4: Glycogen Synthesis (glycogenesis) And Glycogen Degradation (glycogenoysis)

Question 0

What is the role of glycogen stores in both the liver and the muscle?

Answer 0

Liver: storage and export of glucose; maintains blood glucose
-depleted after 12-18hrs of fasting
Essential for glucose homeostasis

Muscle: fuels glycolysis within muscle only. Depleted through prolonged vigorous excise.
Not essential for glucose homeostasis.
Used for high intensity exercise like running away from a lion

Question 1

Describe the structure and location of glycolysis

Answer 1

Glycogen is a highly-branched polysaccharide consisting of D-glucose monosaccharides joined by a-1,4 glycosidic bond and branching through a-1,6 glycosidic bonds.
Location: cytosol of all tissues, mainly in liver (up to 6% of weight) and muscle (1-2% of weight)

Question 2

What are the 2 words/pathways used to describe the storage and breakdown of glycogen?

Answer 2

Synthesis of glycogen➡ glycogenesis.
-when glucose supply is in excess (after meal)

Breakdown of glycogen (glycogenolysis)

• in liver when blood glucose concentration is low (glucose homeostasis)
• in muscle for ATP production during exercise

Question 3

Tell me about the pathway of glycogenesis?

Answer 3

The major regulatory enzymes of glycogenesis is glycogen synthase. Glycogenesis contains 2 other significant features:
A) glycogen synthesis needs a small protein called the glycogen primer to commence
B) glucose must be activated by UTP prior to addition prior to adding the elongating polysaccharide.

Question 4

Tell me about the pathway of glycogenolysis

Answer 4

Pathway:
-regulatory enzyme: glycogen phosphorylase (removed phosphate)
-which breaks the a-1,4 glycosidic bond of glycogen to yield glucose1-P
-the glucose 1-P is converted if glucose 6-P by PHOSPHOGLUCOMUTASE.
-in liver: enzyme G6phosphatase removes the phosphate allowing glucose to diffuse into blood to sustain blood glucose.
-in muscle: the glucose -P enters glycolysis producing ATP.
(This muscle glycolysis nett 3 moles of ATP are produce, because there is no need for the 1st ATP Requiring step ie hexokinase since glucose is already phosphorylated. So more ATP is produced

Question 5

How does 3’5’ cAMP coordinate the synthesis and breakdown of glycogen?

Answer 5

It is formed from an enzyme called adenylate cyclase in response to bonding of a hormone on its membrane receptor.
Soooo.
Hormones: adrenalin or glucagon bind to B-adregenic-type of membrane receptor on adenylate cyclase➡ adenylate cyclase increases cAMP levels inside target cell ➡ cAMP activates protein kinase A ➡ protein kinase A phosphorylates specific proteins➡ phosphorylation leads to changes in enzyme activities and metabolic responses.
Slide 16 of Lecture 5
The effects of cAMP are to inhibit glycogen synthesis and stimulate glycogen breakdown
-cAMP job is to activate cAMP-dependant protein kinase (PKA). The binding of cAMP to PKA activates the catalytic subunit so that PKA can covalently activate of inactivate other proteins and enzymes by phosphorylating them
Eg slide 17

Question 6

How is the regulatory enzyme switched off in the liver?

Answer 6

Glycogenesis in the liver

Question 7

How is the enzyme glycogen synthase regulated?

Answer 7

• insulin is needed to activate glycogen synthase
• insulin activates a specific protein kinase B (PKB) which inactivated glycogen synthase kinase (GSK)
• phosphoprotein phosphatase 1 is active in the presence of insulin. Phosphoprotein phosphatase 1 maintains glycogen synthase in the unphosphorylated, active state.
• when insulin is low or in the presence of glucagon or adrenalin, the synthase is inactive due to the action of glycogen synthase kinase which phosphorylates glycogen synthase
• at same time cAMP activates glycogen breakdown by activating enzymes that lead to heaps and heaps of activation of glycogen phosphorylase which leads to glycogen breaking down to glucose 1-P.
• glycogen phosphorylase is converted from being less active to active state via cAMP.
• muscle contraction releases calcium and activates the phosphorylase kinase enzyme
• glycogenolysis in liver is stimulated by cAMP-independant action of a1-adrenergic receptors

Question 8

How is glycogen phosphorylase regulate?

Answer 8

• in absence of adrenalin or glucagon, glycogen phosphorylase is in the unphosphorylated ‘b’ form. This form can be allosterically activated by AMP in the muscle.
• Ca2+ activates glycogen phosphorylase kinase. This activation doesn’t involve phosphorylation and only lasts for as long as muscle is contracting.
• adrenalin in muscle and liver and glucagon in liver, increase the levels of cAMP➡ Which allosterically activates activates protein kinase ➡ which activates glycogen phosphorylase kinase.
• activated glycogen phosphorylase kinase, phosphorylates the b form (inactive) of glycogen glycogen phosphorylase to the a (active) form ➡ which breaks down glycogen to glucose 1 P.
• phphoprotein phosphatase 1 removes the phosphate from the active form of glycogen phosphorylase back to being inactive.
• in the presence of cAMP, protein kinase A activates an inhibitor of phosphoprotein phosphatase so it can’t convert the a to b form.

Muscle contraction causes nett glycogen breakdown

Question 9

Tell me the summarised action of insulin?

Answer 9

• stimulates glucose uptake by muscle and adipose cells via type-4 GLUT transport proteins
• stimulates glycogen synthesis by activating glycogen synthase
• stimulates glycolysis at the PFK-1 enzyme and PDH
• stimulates fat synthesis at the acetyl CoA carboxylase enzyme
• stimulates protein synthesis

Question 10

Give me the summary action of glucagon

Answer 10

• target tissue is liver and adipose tissue
• stimulates glycogen breakdown in liver by activating glycogen phosphorylase
• stimulates gluconeogenesis in the liver at PFK1/F, 1,6bisP enzyme couple enzyme
• stimulates fat breakdown in adipose tissue by activating the hormone-sensitive lipase
• stimulates protein breakdown