T2 L4: Glycogen metabolism in muscle and liver

• What does the structure of glycogen consist of?

  highly branched polysaccharide of glucose

  large number of ends at which phosphorylase and glycogen synthase can act to ensure rapid breakdown and resynthesis

  consists of:

  • alpha-1,4 linked glucose molecules
  • with alpha-1,6 branch every 8-14 glucose residues
• What is the enzyme involved in breaking down glycogen into glucose molecules?

  phosphorylase
• What is mobilisation?

  the rapid activation of breakdown of stored glycogen in time of metabolic need
• What is the mechanism of glycogen breakdown in liver?

  glycogen to gluc-1-phosphate to gluc-6-phosphate to free GLUCOSE

  for export to other tisses

  is able to do this because expresses enzyme glucose-6-phosphatase
• How does glycogen phosphorylase work to break down glycogen?

  a1-4 linkages broken via phosphorolysis

  removes single units from non-reducing ends to form glucose-1-phosphate

  ATP not involved

  
• How does glycogen degradation work?

  phosphorylase breaks 4 alpha-1,4 links

  transferase breaks next 3 and adds them to the end of another chain

  a-1,6 glucosidase activity of debranching enzyme removes the last glucose left

  back to phosphorylase until next branching point
• How does the cleavage of a-1,6 linkages work at branch points?

  by debranching enzyme

  forms free GLUCOSE

  via hydrolysis (does not involve phosphate)
• How does glycogen synthesis work?

  glucose + ATP + Hk

  Glucose-6-phosphate

  + phosphoglucomutase

  Glucose-1-phosphate

  + UTP

  UDP-Glucose

  + glycogen (N) + glycogen synthase

  Glycogen (N+1)

  + UDP
• How does glycogen synthesis start (priming function)?

  Glycogen synthase can only add glucose units to a pre-existing chain of more than four glucosyl residues

  starts by glycogenin: UDP-glucose donates first glucosyl residue, attaches to tyrosine in glycogenin

  glycogenin extends glucose chain by up to 7 additional residues
• How does glycogen get its branches?

  glycogen synthase extends chain

  branching enzyme transfers block of 7 residues

  branch doesnt form within 4 residues of pre-existing chain
• What is allosteric regulation?

  regulation via conformational changes to an enzyme
• How does the allosteric regulation of phosphorylase work?

  glycogen phosphorylase in muscle is subject to allosteric regulation by AMP, ATP and G6P:

  • AMP (present when ATP depleted) activates phosphorylase
  • ATP and G6P inhibit phosphorylase (signs of high energy levels)
• How does the allosteric regulation of glycogen synthase work?

  activated by G6P
• What are the 2 ways of enzyme regulation?

  allosteric modification

  covalent modification
• What kind of enzymes catalyse phosphorylation?

  protein kinases
• What is dephosphorylation catalysed by?

  protein phosphatases
• How is phosphorylase activated?

  cAMP cascade

  phosphoryaltion of a hydroxyl group in serine residue of phosphorylase

  promote transition to active state

  • phosphoryalted enzyme is less sensitive to allosteric inhibitors, so even if ATP & G6P levels are high, phosphorylase will stay activated
• What effect does induction of cAMP cascade (& phosphorylation) have on glycogen synthase?

  converts enzyme to B conformation (less active)

  so glycogen synthesis inhibited when protein kinases activated
• What is liver glyocogen used for?

  maintain plasma glucose levels between meals
• What is muscle glycogen used for?

  muscle contraction
• Why does gluconeogenesis occur?

  the liver contains less glycogen than is required to sustain glucose metabolism for 24 hours
• Why is glycogen good as an energy store?

  enzymes phosphoprylase and glycogen synthase are very sensitive to regulation by hormones, stress and muscle contraction

  branched structure provides large number of ends
• Why is glycogen bad as an energy store?

  glucose is hydrophilic so associates with water

  increasing overall weight and bulk