Unit 10: Glycogen Metabolism

What is glycogen & where is it found primarily?

• Storage form of glucose

• Liver & skeletal muscle

What are the overall roles of glycogen in the 2 tissues?

Muscle glycogen provides quick burst of energy for aerobic/anaerobic metabolism

• Exhausted in less than hour during vigorous exercise

Liver glycogen serves as reservoir of glucose for other tissues

• Provides glucose b/w meals & during fasting

• Can be depleted in 12-24 hours

What is the amount of stored glycogen compared to the amount of stored fat?

Much less

Where does glycogen breakdown occur?

Non-reducing ends & requires 3 enzymes

• Glycogen phosphorylase

• Glycogen debranching enzyme

• Phosphoglucomutase

How many non-reducing ends are there for synthesis & breakdown to occur?

Multiple → high efficacy

What does glycogen phosphorylases (phosphorylase) do?

• Uses an inorganic phosphate to cleave alpha(1→4) glycosidic bond from non-reducing end (w/o using ATP)

• Releases glucose 1-phosphate as product

• Process repeats until:

  • Reaches 4th glucose molecule from branch point (Sterically hindered at this point)

What do glycogen debranching enzyme (debranching enzyme) performs?

• Transfers 3 glucose molecules

• Cleaves alpha(1→6) glycosidic bond

• Repeats process until:

  • Another branch point encountered

  • Enough glucose released

What does phosphoglucomutase do?

Converts glucose 1-phosphate to glucose 6-phosphate so can be used in glycolysis (muscle) or exported to other cells (liver)

• Readily reversible

How do phosphoglucomutase & phosphoglycerate mutase differ?

• Phosphoglucomutase: uses P-Ser

• Phosphoglycerate mutase: uses P-His

What is the mechanism of hepatic release of glucose?

Separation of glucose 6-P activity in ER & glycolysis in cytosol

• Activate site lies in ER

Where does glycogen synthesis occur?

Virtually all tissues- most predominant in liver

What is the starting point for glycogen synthesis?

Glucose 6-phosphate

• Must be converted to activated form of glucose 1-phosphate prior to adding glycogen

What are the key points of glycogen synthesis?

• hydrolysis of PPi (Pyrophosphate)

  • Releases energy

  • Drives reaction forward

Also glucose uses UTP for activation instead of ATP

What is the activated form of glucose?

UDP-Glucose

What is UDP-glucose added to?

Non-reducing end of glycogen by enzyme glycogen synthase

Does synthase require ATP?

No

Does synthetase require ATP?

Yes

What are the steps of UPD-glucose being added?

• Glu of enzyme displaces UDP

• C₄-OH of nonreducing end displaces Glu of enzyme (n > 4 prevents steric hinderance)

What can glycogen synthase not catalyze formation of?

alpha(1→6) glycosidic bonds that lead to branching point

• Branches added by glycogen-branching enzyme (amylo(1→4) to (1→6) transglycosylase)

  • Transfers terminal segment 6 or 7 glucose molecules from non-reducing end

  • Must be at least 11 residues (must leave at least 4 sugars including branch point)

    • Leaving the 4 prevents any steric hinderance for synthase enzyme

What are the biological advantages of branching?

• Increases water solubility

• Increases number of non-reducing ends

  • Primary advantage; increases efficacy of storing & releasing glucose

Can glycogen synthase begin a new chain de novo?

No, requires primer of at least 8 glucose residues

What are glycogen synthesis & degradation coordinated so that?

Glycogen synthase in nearly inactive when glycogen phosphorylase is full active (& vice-versa)

• Control of both is achieved by reversible phosphorylation

What does the “a” form represent?

Active form

What does the “b” form represent?

Inactive form

What does epinephrine cause in muscle?

Activation of glycogen phosphorylase (breakdown glycogen for energy)

What is glycogen phosphorylase is activated in liver in response to?

Activated by phosphorylase b kinase due to glucagon or low plasma glucose levels

What happens when glucose levels return to normal?

Glucose enters hepatocytes & binds to inhibitory allosteric site on glycogen phosphorylase, which causes conformational change that allows phosphorylase a phosphatase to inactivate glycogen phosphorylase

How is glycogen synthase regulated by?

Reversible phosphorylation

• Phosphorylation via kinase enzyme

  • Activates glycogen phosphorylase (Breakdown)

  • Inactivates glycogen synthase (synthesis)

  • Mobilizes via phosphorylation (glucagon)

• Dephosphorylation via a phosphatase enzyme

  • Inactivates glycogen phosphorylase (breakdown)

  • Activates glycogen synthase (synthesis)

  • Store via dephosphorylation (insulin)

What does insulin want to do?

Store

What does high glucose 6-P want?

Store