s2lec6 - glycogenesis

Chapter 1: Introduction to Gluconeogenesis

  • Importance of Fatty Acids

    • Mobilization of fatty acids occurs to meet demands of tissues, including skeletal muscle.

    • Gluconeogenesis starts after meals and peaks at about 1-2 days post meal.

    • The body can sustain itself without food for extended periods; e.g., hunger strike lasting 150 days.

    • Brain requires glucose; gluconeogenesis primarily supports brain function.

  • Biochemical Pathways

    • No biochemical pathways are entirely reversible.

    • Key irreversible steps exist that cannot change direction due to Gibbs free energy (delta G).

    • Essential pathways include:

      • Conversion of glucose to pyruvate and back is inefficient due to three irreversible steps.

      • Mechanisms exist to work around these steps, requiring energy input from ATP.

  • Energetics of Pathways

    • Gluconeogenesis costs more ATP (and GTP) than glycolysis generates.

    • Overall delta G for gluconeogenesis is -38 kJ/mol versus +84 kJ/mol for reverse glycolysis.

  • Regulatory Mechanisms

    • To prevent futile cycles (making and breaking glucose continuously), regulation occurs mainly at irreversible steps.

    • Carbon sources for gluconeogenesis include lactate, amino acids, and glycerol.

Chapter 2: Glucose to Phosphate Regulation

  • Pathway Interconnections

    • High AMP levels signal low ATP and switch on glycolysis, increasing ATP production.

    • Fatty acid oxidation leads to increased citrate, inhibiting glycolysis.

    • Protein intake raises amino acids (like alanine), which inhibit glycolysis.

  • Glycolysis and Gluconeogenesis Bypasses

    • Three key bypass reactions in gluconeogenesis include processes going from pyruvate to phosphoenolpyruvate.

    • Gluconeogenesis primarily occurs in the liver, which has glucose-6-phosphatase to export glucose into the blood.

    • Lactate from glycolysis generates NAD+ for further glucose production in the liver via the Cori cycle.

    • Glycerol can be converted into gluconeogenic intermediates via dihydroxyacetone phosphate.

Chapter 3: Chain of Glucose - Glycogen Metabolism

  • Glycogen Structure and Function

    • Glycogen is a branched polymer of glucose composed of alpha-1,4 and alpha-1,6 glycosidic linkages.

    • Glycogen is stored primarily in the liver; provides energy during fasting.

  • Synthesis of Glycogen

    • Key enzymes include glycogen synthase (adds glucose) and branching enzyme (creates branches).

    • Regulation of glycogen synthase is critical; it’s the main enzyme responsible for glycogen synthesis.

    • Activation involves phosphorylation of glucose by UTP to form UDP-glucose, which is then incorporated into glycogen.

Chapter 4: New Glucose Molecules

  • Entry Pathways for Glucose

    • Glycolysis uses glucose to form glucose-6-phosphate, which can enter pathways either for glucose or glycogen.

    • Regulation of where glucose goes depends on tissue needs and metabolic signals.

  • Utilization of Amino Acids and Lactate

    • Lactate, amino acids, and glycerol feed into gluconeogenesis, particularly during fasting to maintain glucose levels.

    • Amino acid contribution to gluconeogenesis emphasizes the loss of muscle mass in prolonged fasting.

Chapter 5: Phosphate to Glucose - Glycogen Breakdown

  • Glycogen Degradation

    • Glycogen phosphorylase cleaves glucose from glycogen via inorganic phosphate, producing glucose-1-phosphate.

    • The debranching enzyme facilitates the removal of branches and converts residues appropriately for glucose release.

    • Phosphoglucomutase converts glucose-1-phosphate back to glucose-6-phosphate which can then be dephosphorylated to free glucose.

  • Key Regulatory Enzymes

    • Glycogen phosphorylase is a major enzyme involved in the breakdown and is regulated by phosphorylation.

    • Hormonal control via glucagon leads to glycogen breakdown for glucose release into the bloodstream.

Chapter 6: Kinase and Glycogen - Hormone Regulation

  • Importance of cAMP

    • Glucagon binding to its receptor triggers a signaling cascade involving adenylate cyclase, which increases cAMP levels.

    • cAMP activates protein kinase A (PKA), which regulates glycogen breakdown (activation of phosphorylase) and synthesis (inhibition of synthase).

  • Hormonal Interaction

    • Insulin and glucagon exert opposing effects; insulin activates phosphatase switching on glycogen synthesis while switching off breakdown mechanisms.

    • Regulatory systems help maintain blood glucose levels, particularly after meals or during fasting.

Chapter 7: Conclusion

  • Coordinated Regulation

    • Hormonal signaling ensures glucose availability through glycogen breakdown and gluconeogenesis when blood glucose is low.

    • Glucagon increases glucose from glycogen breakdown and gluconeogenesis, whereas insulin promotes glycogen synthesis and reduces blood glucose levels.