Lecture 04/04 - CH 19: TCA Cycle

Thiamine Deficiency and PVC

  • Thiamine, also known as Vitamin B1, is crucial for the synthesis of thiamine pyrophosphate (TPP).

  • TPP serves as a co-factor for the Pyruvate Dehydrogenase Complex (PDC) which is essential for converting pyruvate to acetyl CoA.

  • Deficiency in thiamine leads to a limiting amount of TPP, resulting in beriberi, which can be:

    • Wet Beriberi: Characterized by edema and fluid retention.

    • Dry Beriberi: Primarily a neurological condition with symptoms such as confusion, memory loss, speech difficulties, and peripheral neuropathies (tingling in fingers and toes).

  • White rice, which is stripped of its outer husk (where nutrients are found), is a common dietary staple in areas with higher incidences of beriberi.

  • Other populations at risk for thiamine deficiency include those with alcoholism or certain medications affecting nutrient absorption, particularly those that reduce gastric acidity.

Overview of the TCA Cycle

  • The TCA cycle begins with the formation of acetyl CoA, transitioning into the next chapter of metabolism.

  • Key Points:

    • Two stages with a total of eight reactions:

    • Stage 1: Involves decarboxylation and carboxylic oxidation.

    • Stage 2: Reforming oxaloacetate for cycle continuation.

  • Acetyl CoA not only comes from glycolysis but also from the oxidation of fatty acids and amino acids under specific dietary conditions.

  • The cycle produces carbon dioxide (CO₂), ATP, and essential electron carriers (NADH, FADH₂).

Detailed Steps of the TCA Cycle

Stage 1: Reactions 1-4

  1. Citrate Formation:

    • Enzyme: Citrate synthase.

    • Reaction: Combines oxaloacetate (4C) and acetyl CoA (2C) to form citrate (6C).

    • Energy from the cleavage of the thioester bond in acetyl CoA drives the reaction, no ATP needed.

  2. Isomerization of Citrate to Isocitrate:

    • Enzyme: Aconitase.

    • This is a two-step process involving dehydration and rehydration, moving the hydroxyl group from carbon 3 to carbon 2 of citrate.

  3. First Redox Reaction and Decarboxylation:

    • Enzyme: Isocitrate dehydrogenase.

    • Converts isocitrate to alpha-ketoglutarate, producing NADH and releasing CO₂.

  4. Second Redox Reaction and Decarboxylation:

    • Enzyme: Alpha-ketoglutarate dehydrogenase complex.

    • Transforms alpha-ketoglutarate into succinyl CoA, producing NADH and releasing CO₂.

Stage 2: Reactions 5-8

  1. Conversion to Succinate:

    • Enzyme: Succinyl CoA synthetase.

    • Succinyl CoA is converted into succinate and ATP (or GTP), utilizing the energy from the thioester bond.

  2. Oxidation of Succinate:

    • Enzyme: Succinate dehydrogenase.

    • Converts succinate into fumarate while generating FADH₂, integrating with the electron transport chain.

  3. Conversion to Malate:

    • Enzyme: Fumarase.

    • Adds water to fumarate to form malate.

  4. Final Redox Reaction:

    • Enzyme: Malate dehydrogenase.

    • Converts malate back into oxaloacetate, producing one more NADH.

Energetics and ATP Yield

  • Each cycle net yield:

    • 3 NADH (7.5 ATP)

    • 1 FADH₂ (1.5 ATP)

    • 1 ATP (or GTP)

    • Total per cycle: 10 ATP.

    • Each glucose molecule effectively generates 20 ATP through two cycles.

Regulation of the TCA Cycle

  • Key regulatory enzymes include:

    • Isocitrate Dehydrogenase: Regulated by ATP (inhibition) and ADP (activation).

    • Alpha-Ketoglutarate Dehydrogenase: Regulated by succinyl CoA and NADH (inhibition).

  • The cycle is governed by energy charge within the cell.

Anaplerotic Reactions

  • Pyruvate carboxylase is a crucial enzyme replenishing oxaloacetate from pyruvate, integrating gluconeogenesis and TCA cycle continuity.

  • The cycle also serves anabolic functions, producing amino acids, glucose precursors, and other biomolecules.

Mnemonic for TCA Cycle

  • "Can I Keep Selling Sex For Money?" - Represents the order of key products in TCA cycle:

    • C: Citrate

    • I: Isocitrate

    • K: α-Ketoglutarate

    • S: Succinyl CoA

    • S: Succinate

    • F: Fumarate

    • M: Malate

    • O: Oxaloacetate

This breakdown provides a comprehensive overview of thiamine's role in metabolic processes, the TCA cycle's intricate steps, energetics, regulation, and mnemonic aids for study purposes.