Citric Acid Cycle: Key Reactions and Energetics

Citric Acid Cycle

Fumarase Reaction

The conversion of fumarate to L-malate is a hydration reaction in the citric acid cycle. Water is added across the double bond of fumarate, producing L-malate.

• Reaction: Fumarate + H2O → L-malate

• Mechanism: Water is added in two parts: first as OH-, then H+.

Equation:

$\text{Fumarate} + H_2O \rightarrow \text{L-malate}$

Malate Dehydrogenase Reaction

This reaction involves the oxidation of malate to oxaloacetate, coupled with the reduction of NAD+ to NADH. It is highly endergonic under standard conditions but proceeds in the cell due to the rapid consumption of oxaloacetate in the next step of the cycle.

• Reaction: Malate + NAD+ → Oxaloacetate + NADH + H+

• Generates: NADH, which is used in the electron transport chain to produce ATP.

Equation:

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

Energetics of the Citric Acid Cycle

ATP Yield from NADH and FADH2

• NADH: Each NADH generated in the cycle yields approximately 2.5 ATP via oxidative phosphorylation.

• FADH2: Each FADH2 yields approximately 1.5 ATP.

Key Point: NADH is generated by glyceraldehyde 3-phosphate dehydrogenase (glycolysis), pyruvate dehydrogenase, and three steps in the citric acid cycle.

ATP Yield from Glucose Oxidation

• 1 glucose → 2 pyruvate (glycolysis) → 2 acetyl-CoA (pyruvate dehydrogenase) → 2 turns of the citric acid cycle

• ATP Yield:

  • Glycolysis: 2 NADH + 2 ATP = 7 ATP

  • Pyruvate dehydrogenase: 2 NADH = 5 ATP

  • Citric acid cycle: 6 NADH + 2 FADH2 + 2 GTP/ATP = 20 ATP

  • Total: 32 ATP per glucose (using 2.5 ATP/NADH, 1.5 ATP/FADH2)

Equation:

$\text{Total ATP from glucose oxidation} = 32$

Regulation of the Citric Acid Cycle

The citric acid cycle is regulated primarily by substrate availability, product inhibition, and allosteric regulation by energy status indicators such as ATP, ADP, NADH, and NAD+.

• Key regulatory enzymes:

  • Citrate synthase

  • Isocitrate dehydrogenase (stimulated by ADP, inhibited by ATP and NADH)

  • α-Ketoglutarate dehydrogenase (inhibited by NADH and succinyl-CoA)

Anaplerotic Reactions

Anaplerotic reactions replenish citric acid cycle intermediates that are removed for biosynthetic processes. These reactions are essential for maintaining the cycle's function.

• Example: Pyruvate carboxylase converts pyruvate to oxaloacetate.

• Other reactions: Reactions 1, 2, and 6 of the cycle are also important for replenishing intermediates.

Additional info: The citric acid cycle is amphibolic, serving both catabolic and anabolic roles, including the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins.