Tricarboxylic Acid Cycle

Tricarboxylic Acid Cycle - Metabolic Merry-Go-Round

• Definition: A pivotal sequence of enzyme-catalysed reactions in all aerobic organisms, central to energy production.
• Alternative Names: Krebs Cycle, Citric Acid Cycle.
• Location: Exclusively in the mitochondrial matrix.
• Central Hub Role: Final common pathway for oxidation of carbohydrates, lipids, and proteins. Provides precursors for biosynthesis.

  ⭐ The TCA cycle is strictly aerobic; it does not operate in the absence of oxygen. oka

Tricarboxylic Acid Cycle - Pyruvate's Passport

The Pyruvate Dehydrogenase Complex (PDC) is a multi-enzyme complex in the mitochondrial matrix. It links glycolysis to the TCA cycle by converting pyruvate to Acetyl-CoA.

• Reaction (Link Reaction):
  • $Pyruvate + CoA + NAD^+ \rightarrow Acetyl-CoA + CO_2 + NADH + H^+$
  • Substrates: Pyruvate, Coenzyme A (CoA), NAD+
  • Products: Acetyl-CoA, CO2, NADH
• PDC Coenzymes (5):
  • Thiamine pyrophosphate (TPP) (B1)
  • Lipoamide
  • CoA (from Pantothenate - B5)
  • FAD (from Riboflavin - B2)
  • NAD+ (from Niacin - B3)
  • 📌 Mnemonic: Tender Loving Care For Nancy.

structure and reaction mechanism)

⭐ Arsenic inhibits PDC by binding to sulfhydryl groups in lipoamide, halting ATP production from glucose via TCA cycle anoxia despite adequate oxygen supply (histotoxic hypoxia).

Tricarboxylic Acid Cycle - Krebs' Eightfold Path

📌 Mnemonic (Intermediates): Citrate Is Krebs' Starting Substrate For Making Oxaloacetate. (Citrate, Isocitrate, α-KG, Succinyl-CoA, Succinate, Fumarate, Malate, Oxaloacetate)

Central aerobic pathway in mitochondrial matrix for acetyl-CoA oxidation. Yields per Acetyl-CoA: 3 NADH, 1 FADH₂, 1 GTP, 2 CO₂ (Total ≈ 10 ATP).

• Regulation: Primarily at three irreversible exergonic steps:
  • Citrate Synthase: Inhibited by ATP, NADH, succinyl-CoA, citrate.
  • Isocitrate Dehydrogenase: Activated by ADP, $Ca^{2+}$. Inhibited by ATP, NADH. (Major control point)
  • α-Ketoglutarate Dehydrogenase Complex: Activated by $Ca^{2+}$. Inhibited by ATP, GTP, NADH, succinyl-CoA.
• Energy Generation (per Acetyl-CoA):
  • NADH: 3 molecules (from Isocitrate DH, α-KG DH, Malate DH).
  • FADH₂: 1 molecule (from Succinate DH - also Complex II of ETC).
  • GTP (SLP): 1 molecule (from Succinyl-CoA Synthetase).
  • CO₂ released: 2 molecules (by Isocitrate DH, α-KG DH).

⭐ Succinyl-CoA Synthetase (or Succinate Thiokinase) performs the sole substrate-level phosphorylation in the TCA cycle, yielding GTP (or ATP).

Tricarboxylic Acid Cycle - Cycle's Command & Control

• Key Regulatory Enzymes:

  • Citrate Synthase
  • Isocitrate Dehydrogenase (Rate-limiting step)
  • α-Ketoglutarate Dehydrogenase Complex

• Regulation: Governed by:

  • Substrate availability (Acetyl-CoA, Oxaloacetate).
  • Product inhibition (e.g., NADH, ATP, Citrate, Succinyl-CoA).
  • Allosteric effectors (see table).
  • Overall energy status: High ATP/ADP & NADH/NAD⁺ ratios $\downarrow$ cycle activity. Ca²⁺ generally activates.

($3 \text{ NADH} \times 2.5 \text{ ATP} + 1 \text{ FADH}_2 \times 1.5 \text{ ATP} + 1 \text{ GTP} = \textbf{10 ATP}$)

• Amphibolic Role: (Dual function)

  • Catabolic: Oxidizes acetyl-CoA.
  • Anabolic: Provides precursors:
    • Citrate $\rightarrow$ Fatty acids, sterols.
    • α-Ketoglutarate $\rightarrow$ Glutamate, other amino acids, purines.
    • Succinyl-CoA $\rightarrow$ Porphyrins, heme.
    • Oxaloacetate $\rightarrow$ Aspartate, other amino acids, purines, pyrimidines; gluconeogenesis.

• Anaplerotic Reactions: (Replenishing)

  • Pyruvate Carboxylase: Pyruvate + $\text{CO}2$ + ATP $\rightarrow$ Oxaloacetate + ADP + $\text{P}\text{i}$ (most important).
  • Others: Glutamate Dehydrogenase (Glutamate $\rightleftharpoons$ α-KG), Transaminases.

⭐ Fluoroacetate (found in some poisonous plants) acts as a potent inhibitor of aconitase after being converted to fluorocitrate (suicide inhibition), leading to citrate accumulation and TCA cycle arrest.

High‑Yield Points - ⚡ Biggest Takeaways

• Location: Mitochondrial matrix; Acetyl-CoA + Oxaloacetate → Citrate.
• Key Products (per Acetyl-CoA): 3 NADH, 1 FADH2, 1 GTP, 2 CO2.
• Rate-limiting enzymes: Isocitrate dehydrogenase (primary), α-ketoglutarate dehydrogenase, citrate synthase.
• Amphibolic pathway: Provides precursors for gluconeogenesis, heme synthesis, fatty acid synthesis.
• Irreversible reactions: Catalyzed by citrate synthase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase complex.
• Total ATP yield: ~10 ATP per acetyl-CoA via oxidative phosphorylation.