BIOC311 Module 2
Page 1: Glycogen Overview
Glycogen: Branched polymer of glucose.
Levels increase after meals; utilized during fasting/exercise.
Glycogen granules: Contain enzymes for synthesis/breakdown, up to 50,000 glucose units.
Purpose of Glycogen Storage:
Faster catabolism than fatty acids.
Usable under anaerobic conditions in muscles.
Maintains osmotic pressure.
Provides Glucose-1-Phosphate (G1P) faster than blood glucose uptake.
Tissue-Specific Roles of Glycogen:
Muscle: Provides local ATP for contraction (2% by weight); cannot release glucose into the blood due to absence of G6P phosphatase.
Liver: Maintains blood glucose levels through glycogen degradation and specific G6P phosphatase expression.
Other Tissues: Small glycogen stores for brief energy needs.
Page 2: Glycogen Structure
Glycogen is a polymer with one reducing end and numerous non-reducing ends.
Glucosyl residues linked by C1-C4 (α(1→4) linkages); branches at C1-C6 every 8-14 residues.
Importance of Branches:
Multiple synthesis and degradation sites.
Non-reducing ends: Where glucose is released during degradation.
Page 3: Glycogen Metabolism
Distinct pathways for synthesis and breakdown due to energy requirements.
Enzymes Involved in Breakdown:
Glycogen phosphorylase (Glycogen → G1P).
Phosphoglucomutase (G1P ⇌ G6P).
UDP-glucose pyrophosphorylase (G1P + UTP → UDP-glucose).
Glycogen synthase (UDP-glucose → Glycogen).
Rate Limiting Enzymes:
Glycogen phosphorylase and glycogen synthase.
Page 4: Synthesis of UDP-Glucose
UDP-glucose synthesis from G1P and UTP is thermodynamically unfavorable, energy input required.
Reaction: G1P + UTP catalyzed by UDP-glucose pyrophosphorylase.
Product: UDP-glucose, an activated donor of glucosyl units.
Page 5: Glycogen Chain Elongation
Glycogen synthase adds glucose units from UDP-glucose to glycogen’s non-reducing ends, forming α(1→4) bonds.
Energetics: Glycogen + G1P + UTP → Glycogen + UDP + 2Pi (energy cost).
UTP replenishment through nucleoside diphosphate kinase.
Regulation: Glycogen synthase is inhibited by ATP, ADP, and Pi; activated by G6P.
Page 6: Glycogenin Function
Glycogenin primes glycogen synthesis by adding glucose residues to itself, starting the glycogen chain.
Mechanism involves transferring glucose from UDPG and elongating the chain before glycogen synthase takes over.
Branching enzyme creates α(1→6) branches every 11 residues.
Page 7: Glycogen Breakdown Process
Steps include:
Generation of G1P (Glycogen phosphorylase).
Debranching (Debranching enzyme).
Conversion of G1P to G6P (Phosphoglucomutase).
Page 8: G1P Generation
Glycogen phosphorylase catalyzes the phosphorolysis of glycogen into G1P.
Regulation includes allosteric interactions and covalent modifications (phosphorylation).
Allosteric control: High ATP inhibits, high AMP activates.
Page 9: Debranching Steps
Utilizes two enzyme activities:
Transfers trisaccharides (α(1→4) glucosyltransferase).
Hydrolyzes glycosidic bond (α(1→6) glucosidase).
Majority of glycogen converts to G1P, some to glucose.
Page 10: G6P Conversion
Phosphoglucomutase converts G1P to G6P for metabolic pathways.
The conversion process includes a phosphoryl transfer, and the reaction is reversible.
Page 11: Summary of Glycogen Metabolism
Muscle uses G6P for glycolysis; liver converts it to glucose for blood circulation.
Glycogen breakdown efficiency: consume 2 ATP for synthesis, generate 33 ATP during breakdown, totaling 97% efficiency.
Page 12: Enzyme Cascades
Covalent modification mechanisms: reversible (e.g., phosphorylation) and irreversible.
Monocyclic and bicyclic cascades modify enzymes E and F as signals for glycogen metabolism.
Page 13: Glycogen Phosphorylase Regulation
Two states: T (inactive) and R (active);
Allosteric activators/inhibitors affect activity based on physiological conditions.
Page 14: Phosphorylase Kinase Role
Activates glycogen phosphorylase and inactivates synthase through phosphorylation.
Its activity is regulated by calcium levels and hormonal signals.
Page 15: PKA Regulation
PKA activated by cAMP; influences glycogen breakdown and inhibits glycogen synthase.
Page 16: Glycogen Synthase Regulation
Phosphorylated form is inactive; dephosphorylation activates synthase, influenced by insulin signaling.
Page 17: PP1c Activity Regulation
PP1c facilitates glycogen synthesis by regulating glycogen synthase and phosphorylase activities.
Page 18: Hormonal Regulation
Insulin signaling inactivates glycogen synthase kinase, activating glycogen synthesis.
Page 19: Glycogen Synthesis Mechanism
Insulin activates pathways to increase glycogen synthase activity.
