Understanding the mechanism-based inactivation of aconitase by fluoroacetate
Aconitase is rapidly inactivated by 2R,3R-fluorocitrate, which is produced from fluoroacetate in the citrate synthase reaction. Interestingly, inactivation by fluorocitrate is accompanied by stoichiometric release of fluoride ion (i.e., one F-ion is lost per aconitase active site). This observation is consistent with “mechanism-based inactivation” of aconitase by fluorocitrate. Suggest a mechanism for this inactivation, based on formation of 4-hydroxy-trans-aconitate, which remains tightly bound at the active site. To assess your answer, consult this reference: Lauble, H., Kennedy, M., et al., 1996. The reaction of fluorocitrate with aconitase and the crystal structure of the enzymeinhibitor complex. Proceedings of the National Academy of Sciences 93:13699–13703.
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