| Citrate synthase begins the TCA cycle by catalyzing the condensation of acetyl-CoA and oxaloacetate to form citric acid. The reaction is driven by cleavage of the high-energy thioester bond of citroyl-CoA, an intermediate in the reaction. A later TCA cycle enzyme, succinyl-CoA synthetase, utilizes the high-energy thioester bond in succinyl-CoA to produce GTP, a high-energy phosphate.
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| TOXICITY OF FLUOROACETATE - A SUICIDE SUBSTRATE |
| Fluoroacetate, originally isolated from plants, is a potent toxin. It is activated as fluoroacetyl-CoA and then condenses with oxaloacetate to form fluorocitrate (Fig. 13.8). Death results from inhibition of the TCA cycle by 2-fluorocitrate, a strong inhibitor of aconitase. Fluoroacetate is an example of a 'suicide substrate', a compound that is not toxic per se, but is metabolically activated to a toxic product. Thus, the cell is said to commit suicide by converting an apparently harmless substrate to a lethal toxin. Similar processes are involved in the activation of many environmental procarcinogens to carcinogens that induce mutations in DNA. |
| Figure 13.8 Toxicity of fluorocitrate - a suicide substrate. Fluorocitrate is a competitive inhibitor of aconitase. OAA, oxaloacetate. |
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| Figure 13.9 Specificity of isomerization during the aconitase reaction. |
| Figure 13.10 Stereochemistry of the aconitase reaction. Aconitase converts achiral citrate to a specific chiral form of isocitrate. Binding of the C-3 hydroxyl (OH) and carboxylate (COO-) groups of citrate on the enzyme surface places the carboxymethyl (-CH2-COO-) group, derived from the oxaloacetate end of the molecule, in touch with the third binding locus in the active site of aconitase. This assures the transfer of the OH group to the CH2 group derived from oxaloacetate, indicated by arrows, rather than that derived from the acetyl group. OAA, oxaloacetate. |
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