Glycogen Metabolism Lecture Sep 9

Question 1

Glycogen is a polymer of what?

Answer 1

Glucose

Question 2

Glycogen is most important in what tissues? For what reasons?

Answer 2

Heart and skeletal muscle: servies as a buffer for glucose 6-phosphate for use within the cell

Liver: serves as a glucose buffer for the blood

Question 3

Defects in glycogen metabolism often present as what two general symptoms?

Answer 3

Fasting hypoglycemia

Muscle pain during exercise

Question 4

What two types of C-C bonds are found in glycogen?

Answer 4

1: 4 - bonds between the 1 and 4 carbons make linear chains
1: 6 - bonds between the 1 and 6 carbons make branch points

Question 5

Wat are the steps of glycogen synthesis?

Answer 5

Glucose 1-phosphate is acted on by UDP glucose pyrophosphorylase to form UDP-glucose

Glycogen synthase adds the UDP-glucose onto the nonreducing end of a growing glycogen chain

It will continue to add UDP-glucose in the direction of the 4 carbon through 1:4 bonds until the chain is about 11 units long.

Branching enzyme (glycosyl 4-6 transferase) then cleaves a piece of the chain off and attaches it to the chian in a 1:6 glycosidic linkage

Both branches can then be extended with 1:4 bonds

Question 6

What are the two important enzyes in glycogen synthesis?

Answer 6

Glycogen synthase (add UDP-glucose in 1:4 bonds to the glycogen chain)

4:6 Transferase (branching enzyme) transfer glucose into 1:6 bond to make a branch.

Question 7

What advantage does branching provide for glycogen?

Answer 7

The branching allows for rapid removal or rapid addition of glucose to the chain because the enzymes can act in hundreds of locations instead of just the one end available on a linear polymer

Question 8

What are the two key enzymes in glycogen degradation (glycogenolysis)?

Answer 8

Glycogen Phosphorylase

Debranching enzyme

Question 9

What does glycogen phosphorylase do?

Answer 9

1. Cleaves units of glucose from glycogen chains
2. Adds inorganic phosphate to make glucose 1-phosphate

Note: phosphorylase cannot cleave glucose when it gets within 4 units of a branch point.

Question 10

What does debranching enzyme do?

Answer 10

It has two activities:

1. 4:4 transferase cleaves a 1:4 glycosidic bond and transfers three glucose units to the end of another chain in a 1:4 bond.
2. alpha-1,6 glucosidase activity hydrolyzes the remaining glucose’s 1:6 bond to release glucose

Question 11

WHat are the two forms of glycogen phosphorylase?

WHich is the more active enzyme? Why?

Answer 11

the a form and the b form.

The a form is more active

Question 12

What protein is in the center of a glycogen polymer?

Answer 12

Glycogenin

It has a serine residue with an OH on which the addition of glucose begins

Question 13

How is glycogen metabolism controlled?

Answer 13

It is controlled trhough phosphorylation of glycogen phosphorylase and glycogen synthase.

Glycogen synthase is inactivated through phosphorylation

Glycogen phosphorylase is activated through phosphorylation.

So just remember that things are unphosphorylated during the fed state, so glycogen synthase is unphosphorylated and active and glycogen phosphatase is unphosphorylated and inactive

Both are phosphorylated during the fasted state, so glycogen synthase is phosphorylated and inactive and glycogen phosphatase is phosphorylated and active in the fasted state.

Question 14

What tissue is affected by both glucagon and epinephrine?

What tissues does glucagon not affect?

Answer 14

Glucagon only affects the liver.
Epinephrine will also affect the liver.

All other tissues are only affected by epinephrine–they don’t have glucagon receptors.

Question 15

What are the 3 arms of regulation in hepatocytes during the fasted state?

Answer 15

1. Glucagon and the beta adrenergic receptors for epinephrine activate cAMP which activated PKA. PKA phosphorylates glycogen synthase to inactivate it and phosphorylates glycogen phosphoylrase kinase to activate it. Glycogen phosphorylase kinase phosphorylates glycogen phosphorylase to activate it, which will break down glycogen to form glucose
2. epinephrine alpha adrenergic receptor activate PLC, which cleaves PIP2 to DAG and IP3. DAG will activate PKC which will phosphorylate glycogen synthase to inactivate it. IP3 will trigger a calcium release which will activated Ca/calmodulin dependent kinase to phosphorylate glycogen synthase to inactivate it. Ca/calmodulin dependent kinase will also phosphorylate glycogen phosphorylase kinase to activate it, which will activate glycogen phosphorylase to undergo glycogenolysis.

