18. Regulation of Glycolysis and Gluconeogenesis Pathways. Organ Specificity.

Regulation of Glycolysis and Gluconeogenesis

1. Core Concept

• Glycolysis and Gluconeogenesis are reciprocal pathways.
• They do not run at full speed simultaneously → this would cause a futile cycle and waste ATP.
• Regulation ensures only one pathway is dominant at a time, depending on:
• Energy needs of the cell
• Hormonal signals
• Substrate availability
• Organ-specific roles

Key Regulatory Molecules (Central Switch)

Fructose-2,6-bisphosphate (F2,6BP)

• Most powerful regulator balancing the two pathways.
• Increases Glycolysis by activating PFK-1.
• Inhibits Gluconeogenesis by inhibiting Fructose-1,6-bisphosphatase.
• Level of F2,6BP is regulated by insulin and glucagon.

Hormonal Regulation

Insulin (Fed State)

• Released when blood glucose is high.
• Promotes glycolysis.
• Inhibits gluconeogenesis.
• Increases F2,6BP → enhances PFK-1 activity.

Glucagon (Fasting State)

• Released when blood glucose is low.
• Promotes gluconeogenesis.
• Inhibits glycolysis.
• Decreases F2,6BP → reduces PFK-1 activity.

Energy Charge Regulation

• High ATP / High Citrate
• Means energy is sufficient.
• Inhibits glycolysis (slows down energy production).
• Stimulates gluconeogenesis.
• High AMP / ADP
• Shows energy deficiency.
• Stimulates glycolysis (need ATP).
• Inhibits gluconeogenesis (expensive ATP process).

Enzyme-Level Regulation

Glycolysis Key Enzymes

• Hexokinase / Glucokinase
• Hexokinase inhibited by glucose-6-phosphate.
• Glucokinase active only when blood glucose is high (liver stores or consumes glucose after meals).
• Phosphofructokinase-1 (PFK-1) – Rate-limiting for glycolysis
• Activated by AMP and F2,6BP.
• Inhibited by ATP and citrate.
• Pyruvate Kinase
• Activated by F1,6BP (feed-forward).
• Inhibited by ATP and alanine.
• Glucagon inactivates liver pyruvate kinase via phosphorylation.

Gluconeogenesis Key Enzymes

• Pyruvate Carboxylase
• Activated by Acetyl-CoA → signals fatty acid oxidation energy supply.
• PEP Carboxykinase (PEPCK)
• Upregulated by glucagon and cortisol.
• Increased transcription during fasting or stress.
• Fructose-1,6-bisphosphatase
• Inhibited by AMP and F2,6BP.
• This is the opposite of PFK-1 regulation, ensuring reciprocal activity.
• Glucose-6-phosphatase
• Present only in liver and kidney → allows release of glucose into blood.

Organ Specificity

Liver

• Main regulator of blood glucose.
• Performs both glycolysis and gluconeogenesis, depending on fed vs fasting state.
• Fed (Insulin high) → Glycolysis ON.
• Fasting (Glucagon high) → Gluconeogenesis ON.

Skeletal Muscle

• Performs glycolysis for its own energy needs.
• Cannot perform gluconeogenesis (no Glucose-6-phosphatase).
• Does not release glucose into blood, only uses it locally.

Adipose Tissue

• Uses glycolysis to generate glycerol-3-phosphate for triglyceride synthesis.

Brain

• Very high demand for glucose via glycolysis.
• Does not perform gluconeogenesis.

Red Blood Cells

• Only do anaerobic glycolysis (lack mitochondria).
• Produce lactate, which is sent to liver for Cori Cycle → supports gluconeogenesis.

Kidney

• Performs gluconeogenesis mainly during prolonged fasting (up to 40% of glucose made here).
• Uses glutamine as a major substrate.