Regulation

Question 1

Which products regulate Glycolysis and how?

Answer 1

Low [ATP] → Stimulates
Low [NAD], High [ATP] → Inhibits

Question 2

Which products regulate Oxidative Phosphorylation and how?

Answer 2

Low [ATP] → stimulates
High [ATP], Low [O2] or [NADH/FADH2] → inhibits

Question 3

Which are the main regulatory steps of Glycolysis?

Answer 3

Step 1: Glucose → G6P (invest 1 ATP)
Step 3: F6P → FBP (invest 1 ATP)
Step 10: PEP → Pyruvate (produces 1 ATP/Glucose)

Question 4

What are the different modulators of Hexokinase vs Glucokinase

Answer 4

Hexokinase: negative allosteric inhibition by G6P

Glucokinase: no feedback inhibition, but Nuclear Glucokinase regulatory protein → Binds GK to sequester it in the nucleus when glucose levels are low

Question 5

How is PFK-1 regulated?

Answer 5

Activated by AMP, F2,6BP
Inhibited by ATP, citrate

When bound to ATP → T state (inactive dimers)
When not bound (when more F2,6BP or AMP) →R state (active tetramer)

Question 6

How is PFK1 allosterically modulated?
What is its active/inactive state?

Answer 6

1. AMP and F2,6P are allosteric activators
2. ATP is an allosteric inhibitor
3. Transition from the T state to the R state activates PFK1
   *AMP is more potent at activating PFK1 than ATP is at inhibiting it

Question 7

What are the modulators of PFK-1 vs PFK-2?

Answer 7

PFK-1:
Inhibited by ATP
Activated by AMP and F2,6P

PFK-2:
Glucagon (in the liver)
Epinephrine → modulate cAMP (2nd messenger) in the muscles

Question 8

How does regulation of PFK2 occur in the liver vs in the heart muscle cells?

Answer 8

Liver isoenzyme = inverse of heart muscle isoenzyme
Liver: Fasting or prolonged exercise → low [blood glucose] → increase in glucagon → increase [cAMP] → PKA active → phosphorylation of PFK-2 → More FBPase activity → decrease [F2,6P]
*Favours gluconeogenesis

Heart muscle isoenzyme: increase in epinephrine → increase [cAMP] → PKA active → phosphorylation of PFK-2 → less FBPase activity → favours glycolysis
*To generate ATP (if need to run away)

Question 9

How is step 10 of glycolysis regulated?

Answer 9

F1,6P = allosteric activator
ATP (end product) = allosteric inhibitor of PK

In the Liver only,
Glucagon Glucagon activated cAMP → activated PKA → PKA phosphorylated PK → hormonal inhibition

Question 10

What are the entry points into glycolysis of Galactose, Fructose and Mannose?

Answer 10

A
Galactose → G6P
Fructose (muscles) → F6P
Mannose → F6P
PFK control
Fructose (liver) → GAP (only problematic)

Question 11

What would be the effect a mutation in FXR which prevents it from dimerizing with RXR?

Answer 11

• Decreased cholesterol levels
• Increased bile acids
• Increased ASBT