Lecture 22 Glycogen Metabolism II

Question 1

What is the purpose of glycogen metabolism?

Answer 1

To maintain blood sugar and provide energy to the muscles

Question 2

Describe regulation of the synthesis of glycogen

Answer 2

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

Question 3

Describe the regulation of the degradation of glycogen

Answer 3

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

Question 4

Compare the GPs that are present in the liver versus the muscle

Answer 4

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

Question 5

If you have mutations present in the GP’s, which diseases result (think of where the GP’s are)

Answer 5

In the liver, a mutation in the GP leads to Hers disease

In the muscle, the mutation in GP leads to McArdle syndrome

Question 6

Describe the allosteric regulation of the liver GP

Answer 6

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

Question 7

Why would you want the GP in the liver to be deactivated in a time of high blood sugar?

Answer 7

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

Question 8

Describe the allosteric regulation of the muscle GP

Answer 8

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

Question 9

Why does it make sense that ATP and G6P are the negative allosteric regulators of muscle GP

Answer 9

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

Question 10

When is glycogenesis favored?

Answer 10

in the FED state

blood glucose is high, insulin is high, and cellular ATP is high

Question 11

When glycogenesis is favored, what states are the two important enzymes in?

Answer 11

GS is in the active form and is dephosphorylated

GP is in the inactive form and is also dephosphorylated

Question 12

When is glycogenolysis favored?

Answer 12

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

Question 13

When glycogenolysis is favored, what are the states that the two important enzymes are in?

Answer 13

GS is in the phosphorylated inactive form

GP is in the phosphorylated active form

Question 14

Describe how insulin is able to regulate glycogen synthesis

Answer 14

1. a high blood glucose leads to the release of insulin from the Beta cells of the pancreas
2. insulin binds to its receptor tyrosine kinase to activate a signaling cascade via the insulin receptor complex
3. PKB is activated and starts strutting her stuff to do her job
4. GLUT 4 is translocated to the membrane
5. 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.
6. 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

Question 15

Describe Type 2 diabetes

Answer 15

Reduced sensitivity to insulin, also known as insulin resistance. This happens from mutations in the insulin receptor and downstream signaling proteins

Question 16

What causes the down regulation in receptor levels?

Answer 16

• elevated insulin
• endocytosis and degradation of the insulin receptor
• defective receptors not being replaced by translation

Question 17

What is a normal blood glucose? Both fasting and fed

Answer 17

fasting 70-100

fed 140

Question 18

What is a pre-diabetic blood glucose? fasting? fed?

Answer 18

Fasting: 100-125
Fed: greater than 140

Question 19

What is a DM blood glucose? fasting? fed?

Answer 19

fasting: above 126

fed above 199

Question 20

Describe the roles of glucagon and epinephrin on the control of GP

Answer 20

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

Question 21

Describe the activation of the phosphorylase kinase

Answer 21

1. In the inactive form
2. increase in calcium from a nerve impulse, muscle contraction, or hormones
3. enzyme is partially active, PKA and hormones act on it to transition it to the fully active state
4. ATP phosphoryl groups can inactivate it or activate it as she pleases I think

Question 22

Describe the regulation by glucagon

Answer 22

1. blood glucose levels are low and the alpha cells of the pancreas release glucagon in hopes of increasing the BG levels
2. Glucagon binds to the GPCR in the liver cells which turns on the G protein
3. Activates AC which forms cAMP
4. cAMP activates PKA
5. 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)
6. PKA also phosphorylates an inhibitor which inactivates PP1
7. Active PK phosphorylates GP which activates it so that the glycogen can be broken down to release extra glucose into the blood

Question 23

What does G6P do in regards to the key enzymes?

Answer 23

activates GS and inactivates GP

Question 24

What does free glucose do in regards to the enzymes?

Answer 24

inhibits GP in the liver but NOT in the muscle

Question 25

What does Ca2+ do in regards to the two enzymes?

Answer 25

activates GSK, which keeps things phosphorylated, which will allow for the GP active, and the GS inactive, favoring the breakdown of the glycogen

Question 26

Describe the “off switch” that is present in the regulation of glycogenolysis

Answer 26

• shuts down when the secretion of the hormone stops
• PK and GP are dephosphorylated and inactivated
• breakdown STOPS
• synthesis is promoted for reserves

Question 27

What is the fate of Glu-1-P in the liver and the muscle?

Answer 27

In the liver, the G1P can be turned into G6P and released as free glucose

In the muscle, G6P cannot be made, so it is used to generate energy

Question 28

Who is the glycogen sensor in the liver cells?

Answer 28

Glycogen phosphorylase

Question 29

Describe GSD I

Answer 29

Von Glerke disease

Defective enzyme: Glucose-6-phosphatase or the transport system

This affects the liver and the kidney, and causes and increased amount of glycogen

Question 30

Describe GSDII

Answer 30

Pompe disease

Defecive enzyme is the alpha 1,4, glucosidase (lysosomal)

all organs are affected with an increased amount of glycogen (MASSIVE) with a normal structure

Question 31

Describe GSD III

Answer 31

Cori disease:

Defective enzyme is alpha 1,6 glucosidase

Affects the muscle and the liver, leads to an increased amount of glycogen that has shorter outer branches

they have light hypoglycemia and hepatomegaly

Question 32

Describe GSD IV

Answer 32

Andersen disease,

defective branching enzyme (alpha 1,4 to alpha 1,6)

affects the liver and the spleen

Normal amounts of glycogen except they have long branches

causes enlargement of the liver and spleen, scarring of tissue

Question 33

Describe GSD V

Answer 33

McArdle disease

defective enzyme is the glycogen phosphorylase

The muscle is affected, and there is a moderately increased amount of glycogen

Rate limiting step of glycogen breakdown. They have weakness and muscle cramps, exercise intolerance, myoglobinuria

Question 34

Describe GSD VI

Answer 34

Hers disease

defective enzyme is the phosphorylase

The liver is affected and there is an increased amount of glycogen

prevents glycogen breakdown in liver, and accumulates. Low blood glucose levels

Question 35

Describe GSD VII

Answer 35

The defective enzyme is phosphofructokinase

It affects the muscle and there is an increased amount of glycogen with a normal structure

Question 36

Describe GSD VIII

Answer 36

The defective enzyme is phosphorylase

It affects the liver and there is an increased amount glycogen with a normal structure

Question 37

Describe the enzyme replacement therapy (ERT)

Answer 37

A recombinant human alpha glucosidase is delivered via intravenous infusion in babies and children