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Glycogen Metabolism

Source: Biochemistry, 8th ed - Lippincott Illustrated Reviews; Basic Medical Biochemistry - A Clinical Approach, 6e

Introduction

Glycogen is the storage form of glucose in the human body. A constant supply of blood glucose is essential for life - particularly for the brain (which almost exclusively uses glucose) and for red blood cells (which have no mitochondria). When dietary glucose is unavailable, stored glycogen is rapidly mobilized to maintain blood glucose levels.

Two main storage sites:

Liver glycogen (~100 g, up to 10% of liver weight) - maintains blood glucose during fasting
Skeletal muscle glycogen (~400 g, 1-2% of muscle weight) - provides energy for contracting muscle via glycolysis

Structure of Glycogen

Glycogen is a highly branched homopolysaccharide made exclusively of α-D-glucose units joined by:

α(1→4) glycosidic bonds - forming the linear chains
α(1→6) glycosidic bonds - at branch points, occurring approximately every 8-10 glucose residues

The branched structure is important because it:

Increases the solubility of glycogen
Provides multiple non-reducing ends simultaneously for rapid synthesis and degradation

Part A: GLYCOGENESIS (Glycogen Synthesis)

Glycogenesis occurs in the cytosol and requires energy from ATP and UTP.

Step 1: Formation of Glucose 6-Phosphate

Glucose + ATP → Glucose 6-phosphate + ADP (catalyzed by hexokinase in muscle or glucokinase in liver)

Step 2: Formation of Glucose 1-Phosphate

Glucose 6-phosphate → Glucose 1-phosphate Enzyme: Phosphoglucomutase (glucose 1,6-bisphosphate is an obligatory intermediate)

Step 3: Formation of UDP-Glucose (Activated Glucose)

Glucose 1-phosphate + UTP → UDP-glucose + PPi Enzyme: UDP-glucose pyrophosphorylase

Pyrophosphate (PPi) is immediately hydrolyzed to 2 Pi by pyrophosphatase, making the reaction irreversible and pulling it forward.
UDP-glucose is the active/donor form of glucose for glycogen synthesis.

Step 4: Primer Requirement - Glycogenin

Glycogen synthase cannot initiate a new chain on free glucose. It requires a primer of at least 4 glucose residues. The primer is provided by the protein glycogenin, which:

Is a self-glycosylating enzyme
Attaches the first glucose from UDP-glucose to its own tyrosine residue
Elongates the chain to 7-8 residues to create the primer

Step 5: Chain Elongation by Glycogen Synthase

Glycogen synthase adds glucose residues from UDP-glucose to the non-reducing ends of the growing glycogen chain, forming α(1→4) bonds
This is the key regulatory enzyme of glycogenesis
UDP is released with each addition

Step 6: Branch Formation by Branching Enzyme

When a chain reaches ~11 glucose units, the branching enzyme (amylo-α(1→4)→α(1→6)-transglycosylase / 4:6 transferase) acts
It transfers a block of 6-8 glucosyl residues from the non-reducing end (breaking an α[1→4] bond) and creates an α(1→6) linkage on an internal residue of the same or adjacent chain
The new branch point must be at least 4 residues from the nearest existing branch

Part B: GLYCOGENOLYSIS (Glycogen Degradation)

Glycogenolysis is not the simple reversal of glycogenesis - it is a distinct pathway with different enzymes.

Step 1: Action of Glycogen Phosphorylase

Glycogen phosphorylase cleaves the α(1→4) bonds at the non-reducing ends of glycogen chains by phosphorolysis (using inorganic phosphate, not water)
Product: Glucose 1-phosphate + shortened glycogen chain
This reaction is energetically favorable as it releases glucose already phosphorylated (no ATP needed)
Important: Phosphorylase stops 4 glucose residues away from a branch point, producing a limit dextrin

Step 2: Action of Debranching Enzyme (2 activities)

The debranching enzyme (α(1→4)→α(1→4)-glucan transferase + amylo-α(1→6)-glucosidase) has two catalytic activities on one protein:

Transferase activity: Transfers 3 of the remaining 4 glucose residues from the branch to another chain end (re-forming α[1→4] linkages), exposing the single glucose at the branch point
Glucosidase activity: Hydrolyzes the α(1→6) bond at the branch point, releasing free glucose (not glucose 1-phosphate)

~90% of glucose from glycogenolysis is released as glucose 1-phosphate
~10% is released as free glucose (from branch points)

Step 3: Phosphoglucomutase

Glucose 1-phosphate → Glucose 6-phosphate
Enzyme: Phosphoglucomutase (same enzyme used in glycogenesis, but running in reverse)

Step 4: Fate of Glucose 6-Phosphate

This is where liver and muscle differ critically:

Tissue	Enzyme	Product	Purpose
Liver	Glucose 6-phosphatase (in ER)	Free glucose	Released into blood to maintain glycemia
Muscle	No glucose 6-phosphatase	Enters glycolysis	Provides ATP for muscle contraction

This is why muscle glycogen cannot maintain blood glucose - muscle lacks glucose 6-phosphatase.

