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Pyruvate Dehydrogenase (PDH) Complex & Tricarboxylic Acid (TCA) Cycle

The PDH complex is essential for converting pyruvate into acetyl-CoA, a critical step linking glycolysis to the TCA cycle.

Pyruvate Dehydrogenase (PDH) Complex

1a. Cellular Location and Tissue Distribution

  • Cellular location: Mitochondrial matrix

  • Tissue distribution: Found in most tissues, particularly active in high-energy-demand tissues like muscles, heart, and brain.

1b. Components of PDH Complex

The PDH complex is a multienzyme complex with:

  • Three enzymes:

    • E1: Pyruvate dehydrogenase

    • E2: Dihydrolipoamide acetyltransferase

    • E3: Dihydrolipoamide dehydrogenase

  • Additional regulatory proteins

1c. Five Cofactors ("TLC For Nancy")

  • T: Thiamine pyrophosphate (TPP)

  • L: Lipoic acid

  • C: Coenzyme A (CoA)

  • F: Flavin adenine dinucleotide (FAD)

  • N: Nicotinamide adenine dinucleotide (NAD⁺)

1d. Regulation of PDH Complex

  • Activated by:

    • Pyruvate and ADP (inhibit pyruvate dehydrogenase kinase, preventing inactivation)

    • Calcium (Ca²⁺) (stimulates pyruvate dehydrogenase phosphatase, leading to activation)

  • Inhibited by:

    • NADH and Acetyl-CoA (activate pyruvate dehydrogenase kinase, leading to inactivation)

    • ATP

1e. PDH Complex Deficiency

  • Causes: Genetic mutations (e.g., PDHA1, PDHB)

  • Symptoms:

    • Neurological issues (developmental delay, seizures, hypotonia)

    • Lactic acidosis (due to excess pyruvate shunted to lactate)

    • Progressive neurodegeneration

  • Diagnosis: Blood/CSF lactate and pyruvate levels, genetic testing, enzyme assays

  • Treatment:

    • Ketogenic diet (alternative fuel from ketones)

    • Dichloroacetate (DCA) (activates PDH phosphatase)

    • Thiamine supplementation (for responsive cases)

Tricarboxylic Acid (TCA) Cycle

The TCA cycle is essential for converting biochemical energy from molecular bonds into ATP, thereby fueling cellular activities.

2a. Effects of Various Molecules on TCA Cycle

  • Inhibitors:

    • NADH, Succinyl-CoA, Citrate, ATP (signal high energy, inhibit key enzymes)

  • Activators:

    • ADP, Calcium (Ca²⁺) (signal low energy, activate key enzymes)

2b. Key Regulatory Enzymes

  1. Citrate Synthase (inhibited by citrate, ATP, NADH, succinyl-CoA)

  2. Isocitrate Dehydrogenase (activated by ADP and Ca²⁺, inhibited by ATP and NADH)

  3. α-Ketoglutarate Dehydrogenase (activated by Ca²⁺, inhibited by NADH and succinyl-CoA)

2c. TCA Inputs/Reactants

  • Acetyl-CoA + Oxaloacetate → Citrate

2d. Uses of TCA Cycle Products

i. Energy Production

  • 1 Acetyl-CoA yields:

    • 3 NADH → 7.5 ATP

    • 1 FADH₂ → 1.5 ATP

    • 1 GTP → 1 ATP

    • Total = 10 ATP per Acetyl-CoA

ii. Metabolic/Biosynthetic Pathways

  • Succinyl-CoA → Heme synthesis

  • Oxaloacetate → Gluconeogenesis

  • α-Ketoglutarate & Oxaloacetate → Amino Acid synthesis

  • Citrate → Fatty Acid synthesis

Pyruvate Dehydrogenase (PDH) Complex

  1. Cellular Location and Tissue Distribution

    • Location: Mitochondrial matrix

    • Tissues: Predominantly found in high-energy-demand tissues like muscles, heart, and brain.

  2. Components:

    • Enzymes:

      • E1: Pyruvate dehydrogenase

      • E2: Dihydrolipoamide acetyltransferase

      • E3: Dihydrolipoamide dehydrogenase

    • Regulatory Proteins: Additional proteins that regulate activity.

  3. Cofactors:

    • Thiamine pyrophosphate (TPP)

    • Lipoic acid

    • Coenzyme A (CoA)

    • Flavin adenine dinucleotide (FAD)

    • Nicotinamide adenine dinucleotide (NAD⁺)

  4. Regulation:

    • Activated by: Pyruvate, ADP, Calcium (Ca²⁺)

    • Inhibited by: NADH, Acetyl-CoA, ATP

  5. Deficiency:

    • Causes: Genetic mutations

    • Symptoms: Neurological issues, lactic acidosis, progressive neurodegeneration

    • Treatment: Ketogenic diet, Dichloroacetate (DCA), Thiamine supplementation

Function of the TCA Cycle

The Tricarboxylic Acid (TCA) Cycle, also known as the Krebs Cycle or Citric Acid Cycle, plays a critical role in cellular metabolism by:

  1. Energy Production: Each turn of the cycle processes one Acetyl-CoA and results in the generation of high-energy molecules:

    • 3 NADH (equivalent to 7.5 ATP)

    • 1 FADH₂ (equivalent to 1.5 ATP)

    • 1 GTP (equivalent to 1 ATP)

    • Total: Approximately 10 ATP per Acetyl-CoA.

  2. Metabolic/Biosynthetic Pathways: The cycle also provides intermediates that are used in various biosynthetic processes:

    • Succinyl-CoA → Heme synthesis

    • Oxaloacetate → Gluconeogenesis

    • α-Ketoglutarate & Oxaloacetate → Amino Acid synthesis

    • Citrate → Fatty Acid synthesis.