Biochemistry of fluoroacetate poisoning. The isolation and some properties of the fluorotricarboxylic acid inhibitor of citrate metabolism

Abstract

It has been suggested that the toxicity of fluoroacetate is due to the enzymic synthesis of a fluorotricarboxylic acid, which ‘jams’ the tricarboxylic acid cycle at the citrate stage. This communication presents the proof of this hypothesis. The inhibitory substance for citrate metabolism synthesized by enzymic action from fluoroacetate has been isolated as a compound in crystalline form of great potency. Under the conditions of test it inhibits the disappearance of approximately 300 times its weight of citric acid in 30 min. The final isolation involved a separation from citric acid by the use of ion-exchange resin, and fractional extraction with ether. It is a monofluorotricarboxylic acid, as shown by its migration on a paper chromatogram, by its fluorine content (estimated spectrochemically), and by its titration curve. It does not give the colour reaction with sodium sulphide for pentabromacetone produced from citric acid by the usual methods. It gives an infra-red band which may be expected from a C-F bond. By a process of exclusion, it is considered to be a fluorocitric acid; a final decision must await synthesis.

Perfusion Studies of the Human Placenta. I. Effect of Estradiol and Human Chorionic Gonadotropin on Citric Acid Metabolism12

“…Fluoroacetate, after conversion to fluorocitrate, inhibits the enzyme aconitase (22) and thus interrupts the Krebs cycle. The marked reduction of placental citrate utilization noted here in the presence of fluoroacetate indicates that such a metabolic pathway is indeed involved in the observed citrate disappearance.…”

Metabolism of fluoroorganic compounds in microorganisms: impacts for the environment and the production of fine chemicals

“…It is a highly toxic compound owing to the in vivo lethal synthesis of (2R, 3R)-2-fluorocitrate, which is an inhibitor of aconitase (Peters et al 1953) and citrate transport across mitochondrial membranes (Kirsten et al 1978). Kelly (1965) and the x-ray structure revealed that the enzyme is a member of the α/β superfamily.…”

Formation and utilization of 3-hydroxy-3-methylglutarate in liver mitochondria of starved and streptozotocin-diabetic rats

“…The 3-hydroxy-3-methylglutaryl-CoA hydrolase activity was assayed by measuring the appearance of free thiol groups by the method of Ellman et al Modena, Italy) and was prepared by the method of Peters et al (1953) and contained about 4% of the inhibitory isomer.…”