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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
3
|
| pubmed:dateCreated |
1992-2-14
|
| pubmed:abstractText |
The enantiomers (+) and (-)-2,2-difluorocitrate have been synthesized. Both are good inhibitors of ATP-citrate lyase, showing competitive inhibition against citrate, with Kis = 0.7 microM for (+)-2,2-difluorocitrate and 3.2 microM for (-)-2,2-difluorocitrate. The inhibition patterns with either ATP or CoA as the varied substrate were uncompetitive and mixed, respectively, but with much weaker inhibition constants. Neither isomer undergoes carbon-carbon bond cleavage as a substrate and there is no evidence of irreversible time-dependent inactivation. When ATP-citrate lyase is incubated with CoA and difluorocitrate, the maximal intrinsic ATPase rate is 10% of the citrate-induced rate for the (+)-enantiomer and 2% for the (-)-enantiomer. 19F-NMR studies confirm that only the (+)-enantiomer is chemically processed. The effects of the difluorocitrate enantiomers on the reaction catalysed by aconitase were examined. (-)-2,2-Difluorocitrate is a competitive inhibitor against citrate (Kis = 1.5 microM), whereas the (+)-enantiomer is a relatively poor mixed inhibitor (Ki greater than 300 microM). The (-)-enantiomer irreversibly inactivates aconitase at 1.1 min-1.mM-1 at 25 degrees C and pH 7.4, whereas no irreversible inhibition is seen with the (+)-enantiomer. Therefore, it would be expected that the (+)-enantiomer would slow the rate of acetyl-CoA synthesis in vivo, without inhibiting the citric acid cycle.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Dec
|
| pubmed:issn |
0014-2956
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
18
|
| pubmed:volume |
202
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
889-96
|
| pubmed:dateRevised |
2007-7-23
|
| pubmed:meshHeading |
pubmed-meshheading:1765100-ATP Citrate (pro-S)-Lyase,
pubmed-meshheading:1765100-Aconitate Hydratase,
pubmed-meshheading:1765100-Animals,
pubmed-meshheading:1765100-Citrates,
pubmed-meshheading:1765100-Indicators and Reagents,
pubmed-meshheading:1765100-Isomerism,
pubmed-meshheading:1765100-Kinetics,
pubmed-meshheading:1765100-Liver,
pubmed-meshheading:1765100-Magnetic Resonance Spectroscopy,
pubmed-meshheading:1765100-Molecular Conformation,
pubmed-meshheading:1765100-Myocardium,
pubmed-meshheading:1765100-Rats,
pubmed-meshheading:1765100-Swine
|
| pubmed:year |
1991
|
| pubmed:articleTitle |
Synthesis and evaluation of (+) and (-)-2,2-difluorocitrate as inhibitors of rat-liver ATP-citrate lyase and porcine-heart aconitase.
|
| pubmed:affiliation |
SmithKline Beecham Pharmaceuticals Ltd., Frythe, Welwyn, England.
|
| pubmed:publicationType |
Journal Article
|