FluoroacetylCoA

Fluoroacetyl-CoA is the CoA thioester of fluoroacetate, a fluorinated analog of acetyl groups. In chemical terms, it is the activated form of fluoroacetate in which the fluoroacetyl moiety (F-CH2-CO-) is linked to coenzyme A by a thioester bond. It is not a common intermediate in normal metabolism but can be formed in organisms that encounter fluoroacetate.

Formation and metabolic context: Fluoroacetyl-CoA is produced when fluoroacetate is activated by acyl-CoA synthetases, such as acetyl-CoA synthetase, in an ATP-dependent ligation reaction: fluoroacetate + CoA + ATP → fluoroacetyl-CoA + AMP + PPi. This activated species can then enter the citric acid cycle via condensation with oxaloacetate.

Mechanism of toxicity: The reaction of fluoroacetyl-CoA with oxaloacetate, catalyzed by citrate synthase, yields fluoro-citrate. Fluorinated citrate inhibits aconitase, blocking the conversion of citrate to isocitrate and disrupting the downstream energy-producing steps of the TCA cycle. This mechanism explains the toxic effects of fluoroacetate in mammals and other organisms that activate the compound to fluoroacetyl-CoA.

Detoxification and research relevance: Some bacteria possess fluoroacetate dehalogenase, which can cleave the C–F bond to form glycolate and fluoride, providing a detoxification route that bypasses CoA activation. In research, fluoroacetyl-CoA serves as a tool to study acyl-CoA chemistry, citrate synthase function, and mechanisms of TCA cycle inhibition. Clinically, fluoroacetate exposure remains hazardous, with management focused on supportive care and detoxification strategies as no widely effective antidotes are available.