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04: TCA Cycle and PDH Complex Overview

TCA Cycle Overview

  • TCA Cycle, also known as Krebs Cycle or Citric Acid Cycle,
  • Two stages:
    • Acetyl-CoA Production (Stage I)
    • Acetyl-CoA Oxidation (Stage II)
  • Major Processes:
  • Pyruvate conversion, Oxidation through a series of enzyme-catalyzed reactions.

Section Objectives

  • Understand TCA cycle characteristics and stages.
  • Identify components of the Pyruvate Dehydrogenase (PDH) Complex.
  • Explain PDH mechanism and reactions associated with TCA cycle.
  • Identify enzymes, intermediates, and cofactors involved.
  • Explain TCA cycle energetics and overall energy from glucose breakdown.
  • Calculate ATP yields for pathways.
  • Explain regulation factors of the citric acid cycle.
  • Describe connections between TCA intermediates and other pathways.
  • Understand anaplerotic reactions.

Cellular Respiration

  • Process where cells consume O2 and produce CO2.
  • Provides more ATP from glucose than glycolysis.
  • Origins date back ~2.5 billion years.
  • Three major stages:
  1. Acetyl CoA production
  2. Acetyl CoA oxidation (TCA cycle)
  3. Electron transfer and oxidative phosphorylation

Stage I: Acetyl-CoA Production

  • Generates ATP, NADH, and FADH2.
  • Carbohydrates release 1/3 of CO2 during this stage.

Stage II: Acetyl-CoA Oxidation

  • Generates more NADH, FADH2, and one GTP.
  • Remaining C atoms from carbohydrates, amino acids, fatty acids released.

Stage III: Oxidative Phosphorylation

  • Majority of ATP generated in catabolism of NADH/FADH2.
  • Involves electron transfer chain, resulting in ATP synthesis.

Energetics of Glucose Oxidation

  • Full oxidation of glucose yields -2840 kJ/mol; only small energy captured in glycolysis (-146 kJ/mol).

PDH Complex

  • Consists of three main enzymes:
  • E1: Pyruvate Dehydrogenase
  • E2: Dihydrolipoyl Transacetylase
  • E3: Dihydrolipoyl Dehydrogenase
  • 5 Cofactors required:
  • TPP (Thiamine pyrophosphate), lipoyl-lysine, FAD, NAD+, CoA-SH.

Decarboxylation of Pyruvate

  • Catalyzed by PDH complex via oxidative decarboxylation.
  • First carbon oxidation forms Acetyl CoA.

TCA Cycle Steps

  1. C-C Bond Formation: Acetyl-CoA + Oxaloacetate → Citrate.
  • Catalyzed by citrate synthase; irreversible.
  1. Isomerization: Via dehydration/rehydration.
  2. Oxidative Decarboxylation: Isocitrate → -Ketoglutarate.
  3. Oxidative Decarboxylation: -Ketoglutarate → Succinyl CoA.
  4. Substrate-Level Phosphorylation: Succinyl CoA → Succinate (GTP formation).
  5. FAD Reduction: Succinate → Fumarate (FADH2 formed).
  6. Hydration: Fumarate → L-Malate.
  7. Final Decarboxylation: Malate → Oxaloacetate (NADH formed).

Net Result of TCA Cycle

  • From one Acetyl-CoA:
  • 3 NADH, 1 FADH2, 1 GTP (equivalent to ATP), yielding significant energy.
  • Full conversion:
  • Acetyl-CoA + 3 NAD⁺ + FAD + GDP + Pi + 2 H₂O → 2 CO₂ + 3 NADH + FADH₂ + GTP + CoA + 3 H⁺.

Regulation of TCA Cycle

  • Key enzymes and steps are regulated:
  • PDH, Citrate Synthase, IDH, KDH.
  • Regulation by substrate availability and product inhibition (NADH, ATP inhibitors; NAD+, AMP activators).
  • Feedback inhibition ensures balance in metabolic pathways.

Anaplerotic Reactions

  • Replenishment of TCA intermediates is critical for metabolic processes.
  • Intermediates serve as precursors in many biosynthetic pathways.

Summary

  • The PDH complex converts pyruvate into acetyl-CoA, utilizing several cofactors.
  • TCA cycle is a crucial catabolic process that produces energy and also serves anabolic roles.
  • Regulation of activity is key to maintaining cellular energy balance, ensuring metabolic pathways function efficiently.