Part C: REGULATION OF GLYCOGEN METABOLISM

Glycogen synthesis and degradation are reciprocally regulated by two mechanisms:

Hormonal regulation (covalent modification - phosphorylation/dephosphorylation)
Allosteric regulation (by metabolite effectors)

Hormonal Regulation

During Fasting / Stress - Glucagon & Epinephrine promote Glycogenolysis

Cascade (cAMP-dependent pathway):

Glucagon (liver) or Epinephrine (liver + muscle) bind to G-protein coupled receptors (GPCRs)
Activated Gs protein stimulates adenylyl cyclase → cAMP ↑
cAMP binds regulatory subunits of Protein Kinase A (PKA) → releases active catalytic subunits
PKA phosphorylates phosphorylase kinase b → phosphorylase kinase a (active)
Phosphorylase kinase a phosphorylates glycogen phosphorylase b → glycogen phosphorylase a (active) → Glycogenolysis begins
PKA also phosphorylates glycogen synthase (active form) → inactive form → Glycogenesis is inhibited

This cascade provides signal amplification: a few hormone molecules activate thousands of phosphorylase molecules.

Calcium/Calmodulin mechanism (in muscle): Nerve impulses trigger Ca²⁺ release. Ca²⁺ binds calmodulin (a subunit of phosphorylase kinase), directly activating the kinase - this links muscle contraction to glycogenolysis, even without hormonal input.

During Fed State - Insulin promotes Glycogenesis

Insulin activates Protein Phosphatase 1 (PP-1)
PP-1 dephosphorylates enzymes:
- Glycogen synthase (inactive) → active → Glycogenesis stimulated
- Glycogen phosphorylase a → b (inactive) → Glycogenolysis inhibited
- Phosphorylase kinase a → b (inactive)

Allosteric Regulation

Effector	Tissue	Effect on Phosphorylase	Effect on Synthase
AMP ↑	Muscle	Activates (phosphorylase b→active)	-
ATP, Glucose 6-P	Muscle	Inhibits phosphorylase b	Activates synthase
Glucose	Liver	Inhibits phosphorylase a	-
Glucose 6-P	Liver	-	Activates synthase

Rationale: In exercising muscle, ATP falls and AMP rises, directly activating glycogenolysis via allosteric mechanism - independent of hormones, providing rapid local response.

Part D: GLYCOGEN STORAGE DISEASES (GSDs)

Deficiencies of enzymes of glycogen metabolism lead to glycogen storage diseases (GSDs). Key examples for exams:

Type	Disease	Enzyme Deficient	Organ	Key Features
Type I	Von Gierke disease	Glucose 6-phosphatase	Liver, kidney	Severe fasting hypoglycemia, hepatomegaly, lactic acidosis
Type II	Pompe disease	Lysosomal α-glucosidase (acid maltase)	All organs	Cardiomegaly, hypotonia, death in infancy
Type III	Cori/Forbes disease	Debranching enzyme	Liver, muscle	Mild hypoglycemia, short outer chains in glycogen
Type IV	Andersen disease	Branching enzyme	Liver	Hepatosplenomegaly, long outer chains, often fatal
Type V	McArdle disease	Muscle phosphorylase	Skeletal muscle	Exercise intolerance, cramps, myoglobinuria; no rise in blood lactate after exercise
Type VI	Hers disease	Liver phosphorylase	Liver	Hepatomegaly, mild hypoglycemia, good prognosis

Summary Diagram (Key Points)

GLYCOGENESIS (Fed state, Insulin ↑):
Glucose → G6P → G1P → UDP-Glucose → Glycogen
Key enzymes: Hexokinase, Phosphoglucomutase, UDP-glucose pyrophosphorylase, 
             Glycogenin (primer), Glycogen synthase (α1→4), Branching enzyme (α1→6)

GLYCOGENOLYSIS (Fasting, Glucagon/Epinephrine ↑):
Glycogen → G1P → G6P → Glucose (liver) or Glycolysis (muscle)
Key enzymes: Glycogen phosphorylase (α1→4), Debranching enzyme (α1→6 + transferase),
             Phosphoglucomutase, Glucose 6-phosphatase (liver only)

Key Exam Points to Remember

UDP-glucose is the activated form (glucose donor) in glycogenesis
Glycogen synthase makes α(1→4) bonds; Branching enzyme makes α(1→6) bonds
Glycogen phosphorylase breaks α(1→4) bonds by phosphorolysis (Pi, not H₂O)
Debranching enzyme has two activities on one protein; releases free glucose at branch points
Liver has glucose 6-phosphatase; muscle does not - this explains the different physiological roles
Glucagon/Epinephrine → cAMP → PKA → phosphorylates phosphorylase (active) and synthase (inactive) - reciprocal control
Insulin → PP-1 → dephosphorylates enzymes - reverses the above
Von Gierke (Type I GSD) = G6-phosphatase deficiency = cannot release glucose from liver
McArdle (Type V GSD) = muscle phosphorylase deficiency = exercise intolerance

References: Biochemistry, 8th ed - Lippincott Illustrated Reviews, Ch. 11; Basic Medical Biochemistry - A Clinical Approach, 6e, Ch. 26

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