Liver glycogen regulation

Question 1

What must high glucose turn on and turn off ?

Answer 1

High glucose must turn on glycogen synthesis & turn off breakdown in liver

Question 2

Between meals, N-terminal tail of phosphorylase a in R state is?

Answer 2

Buried and inaccessible to PP1

Question 3

What happens to the tail when high glucose, shifts to T state?

Answer 3

The tail becomes exposed, and PP1 can dephosphorylate it to inactive b form

Question 4

The conversion of glycogen phosphorylase a from the R state to the T state by the binding of glucose results in?

Answer 4

The activation of PP1 that is associated with the phosphorylase. PP1 converts
glycogen metabolism from a degradation mode to a synthesis mode

Question 5

Why is there a lag between the decrease in glycogen degradation and the increase in synthesis prevents the two pathways from operating simultaneously ?

Answer 5

• This is caused by the fact that there are approximately 10 times more copies of
  phosphorylase a than phosphatase
• Therefore, the activity of glycogen synthase begins to increase only after most of
  phosphorylase a is converted into b

Question 6

Why does regulation by glucose only occurs in liver because ?

Answer 6

• Glut2 transporters – high capacity at high blood glucose concentrations, allowing equilibrium between blood and cytosolic glucose
• Glucokinase rather than hexokinase – high Km (5mM vs 0.1mM)
• Same system as in pancreas

Question 7

What is Glucose not inhibited by compared to hexokinase 1?

Answer 7

Glucokinase not inhibited by G-6-P allowing Glucokinase to be active at high G-6-P concentrations

Question 8

In liver glucokinase/hexokinase IV is maintained ?

Answer 8

Within the nucleus and kept inactive by binding to a regulator protein
- This is stimulated by fructose-6-phosphate

Question 9

Above 5mM, glucose competes with ?

Answer 9

F-6-P causing dissociation of the regulator protein and

releasing active enzyme into cytoplasm

Question 10

What is UDP ?

Answer 10

An activated form of glucose

Question 11

UDP-glucose is synthesised from ?

Answer 11

G-1-P

Question 12

Explain Regulation of glycogen synthesis by PP1?

Answer 12

• PP1 dephosphorylates glycogen synthase, activating it (and phosphorylase kinase and glycogen phosphorylase, deactivating them)

Question 13

What has the reverse effect of glycogen synthase?

Answer 13

For glycogen breakdown it is the reverse: PKA phosphorylates glycogen synthase, deactivating it, and phosphorylates phosphorylase kinase, activating it

Question 14

Downstream of MAPK pathway, you have increased activity of ?

Answer 14

PP1 which reverses effects of PKA and other PKs

Question 15

Explain phosphorylation in response to insulin regulates

PP1 in the liver ?

Answer 15

• ISPK1 phosphorylates PP1 glycogen binding subunit GL on the S1 site serine, activating it
• PP1 then dephosphorylates GS (on) and phosphorylase (off)
• Inhibitor 1 is a PP1-binding protein with low affinity for protein phosphatase 1 in
  the absence of phosphorylation
• A similar process happens in muscle glycogen with the equivalent GM subunit
  affected downstream of insulin (but not directly by glucose)

Question 16

Explain phosphorylation in response to glucagon regulates PP1 in the liver ?

Answer 16

• PKA phosphorylates glycogen phosphorylase
  (on) and glycogen synthase (off)
• Protein kinase A also phosphorylates the site 2
  (S2) serine in the GL subunit, causing PP1 to dissociate from the glycogen particle
• PP1 is maintained in the inactive state through
  binding to Inhibitor 1 protein, which also phosphorylated (and activated) by protein
  kinase A
• A similar process happens in muscle glycogen with the equivalent GM subunit affected downstream of ADRENALINE (not by glucose or glucagon)