Citric acid cycle

The citric acid cycle (TCA cycle; also known as the Krebs cycle) is an essential metabolic pathway at the end of the degradation of all nutrients that yield acetyl-CoA, including carbohydrates, lipids, ketogenic amino acids, and alcohol. Acetyl-CoA is a product of glycolysis (at high glucose levels) or beta-oxidation (at low glucose levels) and the first substrate of the TCA cycle. Over the course of the cycle, acetyl-CoA is oxidized to CO₂ in 8 steps, and the energy that this generates is stored in FADH₂, NADH+H⁺, and GTP. FADH₂, NADH+H⁺ are then oxidized in the mitochondrial respiratory chain (electron transport chain), which ends in ATP synthesis. The intermediates of the TCA cycle are precursors for both anabolic and catabolic processes.

General

• Description: : metabolic pathway that oxidizes acetyl-CoA to CO₂ and generates one molecule GTP and the electron carriers NADH + H⁺ and FADH₂ (pathway is also known as Krebs cycle).
• Site: mitochondria
  • Succinate dehydrogenase is an integral membrane protein of the inner mitochondrial membrane.
  • All other enzymes are found in the mitochondrial matrix.
• Function
  • Energy production: degradation of acetyl-CoA to provide FADH₂ and NADH + H⁺ + CO₂
  • Biosynthesis: provides precursors for both anabolic and catabolic processes (amphibolic center)

Process

• Substrates
  • Pyruvate (derived from the breakdown of glucose in glycolysis) is converted to acetyl-CoA via pyruvate dehydrogenase complex.
  • Oxalacetate (derived either from pyruvate via pyruvate carboxylase or via regeneration within the TCA cycle)
• Steps: acetyl-CoA + oxaloacetate → citrate → isocitrate → α-ketoglutarate → succinyl-CoA → succinate → fumarate → malate → oxaloacetate

Citrate Is Krebs' Starting Substrate For Making Oxaloacetate

• Irreversible reactions
  • Citrate synthase: oxaloacetate → citrate; requires CoA (vitamin B5 pantothenic acid)
  • Isocitrate dehydrogenase: Isocitrate → α-ketoglutarate
  • α-Ketoglutarate dehydrogenase: α-ketoglutarate → succinyl-CoA
    • Requires 5 cofactors: thiamine (vitamin B1), lipoic acid, CoA (vitamin B5 pantothenic acid), FAD (vitamin B2 riboflavin), NAD+ (vitamin B3 niacin)
    • The same cofactors are required by the pyruvate dehydrogenase complex.
• Yield: 1 acetyl-CoA yields 3 NADH+H⁺ + 1 FADH₂ + 1 GTP + 2 CO₂ → 7.5 ATP (from 3 NADH+H⁺)+ 1.5 ATP (from 1 FADH₂) + 1 ATP (from 1 GTP); = 10 ATP

Each C2 unit is completely oxidized to CO₂ and H₂O. Oxaloacetate is recycled for the next TCA cycle.

Regulation

• Occurs at several sites
  • Pyruvate dehydrogenase complex
    • ↑ Acetyl-CoA → inhibits pyruvate dehydrogenase complex
  • Enzymes within the TCA cycle
    • ↑ NADH, FADH₂, ATP, α-ketoglutarate; → inhibit the TCA cycle
    • ↑ ADP levels → stimulate TCA cycle

Under anaerobic conditions, the TCA cycle is inhibited because the electron transport chain cannot regenerate NADH+H⁺ and FADH₂!

Anaplerotic reactions

• Provide intermediates for the TCA cycle
  • Pyruvate carboxylase (cofactor: biotin)
    • Pyruvate + CO₂ + ATP → oxaloacetate + ADP+P_i
  • Malate enzyme
    • Pyruvate + CO₂ + NADPH+H⁺ ⇄ malate + NADP⁺
  • Glutamate dehydrogenase
    • Glutamate + NAD⁺ → α-ketoglutarate + NH₃ + NADH+H⁺

The TCA cycle provides precursors for both anabolic and catabolic processes.

• Inhibition of the TCA cycle results in ketone body production.
  • ↑ Acetyl-CoA → ketogenesis (acetoacetyl-CoA → HMG-CoA → acetoacetate → β-hydroxybutyrate)
  • Causes
    • Prolonged starvation, diabetic ketoacidosis: ↓ (intracellular) glucose → ↓ oxaloacetate → ↑ gluconeogenesis; → ↑ acetyl-CoA
    • Alcohol consumption: hepatic ethanol metabolism (via alcohol dehydrogenase) → ↑ NADH/NAD⁺ ratio → inhibition of the TCA cycle; → ↑ acetyl-CoA