Regulation of glycogen metabolism

Question 1

What are the main enzymes that control synthesis and degradation

Answer 1

1. synthesis – Glycogen synthase

2. Degradation – Glycogen phosphorylase

Question 2

How is glycogen metabolism regulated

Answer 2

1. Regulated by phosphorylation and dephosphorylation of the key regulatory enzymes
2. Enzyme which adds phosphate- kinase
3. Parallels with the way in which fatty acid biosynthesis is regulated

Question 3

What happens when a single signal molecule is activated

Answer 3

1. Reaction cascade- Signalling pathway:
2. 1 Signal molecule
3. –>10 second messengers active
4. –>100 molecules activated
5. –>1000 glucose released

Question 4

What happens in type 2 diabetes

Answer 4

1. Type 2 diabetes – no shortage of insulin but its effect on muscle glycogen synthesis is reduced
2. 300 million cases by 2020
3. Hence, a very active research area

Question 5

What effect does insulin have on glycogen synthase

Answer 5

1. Insulin increases the activity of glycogen synthase
2. Insulin increases the conversion of glycogen synthase from its phosphorylated b form (less active) to its dephosphorylated a form (more active)
3. This pathway is decreased in people with type 2 diabetes- glucose not being converted to glycogen synthase

Question 6

When is glycogen synthase more active

Answer 6

1. When it is not phosphorylates

Question 7

What does insulin do

Answer 7

1. Insulin binds to insulin receptor causing the insulin receptor to phosphorylate IRS1- Insulin receptor substrate1
2. IRS1 is a protein and once phosphorylated it can then bind with PI3K (phosphatidylinositol 3 kinase)
3. PI3K interacts with the membrane to convert phosphatidylinositol-diphosphate (PIP2) to PIP3
4. PIP3 is a potent lipid signalling molecule – present in very small quantities
5. Pip3 signals other receptors that take up glucose from the blood e.g. GLUT 4 receptors
6. PIP3 interacts with PDK, AKT/PKB, mTORC2

Question 8

What does PIP3 interactions with PDK, AKT/PKB, mTORC2 cause

Answer 8

1. PDK1 and AKT both have a domain referred to PH domain- pleckstrin homology domain
2. PH domain anchors PDK1 and AKT to the membrane- useful if want to interact with signal in membrane e.g. PIP3
3. Interaction of PIP3 with AKT causes phosphorylation of AKT, which then phosphorylates GSK3
4. This inhibits GSK3, so Glycogen Synthase is not converted as quickly to less active form so more in active form

Question 9

What phosphorylates Glycogen synthase

Answer 9

1. GSK3 – glycogen synthase kinase 3
2. Inactivates GS by adding phosphate groups to Ser side chains
3. Cannot add P to unphosphorylated GS, (this is unusual for kinases)
4. GS has to be ‘primed’ by Casein kinase II (CKII), -then GSK3 adds 4 further phosphates

Question 10

What effects GSK3 acitivity

Answer 10

1. Dephosphorylated GSK3(active on glycogen synthase) –> Phosphorylated GSK3 (inactive)
2. Converted by insulin and PKB

Question 11

What controls the dephosphorylation of GS

Answer 11

1. Removal catalysed by Phosphoprotein phosphatase 1 (PP1)
2. PP1 acts more quickly if G-6-P is bound to GS
3. so G-6-P is considered an activator of GS

Question 12

Describe Phosphoprotein phosphatase 1 (PP1)

Answer 12

1. A central enzyme in glycogen metabolism
2. Acts on GS (activates)
3. But also act on and inactivates
4. glycogen phosphorylase
5. phosphorylase kinase
6. both crucial in breakdown of glycogen

Question 13

What is the key enzyme controlling degradation

Answer 13

1. Glycogen phosphorylase is the key enzyme

Question 14

How is glycogen phosphorylase regulated

Answer 14

1. Regulated by phosphorylation state
2. More active when phosphorylated
3. Phosphorylase b is phosphorylated to active (phosphorylated) form by phosphorylase kinase (activated by protein kinase A)
4. Phosphorylase a is converted to less active form by phosphoprotein phosphatase 1

Question 15

What are 2 signals for degradation

Answer 15

1. Glucagon signals liver to release glucose into the blood

2. Adrenaline (epinephrine) signals muscles to release glucose for energy production

Question 16

Describe adrenaline/glucagon receptors

Answer 16

1. 7 transmembrane helices and linked to GDP – G-coupled

Question 17

What happens when adrenaline/glucagon receptors are activated

Answer 17

1. When there is a signal they activate forming GTP
2. And the alpha component interacts with adenylate cyclase which convert ATP to cyclic AMP
3. Cyclic AMP then activates protein kinase A by binding
4. Protein kinase A is able to phosphorylate the phosphorylase kinase
5. Phosphorylase kinase then activates glycogen phosphorylase (activates so breakdown increases)
6. Protein Kinase A also has an antagonistic effect on insulin receptor pathway and stimulates production of glycogen synthase into less active form

Question 18

How is muscle glycogen phosphorylase activated

Answer 18

1. Ca2+ – released in muscles to induce contraction which stimulates phosphorylase kinase
2. AMP – builds up in muscle if not enough ATP being produced

Question 19

How is glycogen phosphorylase inhibited in the liver

Answer 19

1. Glucose – so Glycogen Phosphorylase acts as a glucose sensor
2. Binding of glucose to GP causes bound phosphates to be more exposed to removal by PP1

Question 20

Describe the activity of PP1

Answer 20

1. PP1 increases activity of GS by dephosphorylating it
2. PP1 decreases activity of GP by dephosphorylating it
3. PP1 is itself inhibited when phosphorylated by PKA
4. PP1 is bound to the glycogen particle along with its three main substrates (GS, PK and GP)
5. These proteins are held together attached to the glycogen by a glycogen-targeting protein
6. E.g. Specifically GM in muscle

Question 21

Describe action of Glycogen targeting protein Gm

Answer 21

1. Adrenaline signalling and less insulin- in muscle
2. GM is phosphorylated to help bind components together
3. But when signalling from adrenaline and PKA is activated GM is further phosphorylated moving it away from the complex
4. PKA also phosphorylates inhibitor, activating it which inactivates PP1 and the complex falls apart

Question 22

How is Carbohydrate and lipid metabolism are coordinately regulated

Answer 22

1. The signalling factors, insulin, glucagon and adrenaline, have co-ordinated effects on glycogen synthesis, glycogen breakdown and glycolysis as well as on lipid synthesis and breakdown