Glycogen Metabolism and the Pentose Pathway Notes

Lecture Overview

  • Topic: Glycogen Metabolism and the Pentose Pathway.

  • Focus: Synthesis and breakdown of glycogen, major carbohydrate storage in humans, and mechanisms for generating NADPH via the pentose pathway.

Glycogen Storage

  • Definition: Glycogen is a glucose polymer and serves as the primary form of carbohydrate storage in the liver and muscles of humans.

  • Structure:

    • Composed of α-1,4 linked glucose units with α-1,6 branches occurring every 10-12 glucose units.

    • Contains approximately 90% 1-4-linked and 10% 1-6-linked glucose units.

    • Extensive branching allows for multiple non-reducing ends for enzymatic hydrolysis, with only one reducing end for mutarotation.

Glycogen Degradation

  • Enzyme Involved: Phosphorylase a cleaves glycogen at non-reducing ends, releasing glucose-1-P units.

    • This reaction favors product formation.

  • Challenges: Phosphorylase a cannot cleave near 1,6 branch points, necessitating:

    • Transferase enzyme: Converts 1,6 branches into linear 1,4-linked glucose units.

    • α-1,6-glucosidase enzyme: Facilitates further degradation of glycogen.

Glycogen Synthesis

  • Process: Reversal of glycogen breakdown, needing energy input due to the exergonic nature of degradation.

  • Key Enzymes:

    • Involves different enzymes than those used for breakdown; specifically:

      • UDP-glucose pyrophosphorylase: Converts glucose-1-P and UTP to UDP-glucose, releasing inorganic pyrophosphate (PPi).

      • Inorganic pyrophosphatase: Hydrolyzes PPi, facilitating the overall reaction.

      • Glycogen synthetase: Transfers glucose from UDP-glucose to glycogen’s non-reducing end, releasing UDP.

Regulation of Glycogen Metabolism

  • Different Enzyme Systems: Synthesis and degradation use distinct enzymes to prevent energy-wasting futile cycles.

  • Hormonal Regulation:

    • Definition: Hormones are organic compounds synthesized in one tissue and exerting effects on metabolic processes in another.

    • Epinephrine Cascade: Activates glycogen breakdown by stimulating phosphorylase a, involving several signaling events:

      1. Hormone binds to a receptor.

      2. G protein activation.

      3. Activation of adenylate cyclase.

      4. Conversion of ATP to cyclic AMP.

      5. Activation of protein kinase and phosphorylase kinase.

      6. Conversion of phosphorylase b to a.

  • Inactivation of Glycogen Synthase: Also stimulated by epinephrine, understanding the dual regulatory mechanism prevents concurrent activation of synthesis and degradation.

Pentose Phosphate Pathway (PPP)

  • Purpose: Provides NADPH for reductive biosynthesis and generates pentose sugars.

  • Integration: Some reactions integrate with glycolysis and gluconeogenesis, occurring in the cytosol.

  • Phases:

    • Oxidative Phase: Starts with glucose-6-P and produces ribulose-5-P, generating NADPH.

      • Reaction:Glucose-6-Phosphate + 2 NADP+ + H2O → Ribulose-5-Phosphate + 2 NADPH + 2 H+ + CO2

    • Non-Oxidative Phase: Converts excess ribulose-5-P into glycolytic intermediates like G6P or pyruvate.

Key Enzymes in PPP

  • Glucose 6-P Dehydrogenase: Catalyzes the first step, oxidizing glucose-6-P to 6-phosphogluconolactone, reducing NADP+ to NADPH.

  • Lactonase: Opens the lactone to form 6-P-gluconate.

  • 6-P-Gluconate Dehydrogenase: Oxidizes 6-P-gluconate to ribulose 5-P, generating more NADPH.

Non-Oxidative Phase Details

  • Steps:

    • Conversion of ribulose-5-P to ribose-5-P (isomerization).

    • Utilization of transketolase and transaldolase reactions to convert five-carbon sugars to glycolytic intermediates.

  • Transketolase Reaction: Transfers a two-carbon fragment between sugars.

  • Transaldolase Reaction: Transfers a three-carbon fragment.

Stoichiometry

  • Carbon balance confirms conservation through the non-oxidative phase, crucial for biochemical efficiency.