Regulation of the Citric Acid Cycle

• Regulation of the citric acid cycle balances the supply of key intermediates with the demands of energy production and biosynthetic processes.
• Regulation of the citric acid occurs at:

  • PDH complex
  • Citrate synthase
  • Isocitrate dehydrogenase complex
  • Alpha-ketoglutarate dehydrogenase complex
• The citric acid cycle is regulated at the reactions catalyzed by citrate synthase, isocitrate dehydrogenase, and alpha-ketoglutarate hydrogenase. What do these three reactions have in common?

  • They are all close to equilibrium
  • They are all strongly exergonic
  • They all reduce NAD+ to NADH
  • They all carry out substrate level phosphorylation

  They are all strongly exergonic. Each of these three can become rate limiting under some circumstances.
• PDH complex activity is turned off when:

  • Ample fatty acids and acetyl CoA are available as fuel
  • The [ATP]/[ADP] and [NADH]/[NAD+] ratios are high
• PDH complex activity is turned on when:

  • Energy demands are high
  • The cell requires greater flux of acetyl CoA into the citric acid cycle.
• The pyruvate dehydrogenase complex is not regulated by:

  • ADP
  • Fatty acids
  • Covalent modification
  • Acetyl CoA

  ADP. The PDH complex is regulated by allosteric mechanisms and covalent modification (phosphorylation). ATP, acetyl CoA, NADH, and fatty acids inhibit the activity of the PDH complex, whereas AMP, CoA, NAD+, and Ca2+ stimulate the PDH complex.
• Pyruvate dehydrogenase complex is inhibited by ATP, acetyl CoA, NADH, and fatty acids
• Pyruvate dehydrogenase complex is accelerated by AMP, CoA, NAD+ and Ca2+.
• Citrate synthase is inhibited by NADH, succinyl CoA, citrate and ATP.
• Citrate synthase is accelerated by ADP.
• Isocitrate dehydrogenase is inhibited by ATP.
• Isocitrate dehydrogenase is accelerated by Ca2+ and ADP.
• Alpha-ketoglutarate dehydrogenase complex is inhibited by succinyl CoA and NADH.
• Alpha-ketoglutarate dehydrogenase complex is accelerated by Ca2+.
• PDH kinase inhibits the PDH complex by phosphorylation.

  • Allosterically activated by products of the complex
  • Inhibited by substrates of the complex.
• PDH phosphatase reverse the inhibition by PDH kinase
• Regulation of the citric acid cycle occurs at three highly exergonic steps catalyzed by citrate synthase, isocitrate dehydrogenase complex, and alpha-ketoglutarate complex.
• Fluxes are affected by the concentrations of substrates and products

  • End products ATP and NADH are inhibitory
  • NAD+ and ADP are stimulatory
  • Long chain fatty acids are inhibitory.
• The citric acid cycle is regulated in a manner similar to glycolysis. Which molecule is an allosteric activator of both those pathways?

  • ATP
  • NAD+
  • ADP
  • Citrate
  • NADH


  ADP. ADP allosterically activates the glycolytic enzyme PFK-1 as well as the citric acid cycle enzymes citrate synthase and isocitrate dehydrogenase.
• How is the regulation of glucose metabolism through glycolysis and the citric acid cycle coordinated?

  • High ADP level stimulate glycolysis and the citric acid cycle
  • High NADH levels inhibit glycolysis and the citric acid cycle
  • High citrate levels inhibit glycolysis
  • In muscle, Ca2+ release (a signal of muscle contraction) stimulates both glycogen phosphorylase and enzymes of the citric acid cycle.
  • All of the answers are correct.

  All of the answers are correct.
• Some mutations that affect the PDH complex or citric acid cycle enzymes are oncogenic:

  • Downregulation of mitochondrial pyruvate carrier (MPC)
  • Inactivation of the PDH complex
  • Inactivation of succinate dehydrogenase
• Oncometabolites stimulate tumor growth by acting through specific GPCRs in the plasma membrane.
• Which statement regarding regulation of the citric acid cycle is false?

  • Ca2+ is involved in citric acid cycle regulation in vertebrate muscle
  • Dysfunction of the citric acid cycle (like due to mutations of the enzymes in the cycle) is often associated with different types of cancer.
  • In addition to regulation of the PDH complex, regulation of the citric acid cycle occurs by regulation of the enzymes that catalyze strongly exergonic steps.
  • As [NADH]/[NAD+] increases, flux through the cycle increases

  As [NADH]/[NAD+] increases, flux through the cycle increases.
• Tumor cells accumulate lactate and succinate, thus they are oncometabolites.
• Mutations in succinate dehydrogenase and fumarase cause tumors, defining them as tumor suppressors.
• Many glial tumors have mutant NADPH dependent isocitrate dehydrogenase

  • Lose ability to convert isocitrate to alpha-ketoglutarate
  • Gain ability to convert alpha-ketoglutarate to 2-hydroxyglutarate.
• Metabolons are integrated multienzyme complexes that are held together by noncovalent interactions
• Malate dehydrogenase, citrate synthase, and aconitase likely constitute a metabolon.
• Metabolons are:

  • Multienzyme complexes that ensure efficient passage of the product of one enzyme to the next enzyme in the pathway
  • Products of one metabolic pathway that act as allosteric regulators of another pathway
  • Metabolic intermediates in a pathway that act as allosteric regulators of that pathway
  • Individual functional units of regulation for a metabolic pathway or cycle.

  Multienzyme complexes that ensure efficient passage of the product of one enzyme to the next enzyme in the pathway.