3-Fluoro-3-deoxycitrate: A Probe for Mechanistic Study of Citrate-Utilizing Enzymes

Steven E. Rokita, Paul A. Srere, Christopher T. Walsh

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Abstract

The interaction of a novel fluorinated analogue of citrate, 3-fluoro-3-deoxycitrate (3-fluorocitrate), with the four known citrate-processing enzymes is described in this report. Three of the citrate-processing enzymes, citrate synthase, ATP citrate lyase, and citrate lyase, catalyze reversible aldol-type condensations. The fate of 3-fluorocitrate with each enzyme is uniquely related to their mechanisms of action. For citrate synthase, 3-fluorocitrate is a competitive inhibitor. 3-Fluorocitrate is a substrate for the carboxylate activation half-reaction catalyzed by ATP citrate lyase and induces a net ATPase action during conversion to 3-fluorocitryl-S-coenzyme A. Because of the unusual mechanism of citrate cleavage catalyzed by bacterial citrate lyase, 3-fluorocitrate is a mechanism-based inhibitor, acting at two points during turnover of the acetyl enzyme. The fourth citrate-processing enzyme, aconitase, does turn over 3-fluorocitrate catalytically. This enzyme, catalyzing a dehydration and rehydration of citrate, also catalyzes the elimination of HF from 3-fluorocitrate, yielding m-aconitate and fluoride.

Original languageEnglish
Pages (from-to)3765-3774
Number of pages10
JournalBiochemistry
Volume21
Issue number16
DOIs
Publication statusPublished - Aug 1982

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ASJC Scopus subject areas

  • Biochemistry

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