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.
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.
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.
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.
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:
Hormone binds to a receptor.
G protein activation.
Activation of adenylate cyclase.
Conversion of ATP to cyclic AMP.
Activation of protein kinase and phosphorylase kinase.
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.
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.
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.
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.
Carbon balance confirms conservation through the non-oxidative phase, crucial for biochemical efficiency.