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An 18 month-old- child is left unattended while in the kitchen and ingests a small portion of rat poison found in the cupboard found under the sink. The ingredient fluoroacetate reacts with Oxaloacetate to form fluorocitrate. Which pathway of the body is inhibited by this poison?

A. Glycolysis

B. TCA cycle

C. Fatty acid oxidation

D. Fatty acid synthesis

E. HMP pathway

The right answer is -B) TCA cycle.

Fluoroacetate is structurally similar to acetate, which has an important role in cellular metabolism.

Fluoroacetate disrupts the citric acid cycle (also known as the Krebs cycle or TCA cycle- Tricarboxylic acid cycle) by combining with coenzyme A to form Fluoroacetyl CoA, which reacts with oxaloacetate in the presence of citrate synthase (host enzyme) to produce fluorocitrate (Figure-1).

 Activation of Fluoroacetate

Figure-1- Activation of fluoroacetate is brought by Citrate synthase, an enzyme of TCA cycle

Fluorocitrate binds very tightly to Aconitase, to inhibit its action, (Figure-2) thereby inhibiting the citric acid cycle as a whole. This is an example of suicidal inhibition.

 TCA cycle

Figure-2- TCA cycle and the action of Aconitase

The direct effect of Fluoroacetate is on TCA cycle, but indirectly Glycolysis and other pathways are also inhibited.

Effect on Glycolysis

This inhibition results in an accumulation of citrate in the blood. Citrate and fluorocitrate are allosteric inhibitors of phosphofructokinase-1 (PFK-1), a key enzyme in the breakdown of Glucose. As PFK-1 is inhibited cells are no longer able to metabolize carbohydrates, depriving them of energy.

Effect on fatty acid oxidation

Inhibition of TCA cycle inhibits fatty acid oxidation also due to non availability of oxidized coenzymes, and incomplete utilization of Acetyl co A. But these are late implications. TCA cycle is vital to life. Death occurs immediately after its suppression. Directly Fluoroacetate has no effect on enzymes of fatty acid oxidation.

 Similarly fatty acid synthesis and HMP pathway are not directly affected by Fluoroacetate.


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