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Fluoroacetate and Fluorocitrate: Mechanism of Action / Donald D Fordham University Masthead Logo DigitalResearch@Fordham Chemistry Faculty Publications Chemistry 1991 Fluoroacetate and fluorocitrate: mechanism of action / Donald D. Clarke Donald Dudley Clarke PhD Fordham University, [email protected] Follow this and additional works at: https://fordham.bepress.com/chem_facultypubs Part of the Biochemistry Commons Recommended Citation Clarke, Donald Dudley PhD, "Fluoroacetate and fluorocitrate: mechanism of action / Donald D. Clarke" (1991). Chemistry Faculty Publications. 16. https://fordham.bepress.com/chem_facultypubs/16 This Article is brought to you for free and open access by the Chemistry at DigitalResearch@Fordham. It has been accepted for inclusion in Chemistry Faculty Publications by an authorized administrator of DigitalResearch@Fordham. For more information, please contact [email protected]. .. Neurochemical Research, Vol. 16, No. 9, 1991, pp. 1055-1058 Fluoroacetate and Fluorocitrate: Mechanism of Action* Donald D. Clarke1 (Accepted April 22, 1991) The concept of lethal synthesis as suggested by Peters is reviewed in the light of the more recent work in this area. It is suggested that fluorocitrate is a "suicide" substrate for aconitase rather than a competitive inhibitor as originally suggested. The use of these substances to study glial­ neuronal relationships is considered. KEY WORDS: Fluoroacetate; fluorocitrate; fluoroaconitate. In a recent paper (22), it is stated that "The bio­ isomers (2R,3S & 2S,3S) could be ruled out as toxic chemical mechanism by which fluorocitrate and/or fluo­ unless fluoroacetyl-CoA behaved differently than acetyl­ roacetate disrupt the central nervous system and heart CoA when acted on by citrate synthase. Despite this well are not adequately defined". While this statement is cor­ known information there have been a few attempts in rect, the main aim of this review is to distinguish what biochemistry textbooks to assume that the C-F bond of is well defined from what is still controversial about this fluorocitrate must be in a position analogous to the C­ subject. The concept of "lethal synthesis", i.e. the con­ OH bond of isocitrate to cause inhibition of aconitase. version of fluoroacetate to fluorocitrate which in turn In an extreme example it was suggested that the initially inhibits citrate metabolism, orginally proposed by Pe­ formed fluorocitrate was converted to fluorooxaloacetate ters, is still generally well accepted. However, the man­ in the Krebs cycle and on the second turn of the cycle ner in which fluorocitrate produces its toxic effect is still was converted to an isomer of fluorocitrate with the ster­ unsettled. eochemistry assumed to be necessary. Not only does That only one stereoisomer, which they defined as such an assumption contradict the results of Kun's lab­ (-)-erythro-fluorocitrate, is toxic was elegantly and oratory which show that fluorooxaloacetate condenses unequivocally demonstrated by Dumel and Kun (8). The with acetyl-CoA to yield a non toxic isomer (8) but it absolute configuration of this isomer was shown to be had been demonstrated by Clarke et al. (5) that fluoro­ 2R,3R using X-Ray diffraction techniques in Glusker's fumarate is a substrate for fumarase and fluoride is elim­ laboratory (23). inated in the process. The mechanism of this process has been established by Marietta et al. (13). Well before the absolute stereochemistry of the toxic The original suggestion of Peters that fluorocitrate isomer had been established it was appreciated by many was the toxic agent was not based on a definitive iso­ workers in this field that, on the basis of the fact that lation and chemical identification of fluorocitrate. Rather, [1- 14C]acetate yields a labeled citrate which in turn is it was based on a partial purification of the toxic agent converted to isocitrate and then a-ketoglutarate labeled which suggested that it was similar to material later syn­ in the -y-carboxyl group, the absolute stereochemistry at thesized chemically by Rivett (21 ), and was primarily position 3 of 2-fluorocitrate was most likely R. The 3S based on the accumulation of citrate in tissues of fluo­ roacetate poisoned animals. It is only relatively recently 1 Department of Chemistry, Fordham University, Bronx, NY 10458, U.S.A. that a definitive identification of erythro-2-fluoro-[2- * Special issue dedicated to Dr. Louis Sokoloff. 