Glycogen Metabolism

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Glycogen Metabolism

• Introduction

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Storage Polysaccharides
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Why Polysaccharides?

• Rapid mobilization
• Support anaerobic metabolism
• Animals cannot convert fats to glucose
  precursors

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Why Polymers?

• Osmotic Problem!

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Glycogen Metabolism
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Glycogen Breakdown
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Storage Tissues

• Liver Glucose for bloodstream
• Muscle Glucose for anaerobic ATP synthesis
  (Glycolysis)

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Pathway Overview

• Structure of Glycogen
• Glycogen Phosphorylase
• Phosphoglucomutase
• Glycogen Debranching Enzyme

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Structure of Glycogen
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Glycogen Phosphorylasea(1 gt 4) Linkages
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Phosphoglucomutase
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Glycogen Debranching Enzymea(1 gt 6) Linkages
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Reactions of Glycogen Breakdown
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Glycogen Phosphorylase
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Reaction of Glycogen Phosphorylase
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Mechanism of Glycogen Phosphorylase
Binding Crevice Accommodates 4-5 Sugar Residues
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Role of Pyridoxal Phosphate(Vitamin B6
essential cofactor)
Function acid-base catalyst.
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Phosphoglucomutase
Reaction
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Phosphoglucomutase
Mechanism
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Phosphoglucomutase
Regeneration of Glucose-1,6-bisP
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Glycogen Debranching Enzyme
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Glycogen Synthesis
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Phosphoglucomutase
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Phosphoglucomutase
Mechanism
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UDP-Glucose Pyrophosphorylase
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Glycogen Synthase I
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Glycogen Synthase II
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Glycogen Branching
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Thermodynamics and Potential Futile Cycle
Use hydrolysis of PPi to drive glycogen synthesis!
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Control of Glycogen Metabolism

• Glycogen Synthase
• Glycogen Phosphorylase
• Why not UDP-Glucose Pyrophosphorylase?

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Regulatory Mechanisms

• Allosteric Control
• Covalent Modification

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Covalent Modification I(Phosphorylase)
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Covalent Modification II(Glycogen Synthase)
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Allosteric Control I
Enzyme Negative Positive Phosphorylase a
(more active) Glucose Phosphorylase b (less
active) ATP G6P AMP Gycogen Synthase a (high
activity) Glycogen Synthase b (low
activity) ADP Pi G6P
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Allosteric Control II
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Advantages of Covalent Modification

• Sensitivity to more allosteric effectors
• More flexibility in control patterns
• Signal amplification

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Glycogen PhosphorylaseBicyclic Cascade
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Formation of Cyclic AMP (cAMP)
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Activation of Phosphorylase Kinase
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Activation of Phosphorylase
Signal Amplification
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Inactivation of Phosphoprotein Phosphatase I
Importance of Protein-Protein Interactions
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Glycogen Synthase Bicyclic Cascade
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Control of Glycogen Synthase
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Integration of Glycogen Metabolism Control
Mechanisms

• Blood Glucose Levels (Liver)
• Insulin
• Glucagon
• Tissue Glucose Levels (Stress)
• Epinephrine
• Norepinephrine

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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

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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

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Stress Hormones(Adrenyl Gland)
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Glycogen Storage Diseases