Glycogen Metabolism Introduction

Storage Polysaccharides

Why Polysaccharides? Rapid mobilization Support anaerobic metabolism Animals cannot convert fats to glucose precursors

Why Polymers? Osmotic Problem!

Glycogen Metabolism

Glycogen Breakdown

Storage Tissues Liver: Glucose for bloodstream Muscle: Glucose for anaerobic ATP synthesis (Glycolysis)

Pathway Overview Structure of Glycogen Glycogen Phosphorylase Phosphoglucomutase Glycogen Debranching Enzyme

Structure of Glycogen

Glycogen Phosphorylase [  (1 —> 4) Linkages]

Phosphoglucomutase

Glycogen Debranching Enzyme [  (1 —> 6) Linkages]

Reactions of Glycogen Breakdown

Glycogen Phosphorylase

Reaction of Glycogen Phosphorylase

Mechanism of Glycogen Phosphorylase Binding Crevice Accommodates 4-5 Sugar Residues

Role of Pyridoxal Phosphate (Vitamin B 6 – essential cofactor) Function: acid-base catalyst.

Phosphoglucomutase Reaction

Phosphoglucomutase Mechanism

Phosphoglucomutase Regeneration of Glucose-1,6-bisP

Glycogen Debranching Enzyme

Glycogen Synthesis

Phosphoglucomutase

Mechanism

UDP-Glucose Pyrophosphorylase

Glycogen Synthase I

Glycogen Synthase II

Glycogen Branching

Thermodynamics and Potential Futile Cycle Use hydrolysis of PP i to drive glycogen synthesis!

Control of Glycogen Metabolism Glycogen Synthase Glycogen Phosphorylase Why not UDP-Glucose Pyrophosphorylase?

Regulatory Mechanisms Allosteric Control Covalent Modification

Covalent Modification I (Phosphorylase)

Covalent Modification II (Glycogen Synthase)

Allosteric Control I EnzymeNegativePositive Phosphorylase a (more active) Glucose Phosphorylase b (less active)ATP G6P AMP Gycogen Synthase a (high activity) Glycogen Synthase b (low activity) ADP P i G6P

Allosteric Control II

Advantages of Covalent Modification Sensitivity to more allosteric effectors More flexibility in control patterns Signal amplification

Glycogen Phosphorylase Bicyclic Cascade

Formation of Cyclic AMP (cAMP)

Activation of Phosphorylase Kinase

Activation of Phosphorylase Signal Amplification

Inactivation of Phosphoprotein Phosphatase I Importance of Protein-Protein Interactions

Glycogen Synthase Bicyclic Cascade

Control of Glycogen Synthase

Integration of Glycogen Metabolism Control Mechanisms Blood Glucose Levels (Liver) –Insulin –Glucagon Tissue Glucose Levels (Stress) –Epinephrine –Norepinephrine

Maintenance of Blood Glucose Levels Insulin (peptide from the pancreas) –Produced in response to high glucose –Insulin-dependent glucose transporter (GLUT4) –cAMP decreases Glucagon (peptide from the pancreas) –Produced in response to low glucose –Glucagon receptors (liver) - activation of adenylate cyclase –Glycogen breakdown to glucose-6-P –Glucose-6-phosphatase –Glucose enters bloodstream

Response to Stress (Muscle and Other Tissues) ß-adrenergic receptors (muscle and other tissue) –Activation of Adenylate Cyclase –Glucose-6-P for glycolysis Stimulates pancreatic cells to produce glucagon

Stress Hormones (Adrenyl Gland)

Glycogen Storage Diseases