Citric Acid Cycle

MOL 345 Lecture 24: Citric Acid Cycle

Overview of the Citric Acid Cycle (TCA Cycle)

  • Definition: The Citric Acid Cycle, also known as the TCA cycle or Krebs cycle, functions as a central metabolic hub within cells.

  • Location: It takes place inside the mitochondria of eukaryotic cells.

  • **Key Inputs: **

    • Pyruvate

    • Fatty acids

    • Amino acids

    • GTP (Guanosine triphosphate)

    • Acetyl-CoA

  • Energy Yield:

    • The cycle processes these substrates leading to a net yield of approximately 9 ATP molecules per cycle, depending on the conditions.

    • Under aerobic conditions, each NADH generated is equivalent to 2.5 ATP.

Function of the Citric Acid Cycle

  1. Harvesting High-Energy Electrons:

    • The TCA cycle extracts high-energy electrons from carbon fuels, which are critical for further energy production in the electron transport chain.

  2. Metabolic Hub:

    • It acts as a gathering point for metabolites, collecting the end products of various catabolic pathways and providing starting materials for biosynthesis.

Role of NADH under Varying Conditions

  • Anaerobic Conditions:

    • NADH becomes a liability as it cannot properly donate electrons without oxygen.

    • To regenerate NAD+, pyruvate can be converted into products such as lactate (in animals) or ethanol (in microorganisms).

  • Aerobic Conditions:

    • NADH's worth increases as it can produce ATP through oxidative phosphorylation, yielding approximately 2.5 ATP per molecule of NADH generated.

Pyruvate to Acetyl-CoA Conversion

  • Initial Reaction: The first step in the TCA cycle is the oxidative decarboxylation of pyruvate, which involves converting pyruvate into acetyl-CoA:

    • Reaction:
      \text{Pyruvate} + \text{NAD}^+ \rightarrow \text{NADH} + \text{H}^+ + \text{CoA-SH} \rightarrow \text{acetyl-CoA} + \text{CO}_2

  • Enzyme Involved: The reaction is catalyzed by the Pyruvate Dehydrogenase (PDH) Complex, a large enzyme composed of several components, necessitating five essential coenzymes:

    1. Thiamine pyrophosphate (TPP)

    2. Lipoic acid

    3. Flavin adenine dinucleotide (FAD)

    4. Coenzyme A (CoA-SH)

    5. Nicotinamide adenine dinucleotide (NAD)

Mechanism of PDH Processing

  • Step 1: Decarboxylation

    • TPP is critical in the first step; its carbanion form aids in the decarboxylation process of pyruvate:

    • This mechanism is similar to that utilized by pyruvate decarboxylase, but the goal here is to produce acetyl-CoA instead of acetaldehyde.

  • Step 2: Oxidation

    • Involves the oxidation of the intermediate- substrate through lipoamide.

  • Further Steps and Energy Accounting:

    • The 5-step reactions completed by PDH result in the complete conversion of pyruvate to acetyl-CoA, generating NADH and other intermediates crucial for subsequent steps in the TCA cycle.

Key Enzymatic Reactions in TCA Cycle

  1. Succinyl-CoA Synthetase generates GTP from GDP and inorganic phosphate (Pi).

    • Reaction:
      \text{GDP} + \text{Pi} \rightarrow \text{GTP}

  2. Succinate Dehydrogenase facilitates the conversion of succinate to fumarate, reducing FAD to FADH2 in the process.

    • Reaction:
      \text{Succinate} + \text{FAD} \rightarrow \text{Fumarate} + \text{FADH}_2

  3. Fumarase catalyzes the hydration of fumarate to malate.

    • Reaction:
      \text{Fumarate} + \text{H}_2\text{O} \rightarrow \text{Malate}

  4. Malate Dehydrogenase converts malate back into oxaloacetate, producing NADH:

    • Reaction:
      \text{Malate} + \text{NAD}^+ \rightarrow \text{Oxaloacetate} + \text{NADH} + \text{H}^+$$

Regeneration of Oxaloacetate

  • At each turn of the TCA cycle, oxaloacetate is regenerated, making the cycle capable of ongoing metabolic processes. This cyclical nature of the pathway allows continuous harvesting of electrons and energy from substrates entering the cycle.