Describe glycogenesis and glycogenolysis with their regulation. Compare liver and muscle glycogen.

Introduction

• Branching gives many non-reducing ends, so synthesis and breakdown can proceed rapidly at many points at once, and increases solubility

Glycogenesis (synthesis)

Glucose → Hexokinase / glucokinase → Glucose-6-phosphate → Phosphoglucomutase → Glucose-1-phosphate → UDP-glucose pyrophosphorylase + UTP → UDP-glucose (the active donor) → glycogen synthase — adds α-1,4 — rate-limiting → Branching enzyme — transfers a block of 6–8 residues to make an α-1,6 branch

• Glycogenin is the primer — a protein that autoglucosylates itself to start the chain; glycogen synthase cannot begin from nothing
• 2 high-energy bonds are used per glucose added (one ATP, one UTP)
• The branching enzyme is amylo-(1,4→1,6)-transglucosidase

Glycogenolysis (breakdown)

Glycogen → glycogen phosphorylase — needs pyridoxal phosphate; rate-limiting → Cleaves α-1,4 bonds by phosphorolysis, stopping 4 residues from a branch → limit dextrin → debranching enzyme — two activities in one protein → Glucose-1-phosphate (about 90%) + free glucose (about 10%) → G1P → G6P → glucose (liver) or glycolysis (muscle)

• Debranching enzyme has two activities — a 4:4 transferase that moves three residues, and an α-1,6-glucosidase that releases the branch point as free glucose
• Phosphorolysis, not hydrolysis — the product is already phosphorylated, saving one ATP
• Only the liver can release free glucose into the blood, because only it (and the kidney) has glucose-6-phosphatase

Regulation

A. Hormonal — covalent modification

Glucagon (liver) / Adrenaline (liver and muscle) → ↑ cAMP → Protein kinase A → Phosphorylates phosphorylase kinase → Which phosphorylates glycogen phosphorylase → phosphorylase active (a form) and synthase inactive → glycogen broken down

• One signal switches both enzymes in opposite directions — the cell can never synthesise and degrade glycogen at the same time
• Insulin activates protein phosphatase-1, which dephosphorylates both and so promotes storage
• The cascade gives enormous amplification — a few hormone molecules mobilise millions of glucose units

B. Allosteric

Differences Between Liver and Muscle Glycogen

Energetics and Efficiency

• Glycogen is a compromise — less energy-dense than fat, but it can be mobilised within seconds and used without oxygen
• Fat cannot replace it for sudden demand or for anaerobic work

Applied Aspects

• Glycogen storage diseases — Von Gierke (glucose-6-phosphatase), Pompe (lysosomal α-glucosidase), Cori (debranching), Andersen (branching), McArdle (muscle phosphorylase), Hers (liver phosphorylase)
• Carbohydrate loading before endurance events raises muscle glycogen and delays fatigue — a direct application of this pathway
• Liver glycogen lasts only 18–24 hours of fasting; thereafter gluconeogenesis takes over
• Vitamin B6 deficiency impairs phosphorylase — glycogen phosphorylase holds the largest single store of pyridoxal phosphate in the body
• Adrenaline raises blood glucose in seconds, which is why it is part of the fight-or-flight response and why hypoglycaemia causes tremor and palpitations