citric acid cycle regulation

• Exergonic Reactions


  Reactions that release free energy, making them spontaneous (ΔG < 0)
• Endergonic Reactions


  Reactions that absorb free energy, making them non-spontaneous (ΔG > 0)
• Most reactions in central metabolism are exergonic with a large negative ΔG, making them irreversible and not easily reverted
• Burning Glucose


  • Involves a single, uncontrolled combustion reaction
  • Energy is wastefully released as heat
  • No energy is harnessed or stored
• Cellular Metabolism


  • Involves multiple, controlled steps facilitated by enzymes
  • Energy is captured in molecules like NADH and ATP
  • Reduces energy waste and stores chemical energy for cellular work
• Allosteric Regulation


  Regulation of enzyme activity by binding an effector molecule at a site other than the enzyme's active site
• Citrate Synthase


  • Catalyzes the first step, converting oxaloacetate and acetyl-CoA to citrate
  • Inhibitors: NADH, succinyl-CoA, citrate, ATP
  • Activator: ADP
• Isocitrate Dehydrogenase


  • Catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate
  • Inhibitor: ATP
  • Activators: ADP, Ca²⁺
• α-Ketoglutarate Dehydrogenase


  • Catalyzes the conversion of α-ketoglutarate to succinyl-CoA
  • Inhibitors: NADH, succinyl-CoA
  • Activator: Ca²⁺
• Structural Cooperativity


  The ability of conformational changes to propagate through a protein molecule, fundamental in metabolic control
• NADH


  • High levels indicate sufficient ATP production
  • Acts as an inhibitor for several enzymes in the cycle, slowing down the cycle when energy is plentiful
• ADP


  • High levels indicate a need for more ATP
  • Acts as an activator, speeding up the cycle to produce more ATP
• Calcium (Ca²⁺) as a Regulator

  • Activates pyruvate dehydrogenase phosphatase, which activates the pyruvate dehydrogenase complex
  • Activates isocitrate dehydrogenase and α-ketoglutarate dehydrogenase
  • Increases the reaction rate and overall flux through the cycle
• Citric Acid Cycle


  • Primary Goal: Load electrons into highly electronegative carriers (NADH, FADH₂)
  • Redox Nature: Involves oxidation of acetyl groups and reduction of NAD⁺ to NADH
  • Each turn produces 3 NADH, 1 FADH₂, and 1 GTP/ATP, along with 2 CO₂
  • Replenishing the Carbon Skeleton: Ensures the cycle can continue by regenerating oxaloacetate
  • Configuration changes are crucial for efficient electron transfer
• Citrate Synthase


  • Regulation: Inhibited by NADH, succinyl-CoA, citrate, and ATP; activated by ADP
  • Action: Converts oxaloacetate and acetyl-CoA to citrate
  • Importance: Initiates the citric acid cycle by forming a six-carbon molecule
• Aconitase


  • Action: Isomerizes citrate to isocitrate
  • Importance: Facilitates the next oxidative decarboxylation step
• Isocitrate Dehydrogenase


  • Regulation: Inhibited by ATP; activated by ADP and Ca²⁺
  • Action: Converts isocitrate to α-ketoglutarate, producing NADH and CO₂
  • Importance: Produces the first NADH and CO₂ in the cycle
• α-Ketoglutarate Dehydrogenase


  • Regulation: Inhibited by NADH and succinyl-CoA; activated by Ca²⁺
  • Action: Converts α-ketoglutarate to succinyl-CoA, producing NADH and CO₂
  • Importance: Produces the second NADH and CO₂ in the cycle
• Succinyl-CoA Synthetase


  • Action: Converts succinyl-CoA to succinate, producing GTP (or ATP)
  • Importance: Directly produces a molecule of GTP/ATP through substrate-level phosphorylation
• Succinate Dehydrogenase


  • Action: Converts succinate to fumarate, producing FADH₂
  • Importance: Part of both the citric acid cycle and the electron transport chain, bound to the inner mitochondrial membrane
• Fumarase


  • Action: Hydrates fumarate to malate
  • Importance: Prepares the substrate for the final oxidation step
• Malate Dehydrogenase


  • Action: Converts malate to oxaloacetate, producing NADH
  • Importance: Completes the cycle by regenerating oxaloacetate and producing the third NADH
• Regulatory Mechanisms in Metabolism

  • Control of Enzyme Amount: Gene expression and protein synthesis regulation, Protein degradation through the ubiquitin-proteasome system
  • Control of Enzyme Activity: Allosteric Control, Multiple Forms of Enzymes, Reversible Covalent Modifications, Proteolytic Activation
• The citric acid cycle is highly exergonic, meaning it releases a significant amount of energy, making indirect control through intermediate concentration changes unfeasible
• Direct allosteric regulation is essential for controlling the cycle
• Key regulatory points include enzymes involved in the production of NADH, such as isocitrate dehydrogenase and α-ketoglutarate dehydrogenase
• High levels of ADP indicate low ATP production, leading to an increase in enzyme activity to produce more NADH and ATP
• High levels of NADH indicate sufficient energy supply, reducing enzyme activity to prevent overproduction