Studies with Specific Enzyme Inhibitors

Dummel, Robert J.; Kun, Ernest

doi:10.1016/s0021-9258(18)91718-7

Cited by 37 publications

(8 citation statements)

References 4 publications

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“…The yields obtained in the various synthetic and resolution steps were comparable to those reported. The optical rotations attained were also equivalent to those reported by Dummel & Kun (1969). The individual isomers were crystallized as the tricyclohexylammonium salts and used in this form in the enzyme incubations.…”

Section: Methodssupporting

confidence: 67%

“…Results and Discussion (+)-and (-)-erythro-2-Fluorocitrates. The synthetic routes described by Kun and colleagues worked well in our hands both for the separation of the diastereomeric erythro from the threo compounds and also for the separation of (+)-erythro-from the (-)-eryz/iro-2-fluorocitrates by repeated fractional crystallization to equal and opposite optical rotation in accord with literature values (Dummel & Kun, 1969). Subsequent enzymatic experiments required this high degree of purity of (+)and (-)-erythro forms.…”

Section: Methodssupporting

confidence: 63%

“…The (+)and (-)-e/yiAro-2-fluorocitrate enantiomers were synthesized and resolved according to procedures in the literature (Dummel & Kun, 1969). The yields obtained in the various synthetic and resolution steps were comparable to those reported.…”

Section: Methodsmentioning

confidence: 59%

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Stereochemical outcome of processing of fluorinated substrates by ATP citrate lyase and malate synthase

1981

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Section: Methodssupporting

confidence: 67%

Section: Methodssupporting

confidence: 63%

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Stereochemical outcome of processing of fluorinated substrates by ATP citrate lyase and malate synthase

1981

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“…The procedure for the chemical analysis of 3-fluorocitrate is identical with that used for citrate by Hartford (1962). The (+)-and (-)-eryzZiro-2-fluorocitrate enantiomers have been previously synthesized (Dummel & Kun, 1969). [Caution: handle (-)-eryZ¿ro2-fluorocitrate with extreme care.…”

Section: Methodsmentioning

confidence: 99%

3-Fluoro-3-deoxycitrate: a probe for mechanistic study of citrate-utilizing enzymes

1982

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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 cis-aconitate and fluoride.

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“…for inhibition of the enzyme reaction for the conversion of citrate into cis-aconitate. The variation in K1 values may reasonably be attributed, at least in part, to a difference in the proportion of the inhibiting isomer of fluorocitrate, (-)-erythro-fluorocitrate, contained in the fluorocitrate samples used by these workers (Dummel & Kun, 1969).…”

mentioning

confidence: 97%

Fluorocitrate inhibition of aconitate hydratase and the tricarboxylate carrier of rat liver mitochondria

Brand

Evans

Mendes-Mourão

et al. 1973

Biochemical Journal

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1. The effect of biologically synthesized and purified fluorocitrate on the metabolism of tricarboxylate anions by isolated rat liver mitochondria was investigated, in relation to the claim by Eanes et al. (1972) that this fluoro compound inhibits the tricarboxylate carrier at concentrations at which it has little effect on the aconitate hydratase activity. 2. That the inhibitory action of fluorocitrate is at the level of the aconitate hydratase and not at the level of the tricarboxylate carrier is indicated by the following findings. Although the oxidation of citrate and cis-aconitate, but not that of isocitrate, was inhibited by fluorocitrate, the exchange of internal citrate for external citrate or l-malate was not. Had the tricarboxylate carrier been affected, these latter exchange reactions would have been inhibited. 3. By using aconitate hydratase solubilized from mitochondria it was found that with citrate as substrate the inhibition by fluorocitrate was partially competitive (K(i)=3.4x10(-8)m), whereas with cis-aconitate as substrate the inhibition was partially non-competitive (K(i)=3.0x10(-8)m).

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Studies with Specific Enzyme Inhibitors

Cited by 37 publications

References 4 publications

Stereochemical outcome of processing of fluorinated substrates by ATP citrate lyase and malate synthase

Stereochemical outcome of processing of fluorinated substrates by ATP citrate lyase and malate synthase

3-Fluoro-3-deoxycitrate: a probe for mechanistic study of citrate-utilizing enzymes

Fluorocitrate inhibition of aconitate hydratase and the tricarboxylate carrier of rat liver mitochondria

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