Week 3 - Glycogen Metabolism - Skildum

Question 1

What is the difference between how glycogen stored in the liver can be used, compared to storage in skeletal or cardiac muscle?

Answer 1

Glycogen form the liver can be converted to glucose and sent all over the body for use in the blood.
Glycogen in muscle tissue is only turned into glucose-6-phosphate, which means it only goes into glycolysis in the same spot without leaving and going out into the rest of the body.

Question 2

What are the general symptoms of glycogen metabolism disorders?

Answer 2

fasting hypoglycemia (should be converting glycogen to glucose in the liver during fasting)

Muscle pain during exercise (Muscles cannot make gluc-6-phosphate from glycogen when they need it)

Question 3

What are the two types of Carbon bonds in glycogen. What are their functions?

Answer 3

1-4 bonds create linear chains of glucose

1-6 bonds create branches off of the chains

Question 4

Why is a bunch of chains with tons of branching be good for glycogen?

Answer 4

Because you can have a ton of enzymes breaking up chains all over the place

This makes for very rapid glucose release when it is needed

Question 5

What is the direction of glycogen chain elongation?

Answer 5

1’ to 4’

Question 6

In order to attach glucose to the growing glycogen chain, what must a single glucose be attached to?

Answer 6

a UDP, which is cleaved off as glucose is added to the chain

Question 7

What is the key enzyme to glycogen creation?

What disorder is caused when it is not functional?

Answer 7

Glycogen synthase!

Glycogen Synthase Deficiency GSD-0
You have exercise intolerance, cardiac and muscle hypertrophy (Hypertrophy just means tissue enlargement)
This could also be tissue specific, is the deficiency in skeletal or heart muscle? The liver?

Question 8

Describe the symptoms and treatment of glucose-6-phosphatase deficiency or GSD-1 ???

Answer 8

Symptoms:

• Fasting hypoglycemia and lactic acidosis
• Hepatomegaly due to glycogen accumulation
• Hyperuricemia and hyperlipidemia

Treatment:
-Avoid fasting by frequent feeding
-uncooked cornstarch
REMEMBER: This enzyme is only found in the liver!

Question 9

Describe the symptoms and treatment for 1,6-glucosidase activity deficiency in the debranching enzyme. (AKA GSD-3, AKA Cori Disease)
Difference between GSD 3a and GSD 3b?

Answer 9

Symptoms:Fasting hypoglycemia and ketoacidosis, hyperlipidemia. Hepatomegaly with elevated AST/ALT.

GSD IIIa affects liver and muscle.
GSD IIIb affects only the liver.

Treatment: Frequent high carbohydrate meals.
(The problem is that you can’t get rid of that last 1,6 branching glucose residue, so you cant chop up the glycogen)

Question 10

Describe the symptoms and treatment for GSD-4, a deficiency of branching enzyme 4,6-transferase.

Answer 10

Failure to thrive, hepatomegaly, liver failure. Fatal.

This is bad. Basically you can’t branch your glycogen, which makes for some pretty terrible and nonfunctional glycogen…

Question 11

Describe the symptoms and treatment for GSD-5, a deficiency in MUSCLE glycogen phosphorylase.
(AKA McArdle Disease)

In LIVER glycogen phosphorylase it would be GSD-6 or Hers Disease…

Answer 11

-Late childhood onset of exercise intolerance
-myoglobinuria after exercise
Increased creatine kinase
-exagerated increase of creatine kinase and ammonia after exercise.

Treatment: Avoid exercise; try to build tolerance

Question 12

What does glycogen phosphorylase do?

Answer 12

It cleaves units of glucose from a glycogen chain, adding a phosphate group so that it becomes glucose-1-phosphate.
Glc-1-P can then go on to become Glc-6-P in muscle, or all the way to glucose in the liver.

Question 13

Explain the two steps performed by debranching enzyme:

Answer 13

4:4 transferase cleaves a 1:4 glycosidic bond and transfers three glucoses to the end of another chain in a 1:4 bond.

α-1,6 glucosidase hydrolyzes the remaining single glucose’s 1:6 bond to release the glucose.

REMEMBER: Deficiency in 1,6 glucosidase activity results in GSD III. (Cori Disease)

Question 14

Referring to Lineweaver-Burke plots, what should you remember about the Km’s and Vmax’s?

Answer 14

They are inverted, so don’t get mixed up. A higher 1/Vmax will obviosuly mean a lower Vmax.
Just sayin.

Question 15

Phosphorylation is an important regulator of glycogen metabolism. Does phosphorylation occur in the fed or fasting states? How does phosphoryaltion affect glycogen phosphorylase and glycogen synthase?

Answer 15

In the fed state, phosphorylase is inactive and glycogen synthase is active. Both are unphosphorylated.

In the fasted state, phosphorylase is active and glycogen synthase is inactive. Both are phosphorylated.

Question 16

Describe the 2 pathways by which epinephrine acts to deactivate glycogen synthesis in the fasted state:

Answer 16

Starts by activating Phospholipid C which divides into DAG and IP3

DAG activated Prot. Kinase C, which phosphorylates to deactivate glycogen synthase

IP3 activates Ca-dependent kinase which phosphorylates to deactivate glycogen synthase

Question 17

Describe the mechanism by which glucagon inhibits glycogen synthesis and activates glucose production in the fasted state:

Answer 17

Glucagon increases cAMP, which activates PKA.
PKA can then phosphorylate both glycogen synthase to deactivate it and glycogen phosphorylase kinase to activate it. GPK can then phosphorylate and activate glycogen phosphoryase to activate it. GP can then break down glycogen.

Question 18

Describe the mechanism by which insulin encourages glycogenogenesis and discourages glycogenolysis:

Answer 18

Insulin activates PKB
PKB activates protein phosphatase, which can inactivate glycogen phosphorylase kinase and glycogen phosphorylase. It also directly dephosphorylates glycogen synthase

Meanwhile, glycogen synthase is unphosphorylated and active.

Question 19

What does glucose-6-phosphatase do and where is it found?

Answer 19

It converts glucose-6-phosphate to glucose in order to add glucose to the blood!

It is only found in hepatocytes. This means in muscles there is no way to break down glycogen all the way to glucose to put in the blood. They only go to Glc-6-P and then use that for glycolysis.

Question 20

How is the regulation of glucagon different in muscle cells than it is in liver cells?

Answer 20

In muscle cells the fed state is regulated by glucose in the EXACT same way.
The fasting state is a little different.
Epinephrine works the same way, but there is NO glucagon receptor. Ca-dependent kinase can phosphorylate glucagon phosphorylase kinase(GPK) after being activated by Ca from nerve impulses and muscular work can create AMP to activate AMP-K which can allosterically activate GPK. GPK can then activate glycogen phosphorylase and stimulate glycogenolysis to Glc-6-P.

Question 21

Why would the number of chromosomes be increased and their structure abnormal in the cells of a patient with a glycogen storage disorder?

Answer 21

Over proliferation of mitochondria is a compensatory strategy for cells because of their lack of glycogen to use for energy

Question 22

By starving cultured cells and measuring the amount of lactate in their solution it is possible to see what?

Answer 22

Whether or not they have accessible storage of glycogen. NO increase in lactate would indicate that they do not.