Lecture 22 Glycogen Metabolism II Flashcards
What is the purpose of glycogen metabolism?
To maintain blood sugar and provide energy to the muscles
Describe regulation of the synthesis of glycogen
The main enzyme is the glycogen synthase, which is the rate limiting step of the reaction
-glycogen synthase is active in the NONphophorylated “a” form
phosphorylations occur with the help of the glycogen synthase kinase (GSK) which is under the control of insulin and PKA (you want the glucose to STOP being synthesized with high blood sugar, which is when glucose is released
allosterically regulated by glucose-6-phosphate, which is an activator, stabilizing the active form
Describe the regulation of the degradation of glycogen
Key enzyme is the glycogen phosphorylase (GP), which is the rate limiting step of glycogen degradation
enzyme is in two forms:
active “a” in the liver and it is in the Relaxed state, because more stuff is able to access the binding sites
inactive “b” form in the muscle, which is in the T state
Compare the GPs that are present in the liver versus the muscle
The GP in the muscle is allosterically activated by AMP, because there is not enough energy in the muscles, which is what drives the glycogen break down
the GP in the liver is inactivated by free glucose, because the liver reacts to changes in blood glucose, and if your blood glucose is high, then you dont need to break down glycogen
If you have mutations present in the GP’s, which diseases result (think of where the GP’s are)
In the liver, a mutation in the GP leads to Hers disease
In the muscle, the mutation in GP leads to McArdle syndrome
Describe the allosteric regulation of the liver GP
The default form is the active form. When free glucose comes into the liver, it inactivates the enzyme by binding to the active site and switching the enzyme to the T states
Why would you want the GP in the liver to be deactivated in a time of high blood sugar?
Because if you have a high blood sugar, and your GP is active, then it will continue to make glucose which is bad because your blood sugar would sky rocker. But since the liver GP is inactivated by free glucose, this allows for the glycogen breakdown to STOP, essentially letting the glucose in the blood level out
Describe the allosteric regulation of the muscle GP
Default is the inactive form but the enzyme is activated by AMP, which is a signal that the muscle is in need of more energy. The AMP binds to the active site and stabilizes the R state
when the muscle contracts, the ATP is switched to AMP, which signals the breakdown of glycogen
ATP and G6P are negative allosteric inhibitors of muscle GP
Why does it make sense that ATP and G6P are the negative allosteric regulators of muscle GP
Well, if you have a ton of ATP, the muscle cell is not going to need excess energy. Also if you have G6P that also is indicative that you have free glucose in the cell and ALSO free ATP (because that step uses ATP in glycolysis, you know?), so then it makes sense that G6P would be a negative thing for muscle GP
When is glycogenesis favored?
in the FED state
blood glucose is high, insulin is high, and cellular ATP is high
When glycogenesis is favored, what states are the two important enzymes in?
GS is in the active form and is dephosphorylated
GP is in the inactive form and is also dephosphorylated
When is glycogenolysis favored?
In the fasting state, when the blood glucose is low and the glucagon is high
OR exercise: so the cell calcium is HIGH And the AMP is HIGH
When glycogenolysis is favored, what are the states that the two important enzymes are in?
GS is in the phosphorylated inactive form
GP is in the phosphorylated active form
Describe how insulin is able to regulate glycogen synthesis
- a high blood glucose leads to the release of insulin from the Beta cells of the pancreas
- insulin binds to its receptor tyrosine kinase to activate a signaling cascade via the insulin receptor complex
- PKB is activated and starts strutting her stuff to do her job
- GLUT 4 is translocated to the membrane
- PKB phosphorylates GSK3 PP1 (activating it) which is then able to dephosphorylate GS (activates) which can then lead to the CREATION Of glycogen, lowering the glucose levels.
- AT THE SAME TIME AS 5- PKB also phosphorylates GSK3, which is a kinase, and inactivates it. This is important because you want your GS and GP to STAY dephosphorylated and GSK3 would would to rephosphorylate eveyrything, because thats what she do best
Describe Type 2 diabetes
Reduced sensitivity to insulin, also known as insulin resistance. This happens from mutations in the insulin receptor and downstream signaling proteins
What causes the down regulation in receptor levels?
- elevated insulin
- endocytosis and degradation of the insulin receptor
- defective receptors not being replaced by translation
What is a normal blood glucose? Both fasting and fed
fasting 70-100
fed 140
What is a pre-diabetic blood glucose? fasting? fed?
Fasting: 100-125
Fed: greater than 140
What is a DM blood glucose? fasting? fed?
fasting: above 126
fed above 199
Describe the roles of glucagon and epinephrin on the control of GP
Epi and glucagon signal glycogen breakdown
When the blood sugar gets low the LIVER releases glucagon
Muscle activity causes the release of epinephrine, which allows for the activation of GP because you want more glucose to be made available
BOTH mediated with GPCR
Describe the activation of the phosphorylase kinase
- In the inactive form
- increase in calcium from a nerve impulse, muscle contraction, or hormones
- enzyme is partially active, PKA and hormones act on it to transition it to the fully active state
- ATP phosphoryl groups can inactivate it or activate it as she pleases I think
Describe the regulation by glucagon
- blood glucose levels are low and the alpha cells of the pancreas release glucagon in hopes of increasing the BG levels
- Glucagon binds to the GPCR in the liver cells which turns on the G protein
- Activates AC which forms cAMP
- cAMP activates PKA
- PKA phosphorylates GS (inactivates) and phosphorylates PK (activate-remember, you want things to be phosphorylated here so having an active kinase is just good backup)
- PKA also phosphorylates an inhibitor which inactivates PP1
- Active PK phosphorylates GP which activates it so that the glycogen can be broken down to release extra glucose into the blood
What does G6P do in regards to the key enzymes?
activates GS and inactivates GP
What does free glucose do in regards to the enzymes?
inhibits GP in the liver but NOT in the muscle
