Glucose and Glycogen Metabolism

Learning Outcomes

• Draw the structures of glucose and glycogen.

• Outline the metabolic events for the conversion of glucose to pyruvate in the glycolysis pathway.

• Explain the formation of ATP from ADP by substrate-level phosphorylation.

• Describe the regeneration of NAD+ from NADH under aerobic and anaerobic conditions, and the role of lactate dehydrogenase in muscle, etc.

• Give an example of a control mechanism in the regulation of glycolysis.

• Summarise the roles of glycolysis in different tissues (e.g., red blood cells).

Structure and Function of Glucose and Glycogen

Glucose

• Monosaccharide (C6H12O6), primary energy source for cells.

• Approximately 10 g in plasma; highly osmotically active.

• Immediate energy source for cellular metabolism.

Glycogen

• Polysaccharide (branched polymer of glucose).

• Approximately 400 g stored in tissues (mainly liver and muscle).

• Low osmolarity; serves as a medium-term energy reserve.

Glycogen Structure

• Highly branched, with α-1,4 glycosidic bonds in the linear chains and α-1,6 glycosidic bonds at branch points.

• Branching increases solubility and allows rapid release of glucose units.

Role of Glycogen in Liver and Muscle

• Liver: Maintains blood glucose homeostasis (100–120 g stored); sensitive to blood glucose concentration; regulated by insulin and glucagon.

• Muscle: Provides energy for contraction during exercise (250–300 g stored); sensitive to energy needs and regulated by adrenaline, calcium, AMP, and ATP.

Glycogen Synthesis and Breakdown

Glycogen Synthesis (Glycogenesis)

• Catalyzed by glycogen synthase.

• Requires energy (ATP hydrolysis).

• Proceeds via an 'activated' intermediate: UDP-glucose.

Glycogen Breakdown (Glycogenolysis)

• Catalyzed by glycogen phosphorylase.

• Phosphorolysis using inorganic phosphate (Pi), not ATP.

• Final product in liver: glucose; in muscle: glucose-6-phosphate (enters glycolysis).

Note: Synthesis and breakdown are not simple reversals, allowing independent regulation and preventing a futile cycle.

Key Steps in Glycogen Metabolism

• Activation of Glucose: Glucose is phosphorylated to glucose-6-phosphate (by hexokinase in muscle, glucokinase in liver), then converted to glucose-1-phosphate, and finally to UDP-glucose.

• Glycogen Synthase Reaction: UDP-glucose is added to the growing glycogen chain; branching enzyme forms α-1,6 bonds.

• Glycogen Phosphorylase Reaction: Removes glucose units as glucose-1-phosphate; debranching enzyme breaks α-1,6 bonds.

• Glucose-6-phosphatase: Only present in liver and kidney, allowing free glucose release into blood.

Regulation of Glycogen Metabolism

• Allosteric control: Enzyme activity modulated by metabolites (e.g., ATP, AMP).

• Hormonal control: Hormones (glucagon/adrenaline) activate cell surface receptors, triggering internal signaling cascades (e.g., protein kinase activation) that regulate glycogen synthase and phosphorylase.

Glycolysis

Key Points

• Definition: Conversion of glucose (C6) to 2 pyruvate (C3).

• Location: Cytosol (10 soluble enzymes).

• Tissues: All tissues perform glycolysis.

• Functions: ATP synthesis (energy trapping), provides intermediates for fat and amino acid synthesis.

Sources of Glucose for Glycolysis

• Dietary sugars and starch.

• Breakdown of stored glycogen (mainly liver).

• Recycled glucose (from lactic acid, amino acids, or glycerol).

Overview of Glycolysis Pathway

• 10 reactions grouped into 4 stages:

  1. Activation (uses ATP)

  2. Splitting the 6C sugar into two 3C units

  3. Oxidation (removal of 2H atoms, NAD+ to NADH)

  4. Synthesis of ATP (substrate-level phosphorylation)

Activation Stages of Glycolysis

• Reaction 1: Glucose → Glucose-6-phosphate (Hexokinase/Glucokinase, uses ATP)

• Reaction 2: Glucose-6-phosphate → Fructose-6-phosphate (Phosphohexose isomerase)

• Reaction 3: Fructose-6-phosphate → Fructose-1,6-bisphosphate (Phosphofructokinase, uses ATP; key regulatory step)

Splitting and Rearrangement

• Reaction 4: Fructose-1,6-bisphosphate → Glyceraldehyde-3-phosphate + Dihydroxyacetone phosphate (Aldolase)

