L5 - Glycogen Synthesis And Regulation

Question 1

Glucose vs. Glycogen

Answer 1

Glucose:

• Monosaccharide
• 10g in plasma
• osmotically active (can’t be stored in large amounts)
• immediate energy source

Glycogen:

• Polysaccharide
• 400g in tissue stores
• Low osmolarity so can be stored in large quantities
• Medium term fuel source

Question 2

Role of Glycogen Breakdown in Liver: Glucose Homeostasis

Answer 2

Liver causes glycogen breakdown to maintain glucose homeostasis and is under the control of insulin and glucagon. Liver is sensitive to blood glucose concentrations. Supplies glucose to other tissues.

It regulates blood glucose.
Liver uses insulin and glucagon to do this.
Insulin used when high glucose.
Glucagon used when low glucose.

Store glucose as glycogen when blood glucose is high by converting glucose to glycogen when insulin present.

Release glucose when low blood glucose by converting glycogen to glucose when glucagon present.

Glycogen–>Glucose 6-phosphate

Glucose 6-phosphate–> Glucose + Pi

100-120g glycogen in liver

Question 3

Role of Glycogen Breakdown in Muscle: Fuel for Exercise

Answer 3

Glycogen breakdown only occurs in muscles if energy is required and supply is low to allow muscle contraction. Muscle is sensitive to demands of energy.

This is sensitive to adrenaline, Ca2+, ATP and AMP.

Question 4

Structure of Glycogen:

Answer 4

This is a highly branched structure.

This allows it to have many binding sites for enzymes to act on to remove glucose units.

Question 5

Two types of linkages in glycogen:

Answer 5

α-1,4-glycosidic bonds which forms straight chains of glucose.

α-1,6-glycosidic bonds which form the branches on glycogen.

Question 6

Features of Biosynthetic Pathway:

Answer 6

1. Requires ATP, UTP or GTP as a cofactor to drive unfavourable reactions
2. There is usually one or more reactions which are irreversible in a metabolic pathway.
3. In a series of reaction, usually the first and last reactions are tightly regulated.

Question 7

Glycogen Synthesis:

Answer 7

Glucose + ATP –> Glucose 6-phosphate + ADP
HEXOKINASE (muscle) and GLUCOKINASE (liver)

G6-P –> Glucose 1-phosphate
PHOSPHOGLUCOMUTASE - only reversible reaction.

G1-P + UTP –> UDP Glucose + Pi
UDP GLUCOSE PYROPHOSPHORYLASE/ Transferase

UDP Glucose + Glycogen primer molecule = Glycogen + UDP
GLYCOGEN SYNTHASE

UDP-Glucose is continuously added to glycogen to allow elongation of straight chains using glycogen synthase.
A branching enzyme is also used to allow formation of branches.

Question 8

Glucokinase and Hexokinase

Answer 8

Glucokinase in liver has low affinity (high Km) for glucose so only synthesises glycogen at high BGLs. GLUT2 has a high affinity for glucose so takes up glucose readily from blood –> to supply to other tissues.

Hexokinase has a high affinity for glucose (low Km) but uses GLUT4 (insulin dependent; low affinity) so only metabolises glucose at high levels.

Question 9

How is glycogen synthase regulated?

Answer 9

Glycogen synthase when phosphorylated via glycogen synthase kinase - inactive.
When dephosphorylated via protein phosphatase 1 - active.

Question 10

Glycogen Breakdown:

Answer 10

Glycogen + Pi –> Glucose 1-phosphate
GLYCOGEN PHOSPHORYLASE

G-1-P –> glucose 6-phosphate
PHOSPHOGLUCOMUTASE
(Go to glycolysis in muscle due to lack of G-6-Pase. Metabolised to produce energy)

G-6-P + H2O –> Glucose + Pi
GLUCOSE 6-PHOSPHATASE (liver and kidney)

Glycogen phosphorylase is needed to break α-1,4 bonds and a debranching enzyme is needed to break α-1,6 bonds.

Question 11

How is glycogen phosphorylase regulated?

Answer 11

Glycogen phosphorylase when phosphorylated via glycogen phosphorylase kinase - active.
When dephosphorylated via a phosphatase - inactive.

Question 12

How does adrenaline/glucagon causes glycogen breakdown?

Answer 12

Glucagon acts on GPCR -> AC -> cAMP -> PKA

PKA phosphorylates glycogen synthase (inactive) and phosphorylates glycogen phosphorylase indirectly via glycogen phosphorylase kinase (active). This promotes glycogen breakdown.

Question 13

How does insulin inhibit glycogen breakdown?

Answer 13

In the presence of insulin, phosphatase is activated. This dephosphorylates glycogen synthase (active) and glycogen phosphorylase (inactive). This promotes glycogen synthesis.

Question 14

Additional Control of Glycogen Breakdown: Liver

Answer 14

Liver is sensitive to changes in BGLs and under control of insulin and glucagon. When BGLs are high, glucose binds to glycogen phosphorylase and inhibits it.

Question 15

Additional Control of Glycogen Breakdown: Muscle

Answer 15

During muscle contraction, have calcium release from SER. Calcium can bind to calmodulin domain on glycogen phosphorylase kinase and activates the enzyme. This phosphorylates glycogen phosphorylase causing it to be active –> Glycogen breakdown. This provides energy for contracting muscles.

In prolonged exercise, ATP is reduced and AMP is high. ATP - negative modulator/allosteric inhibitor of glycogen phosphorylase - inhibits glycogen breakdown.

AMP - allosteric activator of glycogen phosphorylase - stimulates glycogen breakdown.

Question 16

Glycogen Storage Diseases:

1) Von Gierke’s
2) Pompe’s
3) McArdle’s

Answer 16

1) Defective glucose-6-phosphatase - englarged liver and hypoglycaemia
2) Defective lysosomal glycosidase (important for glycogen breakdown) - cardiac failure and muscle weakness
3) Defective glycogen phosphorylase - exercise intolerance