Metabolic regulation and Glycogen Metabolism

Question 1

How are ATP and AMP key cellular regulators?

Answer 1

• 10% decrease in ATP can affect activity of ATP utilizing enzymes -> leads to increase in AMP (AMP can become more potent allosteric regulator

Question 1

What is feedback inhibition?

Answer 1

Ultimate products of metabolic pathways directly or indirectly inhibit their own biosynthetic pathways
Ex: High ATP inhibits committed step of glycolysis to prevent excess glucose degradation

Question 2

How does AMP differentially affect pathways in different tissues?

Answer 2

Via AMPK

Question 3

How are hexokinase and phosphofructokinase appropriate targets for regulation of glycolytic flux?

Answer 3

• Increased hexokinase activity enables activation of glucose
• Increased phosphofructokinase-1 activity enables catabolism of activated glucose via glycolysis

Question 4

What are the four isozymes of Henokinase?

Answer 4

HK I-IV

HK I: expressed in all tissues, to different levels
HK IV: expressed only in the liver
- higher Km -> responds to higher glucose
- function: clear blood glucose for storage as glycogen
- not inhibited by G6P -> functions at higher glucose

Question 5

What are isozymes?

Answer 5

Isozymes: different enzymes that catalyze the same reaction
- has similar sequences but may have different kinetic properties and be regulated differently

Question 6

What is HK IV (hexokinase IV) regulated by?

Answer 6

Sequestration

Protein “glucokinase regulatory protein (GCKR)” binds to hexokinase IV and confines it to the nucleus, rendering it inactive until needed, thus controlling its access to the cytoplasm where it can phosphorylate glucose

Question 7

How is Phosphofructokinase-1 regulated?

Answer 7

• Commitment step in glycolysis: fructose-6-phosphate -> fructose 1,6-biphosphate
• ATP: substrate but also a negative effect (if there is a lot of ATP, glucose is not spent in glycolysis)

Question 8

When should Glycolysis or Gluconeogenesis be used depending on AMP and ATP? (Regulation of Phosphofructosekinase 1 and Fructose 1,6-Biphosphate)

Answer 8

Glycolysis: if AMP is high and ATP is low
Gluconeogenesis: if AMP is low

Question 9

What is the purpose of Fructose 2,6-biphosphate (F-2,6-bp)? How does it differentially regulate Glycolysis and Gluconeogenesis?

Answer 9

• Regulator intermediate: made to regulate glycolysis and gluconeogenesis
• Activates phosphofructokinase (glycolysis)
• Inhibits fructose 1,6-biphosphatase (gluconeogenesis)

Question 10

How are F-2,6-bp levels regulated?

Answer 10

Through PFK-2 and FBPase-2
- These two enzymes are conjoined and regulated via phosphorylation

Different than enzymes in glycolysis and gluconeogenesis (usually independent)

Question 11

What can Pyruvate be used for?

Answer 11

• Source of new glucose: store energy as glycogen
• Source of acetyl-CoA: store energy as body fat

Question 12

How does acetyl-CoA stimulate glucose synthesis?

Answer 12

• Via gluconeogenesis by activating pyruvate carboxylase

Question 13

What are the two transcription factor pathways influenced by metabolic needs?

Answer 13

Glucose and Insulin pathways

Question 14

Glucose can be stored for later use as Glycogen. What is Glycogen? How can Glycogen be made?

Answer 14

• branched polymer of a(1-4)-linked glucose with a(1-6) linkages every 12-14 glucose units
• Glycogen storage mainly in liver and muscle
• Glycogen degraded to glucose to use in energy production
• Glycogen can be made from excess blood glucose or recycling of glucogenic metabolites (lactate/some AA)

Question 15

What removes the glucose residues from glycogen?

Answer 15

Glycogen Phosphorylase

Question 16

How to deal with branch points in Glycogen?

Answer 16

• Glycogen phosphorylase: works on nonreducing ends until it reaches resides from (a1-6) branch point
• Debranching enzyme: transfers block of 3 residues to non-reducing end of chain
• Debranching enzyme: cleaves the only remaining (a1-6)-linked glucose -> becomes free glucose unit

Question 17

For metabolism, what does Glucose-1-Phosphate have to be isomerized to?

Answer 17

It has to be isomerized to Glucose-6-Phosphate
- This is done by Phosphoglucomutase (similar mechanism to Phosphoglycerate mutase)

Question 18

How is Glucose-6-Phosphate transported out of the liver?

Answer 18

G-6-P is dephosphorylated
- It is isolated in the ER lumen, which allows the use of concentration gradients for glucose and glucose-6-phosphate to control flux out of the liver

Question 19

What is the substrate for glycogen synthesis?

Answer 19

UDP-Glucose

Question 20

What is the substrate for NDP-Sugar Pyrophosphorylase?

Answer 20

Glucose-1-Phosphate
Phosphoglucomutase is reversible:
- In degradation: G-1-P converted to G-6-P
- In synthesis: G-6-P converted to G-1-P

Question 21

Where does regulation happen in glycogen synthesis and degradation?

Answer 21

At irreversible points in the pathway
- similar to glycolysis and gluconeogenesis

Question 22

What controls glycogen breakdown?

Answer 22

Glucagon/Epinephrine signaling pathway:
- starts phosphorylation cascade via cAMP, activates glycogen phosphorylase

Glycogen phosphorylase: cleaves glucose resides off glycogen -> generates glucose-1-phosphate

Question 23

What stimulates the breakdown of glycogen?

Answer 23

Epinephrine and Glucagon

Question 24

What controls glycogen synthesis?

Answer 24

Insulin-signaling pathway:
- increases glucose import into muscle, stimulates activity of muscle hexokinase, activate glycogen synthase

• Increased hexokinase activity: allows activation of glucose
• Glycogen synthase: makes glycogen for energy storage

Question 25

What controls glycogen synthesis?

Answer 25

Phosphorylation

Question 26

How does Insulin signaling activate glycogen synthase?

Answer 26

By inactivation GSK3