Lecture 16+17: Glycolysis, PDH, TCA Flashcards
(38 cards)
Possible fuel sources for ATP and their storage forms
Glucose (glycogen), fatty acids (triglycerides), amino acids (proteins)
How does alcohol inhibit gluconeogenesis (clinical case)? How can it be treated?
Treatment with thiamine, glucose infusion
Key regulated steps in glycolysis
Hexokinase, PFK, pyruvate kinase
ATP investment and return steps in glycolysis
Net = 2 ATP (2 in, 4 out)
High energy phosphate donors in glycolysis
1,3-bisphosphoglycerate and phosphoenolpyruvate (PEP)
What does iodoacetate inhibit?
Generation of NADH by G3P DH in glycolysis
How is NADH re-oxidized to NAD in aerobic conditions?
Reducing equivalents from NADH are transported by shuttles to the ETC and finally to O2
How is NADH re-oxidized to NAD to anaerobic conditions?
NADH reduces pyruvate to lactate via lactate DH
Pasteur effect
Anaerobic fermentation of pyruvate into acetaldehyde then reduction by alcohol DH and NADH into EtOH in yeast. Inhibited by oxygen.
How is glucokinase different from hexokinase?
What roles does glucokinase play compared to hexokinase?
Because glucokinase is most sensitive to changes in [gluc.] at physiological ranges, it acts as a glucose sensor for the liver and pancreas. Hexokinase instead wants to bring in glucose as quickly as possible, especially with high energy demand (e.g. working muscle).
How does glucokinase play a role in glucose dysregulation in diabetes?
Liver glucokinase is positively controlled by insulin, and so is low in diabetes -> impaired blood glucose response.
Mature Onset Diabetes of the Young (MODY2)
Inhibitory mutation in beta cell glucokinase resulting in insufficient insulin release despite high blood glucose.
Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI)
Activating mutation in beta cell glucokinase leading to insulin production even with low blood glucose.
GLUT2 vs GLUT4
GLUT4 is found in muscle and fat and is activated by insulin and anoxia.
GLUT2 acts independent of insulin and is part of glucose sensing in the liver/pancreas by achieving rapid equilibrium with blood glucose.
How is PFK regulated?
Activation: ADP, AMP, F-2,6-bisPi
Inhibition: ATP (feedback), citrate
Why are AMP and ADP more sensitive indicators of changes in [ATP]?
ADP is generally at a lower concentration -> larger percent changes
[AMP] is 2nd order to [ADP] by myokinase (adenylate kinase), so a 3x increase in ADP leads to a 9x increase in AMP
Why does citrate inhibit PFK?
Citrate buildup is an indicator of available alternate fuel, i.e. fatty acid oxidation produces acetyl-CoA. Acetyl-CoA can’t be transported out of the mitochondria, so it is instead converted to citrate which can be transported to the cytosol where PFK is located.
What role does fructose-2,6-bisphosphate play? How is it regulated?
F26BP is important in signaling for control of glycolysis/gluconeogenesis in the liver. Glucagon (low blood gluc.) activates Protein Kinase A, inhibiting PFK2 and activating F26BPase -> decreased PFK activity in liver
How is fructose-2,6-bisphosphate regulated in muscle?
PFK2/F26BPase don’t have the PKA phosphorylation site in muscle, and so are not affected by glucagon.
Role of the liver in glucose levels
The body mainly uses the glycogen stores in the liver to regulate blood glucose in close coordination with the pancreas via insulin/glucagon.
Why is PFK the primary regulated step in glycolysis and not hexokinase?
Glucose-6-P can go to glycolysis, glycogen, or the PPP. Inhibition of hexokinase by G6P means, with little flux to glycogen/PPP, hexokinase activity follows PFK. When PFK activity increases/decreases, so does hexokinase activity.
How is pyruvate kinase regulated in muscle?
Weak competitive inhibition by ATP
How is pyruvate kinase regulated in the liver?
Strong allosteric inhibition by ATP; also inhibited by Ala and PKA phosphorylation. Depends on high F16bP levels.