• Reaction 5: Dihydroxyacetone phosphate ↔ Glyceraldehyde-3-phosphate (Triose phosphate isomerase)

Oxidation and ATP Synthesis Steps

• Reaction 6: Glyceraldehyde-3-phosphate + NAD+ + Pi → 1,3-Bisphosphoglycerate + NADH + H+ (Glyceraldehyde-3-phosphate dehydrogenase)

• Reaction 7: 1,3-Bisphosphoglycerate + ADP → 3-Phosphoglycerate + ATP (Phosphoglycerate kinase; substrate-level phosphorylation)

• Reaction 8: 3-Phosphoglycerate → 2-Phosphoglycerate (Phosphoglycerate mutase)

• Reaction 9: 2-Phosphoglycerate → Phosphoenolpyruvate (Enolase)

• Reaction 10: Phosphoenolpyruvate + ADP → Pyruvate + ATP (Pyruvate kinase; substrate-level phosphorylation, irreversible)

ATP Yield from Glycolysis

• Early stages consume 2 ATP.

• Later stages produce 4 ATP (net gain: 2 ATP per glucose).

• 2 NADH produced (potential for further ATP via oxidative phosphorylation).

Anaerobic Glycolysis

• When O2 is limited, pyruvate is converted to lactate to regenerate NAD+ for glycolysis.

• Reaction:

• Catalyzed by lactate dehydrogenase; reversible reaction.

Metabolic Fates of Pyruvate

• Aerobic conditions: Pyruvate → Acetyl CoA → Citric acid cycle → CO2

• Anaerobic conditions: Pyruvate → Lactate (in animals) or Ethanol (in microorganisms)

• Excess calories: Pyruvate can be converted to fatty acids.

Regulation of Glycolysis

• Allosteric control: Key enzyme is phosphofructokinase (PFK).

• ATP acts as an allosteric inhibitor; AMP and ADP act as activators.

• Feedback inhibition ensures glycolysis matches cellular energy needs.

Specialised Functions in Tissues

• Skeletal muscle: Rapid ATP production during intense exercise.

• Red blood cells: Glycolysis is the only ATP source (no mitochondria).

• Brain: Major ATP source; cannot use fats as fuel due to the blood-brain barrier and lack of β-oxidation enzymes.

Summary of Glycolysis

• Main catabolic pathway for glucose in all tissues.

• Only pathway that can yield energy under both aerobic and anaerobic conditions.

• Net yield: 2 ATP per glucose (plus potential ATP from NADH in mitochondria).

• Provides intermediates for biosynthetic pathways (e.g., fats, amino acids).

The Warburg Effect

• Tumor cells preferentially use anaerobic glycolysis, producing lactate even when oxygen is present (aerobic glycolysis).

• Lactate production can be up to 200x higher than in healthy cells.

• Function is still under investigation; may be useful for diagnosis or therapy.

Table: Hexokinase vs Glucokinase

Additional info: Hexokinase is adapted for low glucose concentrations, ensuring all tissues can phosphorylate glucose. Glucokinase acts as a glucose sensor in the liver, functioning efficiently at higher glucose concentrations.

Sample Multiple Choice Questions (MCQs)

1. What are the end products of glycolysis under aerobic and anaerobic conditions?

   • A. carbon dioxide and lactate

   • B. acetyl CoA and lactate

   • C. pyruvate and lactate

   • D. pyruvate and acetyl CoA

   • E. acetyl CoA and pyruvate

2. In which three cell types is the glycolysis pathway of particular importance?

   • A. Brain, skeletal muscle, and red blood cells

   • B. Adipose tissue, skeletal muscle, and red blood cells

   • C. Brain, liver, and red blood cells

   • D. Liver, skeletal muscle, and red blood cells

   • E. Brain, liver, and skeletal muscle

3. The net yield of ATP from anaerobic glycolysis is:

   • A. 1 ATP per glucose molecule

   • B. 2 ATP per glucose molecule

   • C. 4 ATP per glucose molecule

   • D. 6 ATP per glucose molecule

   • E. 8 ATP per glucose molecule

4. Which two reactions in glycolysis result in direct production of ATP by substrate level phosphorylation? Those catalysed by:

   • A. hexokinase and pyruvate kinase

   • B. aldolase and pyruvate kinase

   • C. 3-phosphoglycerate kinase and pyruvate kinase

   • D. hexokinase and 3-phosphoglycerate kinase

   • E. aldolase and 3-phosphoglycerate kinase