Fluoroacetyl coenzyme

Chenoweth believes that an explanation of the above results may lie in the reactions occurring before the entrance of fatty acid metabolites into the citric acid cycle. Activated acetate, i.e. acetyl coenzyme A (AcCoA) is the end-product of fatty acid metabolism prior to its condensation with oxalacetate to form citrate. Possibly fluoro-fatty acids behave like non-fluorinated fatty acids. The end-product before the oxalacetate condensation could be the same for all three fluorinated inhibitors, viz. fluoroacetyl coenzyme A (FAcCoA). Fluorocitrate could then be formed by the condensation of oxalacetate with FAcCoA, thereby blocking the citric acid cycle. The specificity of antagonisms must therefore occur before entrance of the metabolites into the citric acid cycle. 

F. Huang, S.F. Haydock, D. Spiteller, T. Mironenko, T.-L. Li, D. O Hagan, P.F. Leadlay, J.B. Spencer, The gene cluster for fluorometabolite biosynthesis in Streptomyces cattleya-. A thioesterase confers resistance to fluoroacetyl-coenzyme A, Chem Biol. 13 (2006) 475-484. 

Huang F, HaydockSF, Spiteller D, Mironenko T, Li T-L, O Hagan D, Leadlay PF, Spencer JB (2006) The Gene Cluster for Fluorometabolite Biosynthesis in Streptomyces cattleya A Thioesterase Confers Resistance to Fluoroacetyl-Coenzyme A. Chem Biol 13 475... 

Fluoroacetate produces its toxic action (after conversion to fluorocitrate) by inhibiting the Kreb s cycle. The compound is incorporated into fluoroacetyl coenzyme A, which condenses with oxaloacetate... 

Fanshier et al. (1964) have shown that the aconitase-inhibitory effect of synthetic monofluorocitrate is due to one isomer, synthesized enzymatically from fluoroacetyl coenzyme A and oxaloacetate. They separated diastereoisomers of synthetic mono-fluorocitric acid, compared the chemical and enzyme-inhibitory properties of these with enzymatically formed isomers, and found that the DL-erythro form of fluoro-citrate is the diastereoisomer which inhibits aconitase action. Infrared spectroscopy helped to characterize the DL-erythro and DL-threo isomers. 

It exerts its effect by being an inhibitor of the Krebs cycle. Fluoroacetate substitutes for acetate and is converted to fluoroacetyl CoA. This is condensed with oxaloacetate to produce fluorocitrate in other words citrate synthase uses fluoroacetate as a substrate and forms fluorocitrate that inhibits aconitase (reaction 2 in Fig. 10-9A and B). If the Krebs cycle is not functioning correctly, the rate of NADH production will be insufficient to maintain the mitochondrial proton gradient, and the ATP concentration will decline. A further complication is that processes such as the Krebs cycle have an important role in regenerating moiety carrier molecules. If the cycle is inhibited, then vital carriers such as oxaloacetate and coenzyme A become depleted. 

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