Skildum- Glycogen Metabolism

Question 1

What is glycogen?

Answer 1

1. Polymer of glucose.

2. A glucose storage molecule for most cell types,

Question 2

For what cell types is glycogen most important?

Answer 2

1. Heart and skeletal muscle: Serves as a buffer for glucose 6-phosphate for use within the cell
2. Liver: Serves as a glucose buffer for the blood

Question 3

Defects in glycogen metabolism present as…

Answer 3

fasting hypoglycemia

muscle pain during exercise

Question 4

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

Answer 4

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

Question 5

What is UDP glucose?

Answer 5

1. The substrate for glycogen synthesis–a charged up glucose
2. Glucose that is coiled onto a spring
3. Has 2 phosphates and a nice nucleotide base handle for enzymes

Question 6

What happens in the presence of insulin to glycogen synthesis?

Answer 6

Insulin signaling ACTIVATES protein phosphatase-1, which dephosphorylates glycogen synthase, activating glycogen synthase

Question 7

What happens to glycogen synthesis in the absence of insulin?

Answer 7

Glycogen synthase kinase-3 is active, which phosphorylates and inactivates glycogen synthase

Question 8

The direction of elongation goes towards what carbon?

Answer 8

The 4 carbon

Question 9

Glycogen synthesis: What happens during elongation?

Answer 9

1. Glycogen synthase continues to add UDP-glucose to the chain. Elongation continues linking glucose in 1:4 bonds until the chain is ~11 units long.
2. Branching enzyme (glycosyl 46 transferase) then cleaves a piece of the chain off, and attaches it to the chain in a 1:6 glycosidic linkage. Both branches then can be extended with 1:4 bonds.

Question 10

What are the key enzymes in glycogen synthesis (glycogenogenesis)?

Answer 10

Glycogen synthase and 4:6 transferase

Question 11

What happens if glycogen synthase is deficient?

Answer 11

1. Low/no glycogen storage.

2. Caused by mutation, mutation causes GSD 0

Question 12

WHat happens if 4:6 transferase is deficient?

Answer 12

1. Defect in a branching enzyme: a.k.a. amylo-4:6-glucosidase a.k.a. branching enzyme
   mutation causes GSD IV, Anderson disease

Question 13

What advantages does branching provide to the huge glucose polymer?

Answer 13

Structure is puff ball of glucose with glycogenic protein in middle.

This is a branched polymer which is unique in biology. Most polymers are unbranched, strictly linear. Glucose is central to metabolism in the cell, this shape allows the cell to have 100 different points where you can break off glucose simultaneously. Allows you to finely control intracellular glucose concentration and match it to work demand. Cell makes gene expression changes in response to energy demand, but those are long term adaptations. Gly synth/degradation is short term glucose buffer. It can be a short term buffer b/c enzymes can act one way or another in many diff directions. Branching also increases solubility, meaning more exposed OH groups from glucose.

Question 14

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

Answer 14

1. Glycogen phosphorylase: cleaves units of glucose from glycogen chains and adds inorganic phosphate to make glucose 1-phosphate. Phosphorylase can not cleave glucose when it gets within four units of a branch point.
2. Debranching enzyme has 2 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) α-1,6 glucosidase activity hydrolyzes the remaining glucose’s 1:6 bond to release glucose

Question 15

Mutations in muscle glycogen phosphorylase cause what disease?

Answer 15

GSD V McArdles disease

Question 16

Mutations in liver glycogen phosphorylase causes what disease?

Answer 16

GSD VI (Hers disease).
Deficiency in 1,6 glucosidase activty result in GSD III.

Question 17

WhMutations in 1,6 glycosidase result in what disease?

Answer 17

GSD III a- liver and muscle b-only liver

Question 18

When looking at a line weaver plot, how do you know which enzyme is the most active?

Answer 18

More active enzyme has:
SMALLER km
Lower 1/vmax–> vmax is higher

Question 19

Glycogen metabolism is controled by what two enzymes?

Answer 19

The phosphorylation of glycogen phosphorylase and glycogen synthase

Question 20

What happens to the two key enzymes in the fed state?

Answer 20

Phosphorylase is inactive and glycogen synthase is active. Both are unphosphorylated.

Question 21

What happens to the two key enzymes in the fasted state?

Answer 21

Phosphorylase is active and glycogen synthase is inactive. Both are phosphorylated.

Question 22

What is GSD 0?

Answer 22

1. Glycogen synthase deficiency.
2. Rare autosomal recessive
3. Normal glucose tolerance; variable clinical presentation of exercise intolerance, cardiac and muscle hypertrophy

Question 23

What is GSD I?

Answer 23

1. Von Giercke Disease
   Deficiency in glucose 6-phosphatase.
2. Fasting hypoglycemia, lactic acidosis. Hepatomegaly due to glycogen accumulation. Hyperuricemia and hyperlipidemia.
3. Treatment:
   Avoid fasting by frequent feeding, uncooked cornstarch

Question 24

What is GSD III?

Answer 24

Deficiency of 1,6-glucosidase activity of debranching enzyme.

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.

Question 25

What is GSD IV?

Answer 25

Deficiency of branching enzyme, 4:6-transferase.

Failure to thrive, hepatomegaly, liver failure. Fatal.

Question 26

What is GSD V?

Answer 26

McArdle Disease
Deficiency of muscle glycogen phosphorylase.

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