Page 20: Glycogen Breakdown Mechanism
Hormonal signals activate PKA, trigger glycogen breakdown via phosphorylase kinase.
Page 21: External Signaling Mechanism
Hormonal signaling pathways affect cellular responses and glycogen metabolism.
Page 22: Regulation of Muscle vs Liver
Both tissues respond to hormones, but differ in receptors and signaling pathways for glycogen metabolism.
Page 23: Muscle Glycogen Synthesis
Mechanisms involve high insulin and glucose levels, activating glycogen synthase.
Page 24: Liver Glycogen Synthesis
Insulin inhibits GSK3β, enabling synthesis and dephosphorylation of glycogen synthase.
Page 25: Liver Glycogen Breakdown
Stress hormones and glucagon trigger glycogen breakdown pathways in the liver.
Page 26: Glycogen Storage Diseases
Type 1 (G6P deficiency): Symptoms include liver enlargement and hypoglycemia.
Type 5 (Muscle phosphorylase deficiency): Leads to exercise cramps.
Type 6 (Liver phosphorylase deficiency): Causes hypoglycemia due to impaired glycogen breakdown.
Page 27: Pyruvate Dehydrogenase Complex (PDC)
Enzyme complex catalyzing pyruvate to Acetyl-CoA in mitochondria, crucial for aerobic metabolism.
Page 28: PDC Structure
Composed of multiple enzymes requiring various coenzymes (TPP, lipoic acid, CoA, FAD, NAD+).
Page 29: PDC Reactions
Overview of enzymatic functions and substrate channeling.
Page 30: E2 Functionality
Role of CoA substitution and generation of high-energy Acetyl-CoA.
Page 31: E3 Functionality
Restoration of E2 and own FAD for subsequent reactions; generates NADH.
Page 32: PDC Regulation
Controlled by product inhibition and phosphorylation/dephosphorylation of E1.
Page 33: Phosphorylation Effects
Inactivation through PDK and activation through PDP based on cellular energy state.
Page 34: Citric Acid Cycle (CAC)
Series of reactions generating CO2, NADH, and GTP/ATP; connects to metabolic pathways.
Page 35: Key Enzymes in CAC
Citrate synthase and aconitase notable for C-C bond formation and isomerization.
Page 36: Additional CAC Enzymes
Isocitrate and α-KG dehydrogenases facilitate NADH and GTP generation during oxidative decarboxylation.
Page 37: Succinyl-CoA Generation
Produces GTP/ATP and marks completion of one acetyl-CoA oxidation.
Page 38: CAC Recycling Steps
Include succinate dehydrogenase, fumarase, and malate dehydrogenase.
Page 39: Energy Balance Sheet
Comprehensive overview of ATP generation from glycolysis, PDC, and CAC.
Page 40: CAC Regulation
Three key enzymes regulated by substrate availability and product inhibition.
Page 41: Regulation of Isocitrate Dehydrogenase
Product inhibition by NADH and allosteric activation by ADP.
Page 42: α-Ketoglutarate Dehydrogenase Regulation
Inhibited by NADH and succinyl-CoA; activated by Ca2+.
Page 43: Summary of Regulatory Points
Highlight communication pathways in metabolic regulation.
Page 44: CAC Functions
Influences energy state, redox state, and availability of key compounds.
Page 45: Anaplerotic Reactions
Replenish CAC intermediates; include pyruvate carboxylase and transamination reactions.
Page 46: Overview of Key Transition Reactions
Key conversions and regulatory points in metabolism are summarized.
Page 47: Mitochondrial Structure
Description of mitochondrial components and their functions in oxidative phosphorylation.
Page 48: Electron Transport Chain (ETC)
Details of electron flow through mitochondrial complexes and their role in proton gradient generation.
Page 49: H+ Translocation Coupling
Mechanism of H+ flow and energy release as electrons pass through the ETC.
Page 50: Alternative CoQ Reduction Pathways
Various pathways contribute to the reduction of CoQ for electron transfer.
Page 51: The Q Cycle
Mechanism detailing electron transfer at Complex III for efficient energy production.
Page 52: Complex IV Functions
Key role in converting electrons from CytC into water, with proton pumping action.
Page 53: ATP Synthesis Mechanism
F1 sector of ATP synthase generates ATP through rotation; processes involved in catalysis.
Page 54: P/O Ratio
Explanation of ATP production efficiency in relation to oxygen consumption.
Page 55: Evidence of Chemiosmotic Coupling
Various observations support the chemiosmotic theory of ATP synthesis.
Page 56: Mitochondrial Chemical Uncouplers
Functional impacts of uncouplers on respiration and ATP synthesis.
Page 57: Mitochondrial Origins
Historical evolution, including endosymbiotic events leading to modern organelles.
Page 58: Mitochondrial DNA
Distinctive traits, genes present, and reliance on nuclear genes for mitochondrial function.
Page 59: Mitochondrial Diseases
Impact of mtDNA mutations and nucleotide coordination on cellular health and metabolism.
Page 60: Respiratory Control Mechanisms
ATP utilization and its effect on electron flow and oxygen consumption rates.