PMID: 8942997Nov 26, 1996Paper

The reaction of fluorocitrate with aconitase and the crystal structure of the enzyme-inhibitor complex

Proceedings of the National Academy of Sciences of the United States of America
H LaubleC D Stout

Abstract

It has been known for many years that fluoroacetate and fluorocitrate when metabolized are highly toxic, and that at least one effect of fluorocitrate is to inactivate aconitase. In this paper we present evidence supporting the hypothesis that the (-)-erythro diastereomer of 2-fluorocitrate acts as a mechanism based inhibitor of aconitase by first being converted to fluoro-cis-aconitate, followed by addition of hydroxide and with loss of fluoride to form 4-hydroxy-trans-aconitate (HTn), which binds very tightly, but not covalently, to the enzyme. Formation of HTn by these reactions is in accord with the working model for the enzyme mechanism. That HTn is the product of fluorocitrate inhibition is supported by the crystal structure of the enzyme-inhibitor complex at 2.05-A resolution, release of fluoride stoichiometric with total enzyme when (-)-erythro-2-fluorocitrate is added, HPLC analysis of the product, slow displacement of HTn by 10(6)-fold excess of isocitrate, and previously published Mössbauer experiments. When (+)-erythro-2-fluorocitrate is added to aconitase, the release of fluoride is stoichiometric with total substrate added, and HPLC analysis of the products indicates the formation of oxalosuccinate, and its deriva...Continue Reading

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Jul 24, 2010·The Journal of Biological Chemistry·Kuo-Hsiang Tang, Robert E Blankenship
Sep 3, 2010·The Journal of Biological Chemistry·Kuo-Hsiang TangYinjie J Tang
Feb 10, 2007·Toxicological Reviews·Alex T ProudfootJ Allister Vale
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