1.08 - The TCA Cycle

Question 1

Describe AcetylCoA as the centre point of metabolism

Answer 1

Mitochondrial compartment prevents futile cycles
FAs enter the mitochondria via Carnitine shuttle system
Glucose enters as pyruvate (post-glycolysis)
Destination for metabolic fuels is the TCA cycle
Entry to the TCA cycle (for catabolism) is via Acetyl-CoA
TCA cycle links to ATP synthetic machinery

Question 2

What hormonal signals and cellular redox states signal for glycolysis

Answer 2

Adrenaline and glucagon
Decreased [ATP]/[ADP] and decreased [NADH]/[NAD+] indicate a low energy state
All promote glycogen breakdown and signal for glycolysis to occur

Question 3

Describe the fate of pyruvate after glycolysis

Answer 3

Glycolysis (cytoplasm) ends at the formation of pyruvate
Pyruvate enters the mitochondria via carrier
Pyruvate dehydrogenase converts Pyruvate to AcetylCoA (releases a lot of energy –> essential irreversible)
Complex process –> greater regulation
Pyruvate + CoA + NAD+ –> AcetylCoA + CO2 + H+ + NADH

Question 4

Describe FA entry in to the mitochondria

Answer 4

Complex transport system in to matrix
Transporter linked to enzymes
Antiporter mechanism of transport (Carnitine Transporter)
  -Transport inhibited by Malonyl-CoA
  -First intermediate of FA synthesis
β-oxidation generates acetyl-CoA
Occurs in mitochondrial matrix

Question 5

Describe Amino Acid entry to the mitochondria

Answer 5

Amino Acids and TCA cycle intermediates are interchangeable
Entry may be via many points
Several enter as pyruvate

Question 6

Describe the TCA Cycle

Answer 6

Series of oxidative reaction within the mitochondrial matrix
Entry point is the production of citrate (6C) from oxaloacetate (4C)
The substrate at this entry point is Acetyl CoA (2C)
The cycle continues and reforms Oxaloacetate with the loss of 2 carbon atoms as CO2
Concentrations of intermediates are low
A molecule of GTP (and hence ATP) is produced by substrate level phosphorylation
The reduced cofactors NADH & FADH2 are produced in each turn

Question 7

What is the fate of the reduced cofactors NADH and FADH2 after the TCA cycle

Answer 7

Then used to make energy in the form of ATP

They carry electrons –> Electrons have potential energy

Question 8

List the steps in the TCA Cycle

Answer 8

Oxaloacetate + Acetyl CoA --> Citrate
Cis-Acotinate
Iso-Citrate
alpha Keto Glutarate
Succinyl-CoA
Succinate
Fumarate
Malate
Oxaloacetate

Question 9

Describe the generic regulatory mechanism on the TCA cycle

Answer 9

Substrate supply: entry point for AcetylCoA
Committed Step: Isocitrate to alphaKG is the commitment
Metabolic branch points: Citrate has two fates - TCA or FA synthesis
Feed-back/forward loops: several products and late stage intermediates
Cellular energy status: NADH/NAD + ATP/ADP ratio

Question 10

Describe how the TCA cycle leads to lipid biosynthesis

Answer 10

Energy charge increased (Increased [ATP])
Reduced requirement for glycolysis and β-oxidation pathways
TCA cycle inhibited “post-citrate”
Results in increased [citrate]
Citrate transported to cytoplasm for fatty acid synthesis

Question 11

Describe how the TCA cycle leads to carbohydrate biosynthesis

Answer 11

Numerous amino acids converted to TCA intermediates
OAA may be ‘siphoned’ off towards Phospoenyl Pyruvate (PEP)
PEP penultimate intermediate in glycolysis pathway
Reaction bypasses pyruvate

Question 12

Describe how the TCA cycle can lead to biosynthesis of various other molecules

Answer 12

Amino acids constitute a dynamic pool
TCA cycle facilitates inter-conversion
Several points
Porphyrins used to generate heme derivatives (cytochromes)
Pyruvate may form OAA to increase amount of TCA intermediates