Question 16

How is glycogen metabolism regulated during the fed state in hepatocytes?

Answer 16

Insulin binds to its tryosine kinase receptor.

This activates IRS-1, which recruits PI3

PI3K activates PDK, which activates PKB

PKB phosphorylates protein phosphatase-1 to activate it.

Protein phosphtase 1 dephosphorylates Glycogen Synthase to ACTIVATE it.

Protein phosphatase 1 dephosphorylates phosphorylase kinase to INACTIVATE it. Thus, glycogen phosphorylase kinase cannot activate glycogen phosphorylase a and you do not get glycogenolysis.

Question 17

What are the 4 regulatory arms in skeletal muscle during the fasted state?

Answer 17

In skeletal muscle there are no glucagon receptors, so the regulation occurs through epinephrine and AMP.

1. The epinephrine beta receptors (through cAMP, PKA, glycogen phosphorylase kinase, glycogen phosphorylase (active) and glycogen synthase inactive.
2. The epinephrine alpha receptors through the IP3/DAG signal

3, When work is going on in the muscle, AMP increases. AMP allosterically activates AMP-K, which phosphorylates glycogen phosphorylase kinase to activate glycogen phosphorylase.

4. Nerve impulses cause an increase in Ca++, which causes an activation of Ca++/calmodulin dependent kinase which activates glycogen phosphorylase kinase to activate glycogen phosphorylase

Question 18

Match the following:

Kinases

Phosphorylases

with the following:

glycogenolysis

glycogenogenesis

Answer 18

glycogenolysis: Kinases phosphorylate glycogen phosphatase to activate it and phosphorylate glycogen synthase to inactivate it.

Glycogogenesis: phosphatases dephosphorylate glycogen synthase to activate it and dephosphorylate glycogen phosphorylase kinase to deactivate it and thus deactiveate glycogen phosphorylase.

Question 19

What causes GSD 0?

What are the symptoms?

Treatment?

Answer 19

GSD 0 is glycogen synthase deficiency.

This means that the body doesn’t have the capacity to store glucose as glycogen.

It presents with normal glucose tolerance; variable clinical presentation of exercise intolerance, cardiac and muscle hypertrophy

This may be implicated in SIDs

Question 20

What cuases GSD I?

WHat else is it called?

What are the symptoms?

Treatment?

Answer 20

GSD I or von Giercke disease is a deficiency i glucose 6-phosphatase

This means the liver can’t take glycose 6 phosphate made from glycogenolysis and turn it into glucose for the rest of the body.

This results in fasting hypoglycemia, lactic acidosis, hepatomegaly (due to glycogen accumulation), hyperuricemia, and hyperlipidemia

Treatment: avoid fasting by frequend feeding with uncooked cornstarch

Question 21

What causes GSD III?

What is a nother name for it?

Symptoms?

Treatment?

What are the two forms of the disease?

Answer 21

GSD III is also called Cori disease.

It is a deficiency of 1,6-glucosidase activity of the debranching enzyme.

This means you can’t move the glucose that is bound in a 1;6 bond.

You develope fasting hypoglycemia, ketoacidosis and hyperlipidemia. Also hepatomegaly with elevated AST/ALT.

THERE ARE TWO FORMS!

GSDIIIa affects liver AND muscle. GSDIIIb affects liver only. (so you’d rather have b)

Treat with frequent high carb meals

Question 22

What causes GSD IV?

What are the symptoms?

Answer 22

GSD IV is caused by deficiency of the 4:6 transferase branching enzyme.

This is an inability to form branches in glycogen, thus an inability to synthesize glycogen in general.

The symptoms are FTF, hepatomegaly and liver failure. Typically fatal.

Question 23

What causes GSD V?

What is another name for it?

Symptoms?

Treatment?

Answer 23

GSD V is also known as McArdle disease

This is a deficiency of muscle glycogen phosphorylase, so you have an inability to undergo glycogenolysis in the muscles–an inability to use glycogen stores

This is a late childhood onset of exercise intolerance, myoglobinuria after exercise, increased creatine kinase (exp during exercise) and exaggerated increase in ammonia after exercise

Treatment: avoid exercise or try to build tolerance