3H]citrate was achieved by adding carrier material, de- 1055 0364-3190/91/0900-1055$06.50/0 © 1991 Plenum Publishing Corporation 1056 Clarke rivativizing as the trimethyl ester benzoate and separa­ beling of glutamine. Later work suggested that this small tion by HPLC (20). In that study [29-3 H]-29- pool was located in glial cells. On this basis it would fluorostigmasterol was fed to tobacco hornworms (Man­ seem that acetate thiokinase is largely or exclusively in duca sexta) and 0.012% of the administered dose was glia, an assumption that remains to be rigorously proven. converted to (2R,3R)-2-fluoro-[2-3H]citrate. This low Other corollaries of the metabolic pools hypothesis have conversion is consistent with the fact that previous at­ received support from immunocytochemical studies viz. tempts using 14C labeled precursors all failed to result that glutamine synthesase (16) and glutamate dehydro­ in a definitive chemical identification of 2-fluorocitrate. genase (1) are enriched in glial cells. This idea that fluo­ This also makes the original suggestion of Peters that rocitrate is having its effect in glial cells was further fluorocitrate is inhibiting aconitase competitively rather developed in Fonnum's laboratory (17). These authors implausible. found that injection of 1 nanomole of fluorocitrate in­ Over the years many investigators have failed to trastriatally induces an in vivo condition in which glial find large accumulations of citrate in fluoroacetate poi­ metabolism is selectively impaired. They used this con­ soned animals, especially in brain tissue, and thus have dition as a model for the study of metabolic relationships questioned the validity of Peters' explanation. In fact between neurons and glial cells and to assess the im­ Peters and Shorthouse (19) and later Morselli et al. (14) portance of glial cells for brain function in vivo. suggested that "lethal synthesis" occurred in other or­ By analogy with the Sokoloff deoxyglucose method gans and fluorocitrate was then carried to brain tissue to for studying brain metabolism and relating it to function produce its toxic effect. Kidney, heart and liver are the we considered that labeled fluoroacetate might be a pos­ tissues in which most investigators have been able to sible radiochemical marker for studying glial metabo­ demonstrate significant elevations of citrate in fluoroac­ lism. Sokoloff had similar ideas (private communication). etate poisoned animals. However, [14C]fluoroacetate was the only material com­ When tracer studies were brought to bear on the mercially available and it would have required toxic doses subject Quastel's group (12) showed that the most not­ of that material to get sufficient radioactivity into brain able change observed in the brains of fluoroacetate poi­ tissue for such experiments. We were able to convince soned rats was decreased labeling of glutamine from Dr. Richard Young of the New England Nuclear Corp. glucose or other precursors and these effects could be to prepare highly labeled [2-3H]fluoroacetate for us and demonstrated in brain slices. Hence they suggested that this material allowed us to do tracer studies to test this glutamine synthetase may be inhibited. We were able to hypothesis, viz. that [3H]fluoroacetate would be acti­ show that fluorocitrate did not inhibit purified glutamine vated in glia and be converted to [3H]fluorocitrate which synthetase from sheep brain (7). Rather we advanced the would accumulate there and be detectable by autora­ theory that aconitase was being inhibited in a pool of diography. Approx. 1% of a dose of labeled fluoroace­ citric acid cycle intermediates that was much smaller tate administered to rats i. p. enters brain cortex and of than the total pool in brain cells (7). Later work sug­ this only < 0.02% was found in the fraction containing gested that this pool is probably in glial cells while the fluorocitrate. The fluorocitrate fraction in heart ac­ larger pools are in neurons. The experiments on brain counted for 0.25% of the tracer and in kidney for 0.35% slices also indicated that fluoroacetate must be converted (6). This agrees with previous reports in the literature. to fluorocitrate in brain tissue. In that work we attempted The analogy with the Sokoloff deoxyglucose method to isolate labeled fluorocitrate when using [U-14C]-as­ was flawed because no accumulation of labeled fluoro­ partic acid as the tracer. The precursor produces labeled citrate was observed to occur over time. Rather increased oxaloacetate which in turn should produce labeled fluo­ release of tritium into water was found. However, when rocitrate. We failed to detect it (10). However, as men­ autoradiographs were made of different brain areas dif­ tioned above the degree of conversion of fluoroacetate ferential labeling was observed consistent with the pos­ to fluorocitrate is quite low and we would have had to tulate that glia were much more heavily labeled than use almost 100% 14C labeled substrates to have found neurons (15). Tritiated acetate, which is much more readily it. This alerted us to the need to use tritium labeled available than is tritiated fluoroacetate, also yielded sim­ material for tracer experiments in search of labeled fluo­ ilar autoradiographs in experiments of short duration when rocitrate. little of the tritium had been released into water. The metabolic compartmentation hypothesis pro­ When toxic doses of labeled fluoroacetate are used posed by Berl and Clarke (3) was the basis for the above it is possible to get sufficient quantities of labeled ma­ explanation of "lethal synthesis" of fluorocitrate occur­ terials for chemical isolation and study. This approach ring in a small compartment characterized by rapid Ia- has been used recently (22) in conjunction with 19F hnd Fluoroacetate and Fluorocitrate: Mechanism of Action 1057 13C NMR.
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