fluorocitrate

Fluorocitrate is the fluorinated analog of citrate and functions primarily as a metabolic toxin. It is produced in organisms that process fluoroacetate, a natural or introduced compound found in certain plants and as a component of some rodenticides. When fluoroacetate is taken up by cells, it is converted to fluoroacetyl-CoA by acetyl-CoA synthetase, and fluoroacetyl-CoA condenses with oxaloacetate via citrate synthase to yield fluorocitrate.

The key biochemical action of fluorocitrate is the inhibition of aconitase, the mitochondrial enzyme that interconverts citrate, cis-aconitate, and isocitrate in the citric acid cycle. Fluorocitrate binds to the enzyme’s iron-sulfur cluster, resulting in tight, often irreversible inhibition. This blocks the citric acid cycle, leading to citrate accumulation, reduced formation of NADH and FADH2, impaired ATP production, and metabolic energy failure, particularly in energy-demanding tissues such as the heart and brain.

In toxicology, fluorocitrate is considered the active toxin responsible for fluoroacetate poisoning. Symptoms can include nausea, vomiting, weakness, confusion, seizures, arrhythmias, and signs of metabolic distress. Exposure can occur through ingestion of fluoroacetate-containing plants (for example, Dichapetalum cymosum) or through certain rodenticides that release fluoroacetate. There is no widely available specific antidote; management is supportive and may include decontamination and measures to maintain organ function while the toxin is metabolized and excreted.

Chemically, fluorocitrate is the metabolite linked to disruption of cellular energy metabolism and provides a clear example of how a single metabolic inhibitor can derail the citric acid cycle. Research uses include studying enzyme inhibition within respiration and the regulation of the TCA cycle.