Fluorocitrate, lethal synthesis

Substances of toxicological significance Monofluoro-acetate Aconitase (tricarboxylic acid, (,Dichapetalum Krebs cycle) cymosum) No clinical uses Becomes incorporated into fluoroacetyl coenzyme A, which condenses with oxaloacetate to form fluorocitrate ( lethal synthesis )... 

Fluoroacetate undergoes a "lethal synthesis"(18) to 2-fluorocitrate which may reversibly inhibit aconitase and which irreversibly binds to a membrane-associated citrate transport protein(19,20). Insecticidal and other biocidal uses of fluoroacetate (or its metabolic precursors) received considerable attention twenty-five years ago( ) but most uses have been abandoned due to high nonspecific vertebrate toxicity of these compounds. Vfe have reported the use of o)-fluoro fatty acids and their derivatives as delayed-action toxicants for targeted... 

Phytosterol dealkylation can be harnessed in insects to release a fluoroacetate equivalent from a 29-fluorinated sterol. Moreover, the fluorocitrate which then results from the "lethal synthesis" can be isolated and chemically characterized. hope that the range of insects susceptible to the 29-fluorophytosterols and more commercially viable analogs will be further explored. Furthermore, we urge wider scrutiny of insect biochemical pathways in search of possible targets for suicide substrates or latent toxin release. 

Among the most deadly of simple compounds is sodium fluoroacetate. The LD50 (the dose lethal for 50% of animals receiving it) is only 0.2 mg/kg for rats, over tenfold less than that of the nerve poison diisopropylphosphofluoridate (Chapter 12).a b Popular, but controversial, as the rodent poison "1080," fluoroacetate is also found in the leaves of several poisonous plants in Africa, Australia, and South America. Surprisingly, difluoroacetate HCF2-COO is nontoxic and biochemical studies reveal that monofluoroacetate has no toxic effect on cells until it is converted metabolically in a "lethal synthesis" to 2R,3R-2-fluorocitrate, which is a competitive inhibitor of aconitase (aconitate hydratase, Eq. 13-17).b This fact was difficult to understand since citrate formed by the reaction of fluorooxalo-acetate and acetyl-CoA has only weak inhibitory activity toward the same enzyme. Yet, it is the fluorocitrate formed from fluorooxaloacetate that contains a fluorine atom at a site that is attacked by aconitase in the citric acid cycle. 

Fluoroacetic acid, fluorocitric acid and lethal synthesis . 1504... 

Compound 1080 is absorbed from the gastrointestinal tract, respiratory tract, mucous membranes, and wounds (Holstege et al, 2007). Different routes of exposure do not have a remarkable effect on toxicity. The mechanism of action for SMFA is blockage of the Krebs cycle. Metabolic activation by the formation of fluorocitrate is required a process known as lethal synthesis. Fluoroacetate is converted to fluoroacetyl-CoA and then converted by the enzyme... 

The activity of an enzyme may be inhibited by the presence of a toxic metabolite. Sodium fluoroacetate, known as rat poison 1080, is extremely toxic to animals. The toxic action, however, is not due to sodium fluoroacetate itself but to a metabolic conversion product, flu-orocitrate, formed through a reaction commonly known as "lethal synthesis," as shown in Figure 5.3. The resulting fluorocitrate is toxic because it is inhibitory to aconitase, the enzyme responsible for the conversion of citrate into czs-aconitate and then into isocitrate in the tricarboxylic acid cycle. Inhibition of aconitase results in citrate accumulation. The cycle stops for lack of metabolites, leading to disruption of energy metabolism. 

Synthesis of fluorocitrate from fluoroacetate through lethal synthesis." Inhibition of aconitase shuts down TCA Cycle. 

In the cellular metabolism F. reacts with citrate synthase to form (2R,3R)-2-fluorocitrate (QH7FO7, Mr 210.12), which inhibits transport of citrate through mitochondrial membranes. The lethal synthesis of fluorocitrate, however, only contributes to a small extent to the toxic activity. D. toxicarium stores F. in its extremely toxic seeds in the form of cu-fluorofatty acids, principally co-fluorooleic acid (C,gH33F02, Mr 300.46). Fluoroacetyl-CoA functions here as a starter unit. The biosynthesis of F. from fluoride ions has not been elucidated. 

The quantitative and qualitative response among different species to fluoro-acetic acid is unique [115]. Lethal doses range from 50 [xg/kg in dogs to 50 mg/kg in some monkeys, while some data indicate that man is intermediate. The mouse responds like the monkey, while the cat and rabbit are nearly as sensitive as the dog. Fluoroacetate is biochemically converted into fluorocitrate, a lethal synthesis, which results in the inhibition of a step in the tricarboxylic acid cycle. Various species may die from central nervous system stimulation, others from cardiac irregularities, and others from a combination of central and cardiac effects. A simple explanation for these variations is not available. 

---