phosphocreatine}$ (stores energy)

During contraction (high ADP): $\text{Phosphocreatine}+\text{ADP}\to \text{Creatine}+\text{ATP}$ (releases energy)

Creatine:

OC(=O)CN(C)C(=N)N

 
Phosphocreatine:

OC(=O)CN(C)C(=N)NP(=O)(O)O

Sequential Activation During Exercise

1. Immediate (seconds): phosphocreatine buffer
2. Early (seconds–minutes): AMP → allosteric phosphorylase b activation
3. Sustained: ${\text{Ca}}^{2+}$ → phosphorylase b kinase → phosphorylase a
4. Hormonal (epinephrine): cAMP → PKA → full cascade

Physiological Effects of Epinephrine

Effect	Metabolic Consequence
↑ Heart rate, blood pressure	Increased O₂ delivery to tissues
↑ Glycogenolysis (muscle + liver)	More glucose for fuel
↓ Glycogen synthesis	Glucose not stored
↑ Gluconeogenesis (liver)	Sustained glucose supply
↑ Glycolysis (muscle)	More ATP for contraction
↑ Fatty acid mobilization	Alternative fuel
↑ Glucagon / ↓ Insulin	Reinforces metabolic effects

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Glycogen Storage Diseases

Clinical relevance

Defects in glycogen metabolism enzymes cause accumulation of abnormal glycogen or hypoglycemia, with tissue-specific consequences.

Type	Name	Enzyme Defect	Organ	Key Symptoms
0	—	Glycogen synthase	Liver	Hypoglycemia, high ketones, early death
Ia	Von Gierke	Glucose-6-phosphatase	Liver	Hepatomegaly, kidney failure
Ib	—	Microsomal G6P translocase	Liver	As Ia + susceptibility to infections
II	Pompe	Lysosomal glucosidase	Skeletal + cardiac muscle	Infantile: death by age 2; adult: muscular dystrophy-like
IIIa	Cori / Forbes	Debranching enzyme	Liver, skeletal + cardiac muscle	Hepatomegaly, myopathy
IV	Andersen	Branching enzyme	Liver, skeletal muscle	Hepatosplenomegaly, myoglobinuria
V	McArdle	Muscle phosphorylase	Skeletal muscle	Exercise cramps, myoglobinuria
VI	Hers	Liver phosphorylase	Liver	Hepatomegaly
VII	Tarui	Muscle PFK-1	Muscle, erythrocytes	As V + hemolytic anemia
VIII/IX	—	Phosphorylase kinase	Liver, leukocytes, muscle	Hepatomegaly
XI	Fanconi-Bickel	GLUT2	Liver	Failure to thrive, rickets, kidney dysfunction

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Exam-Type Question

Q: Reaction $\text{ATP}+\text{Creatine}\to \text{ADP}+\text{Creatine-P}$ proceeds left-to-right:
a. During muscle contraction
b. When the respiratory chain is uncoupled
c. In muscle at rest
d. If creatine kinase content is increased

Answer: C — at rest

• At rest, ATP is abundant → stored as phosphocreatine (left-to-right ✓)
• (a) During contraction, phosphocreatine donates phosphate to ADP → reaction runs right-to-left
• (b) Uncoupling = no ATP formed → ADP accumulates → reaction runs right-to-left
• (d) Enzyme amount never changes reaction direction, only rate

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TLDR - 05 - Glycogen Metabolism

Glycogen is a highly branched glucose polymer that serves as the primary carbohydrate reserve — in the liver for blood glucose homeostasis, and in muscle for rapid ATP production.

Synthesis (Glycogenesis)

Glucose is activated as UDP-glucose (irreversible, PPi hydrolysis drives it), then transferred onto glycogen by glycogen synthase (α1→4 bonds). Branching enzyme introduces α1→6 branch points. A protein primer, glycogenin, initiates the chain at Tyr194.

Breakdown (Glycogenolysis)

Glycogen phosphorylase cleaves α1→4 bonds phosphorolytically (releasing glucose-1-P, not free glucose). It stalls 4 residues from branch points; debranching enzyme (transferase + glucosidase activities) resolves branches and releases one free glucose per branch.

Regulation — the key principle

The two key enzymes are always regulated reciprocally:

State	Phosphorylase	Glycogen Synthase
Phosphorylated	Active (a)	Inactive (b)
Dephosphorylated	Less active (b)	Active (a)

Hormonal cascade: Glucagon/Epinephrine → adenylate cyclase → cAMP → PKA → phosphorylase b kinase → phosphorylase a (active) + GS-b (inactive) → glycogenolysis.

Insulin reverses this: activates PKB → inactivates GSK3 → GS stays active; activates PP1 → dephosphorylates both enzymes → glycogen synthesis.

Tissue differences

	Liver	Muscle
Primary role	Blood glucose buffer	Local ATP supply
Glucose transporter	GLUT2	GLUT4
Glucose-6-phosphatase	✅ (releases free glucose)	❌ (glucose-6-P → glycolysis only)
Dominant regulator	Hormonal (glucagon/insulin)	Energy charge (ATP/AMP, Ca²⁺)

ATP buffers in muscle (fastest to slowest)

1. Phosphocreatine → immediate (seconds)
2. Glycogenolysis → allosteric (AMP) + Ca²⁺ → phosphorylase a
3. Epinephrine cascade → cAMP → PKA → full hormonal activation

Glycogen storage diseases

Enzyme defects in the glycogen metabolism pathway cause accumulation of abnormal glycogen or hypoglycemia. Key examples: Von Gierke (no G6Pase → hepatomegaly + hypoglycemia), Pompe (no lysosomal glucosidase → cardiomyopathy), McArdle (no muscle phosphorylase → exercise intolerance + myoglobinuria).