Farnesyl pyrophosphate synthetase. Mechanistic studies of the 1'-4 coupling reaction with 2-fluorogeranyl pyrophosphate.

C. D. Poulter, J. C. Argyle, Eugene A Mash

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Abstract

The mechanism of the 1'-4 coupling reaction between isopentenyl pyrophosphate and geranyl pyrophosphate catalyzed by farnesyl pyrophosphate synthetase from porcine liver was studied with the allylic substrate analogue 2-fluorogeranyl pyrophosphate. 2-Fluorogeranyl pyrophosphate is an alternate substrate for the enzyme, yielding 6-fluorofarnesyl pyrophosphate upon condensation with isopentenyl pyrophosphate. The Michaelis constant for the fluoroanalogue, Km = 1.1 micron, is similar to that measured for geranyl pyrophosphate, Km = 0.7 micron. However, the rate of condensation with the fluoroanalogue was only 8.4 X 10(-4) that of the normal reaction. A similar rate of depression (4.4 X 10(-3)) was found for solvolysis of geranyl methanesulfonate and the corresponding 2-fluoro derivative, reactions known to proceed via cationic intermediates. In contrast, displacement of chlorine from geranyl chloride and 2-fluorogeranyl chloride by cyanide showed a small (2-fold) rate enhancement for the fluoro compound. Finally, 2-fluorogeranyl pyrophosphate is a competitive inhibitor against geranyl pyrophosphate. These data are interpreted in terms of an ionization-condensation-elimination mechanism for the 1'-4 coupling reaction.

Original languageEnglish (US)
Pages (from-to)7227-7233
Number of pages7
JournalJournal of Biological Chemistry
Volume253
Issue number20
StatePublished - Oct 25 1978
Externally publishedYes

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Geranyltranstransferase
Condensation
Chlorides
Chlorine
Cyanides
Substrates
Liver
Ionization
Swine
Derivatives
Enzymes
2-fluorogeranyl pyrophosphate
geranyl pyrophosphate
isopentenyl pyrophosphate

ASJC Scopus subject areas

  • Biochemistry

Cite this

Farnesyl pyrophosphate synthetase. Mechanistic studies of the 1'-4 coupling reaction with 2-fluorogeranyl pyrophosphate. / Poulter, C. D.; Argyle, J. C.; Mash, Eugene A.

In: Journal of Biological Chemistry, Vol. 253, No. 20, 25.10.1978, p. 7227-7233.

Research output: Contribution to journalArticle

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abstract = "The mechanism of the 1'-4 coupling reaction between isopentenyl pyrophosphate and geranyl pyrophosphate catalyzed by farnesyl pyrophosphate synthetase from porcine liver was studied with the allylic substrate analogue 2-fluorogeranyl pyrophosphate. 2-Fluorogeranyl pyrophosphate is an alternate substrate for the enzyme, yielding 6-fluorofarnesyl pyrophosphate upon condensation with isopentenyl pyrophosphate. The Michaelis constant for the fluoroanalogue, Km = 1.1 micron, is similar to that measured for geranyl pyrophosphate, Km = 0.7 micron. However, the rate of condensation with the fluoroanalogue was only 8.4 X 10(-4) that of the normal reaction. A similar rate of depression (4.4 X 10(-3)) was found for solvolysis of geranyl methanesulfonate and the corresponding 2-fluoro derivative, reactions known to proceed via cationic intermediates. In contrast, displacement of chlorine from geranyl chloride and 2-fluorogeranyl chloride by cyanide showed a small (2-fold) rate enhancement for the fluoro compound. Finally, 2-fluorogeranyl pyrophosphate is a competitive inhibitor against geranyl pyrophosphate. These data are interpreted in terms of an ionization-condensation-elimination mechanism for the 1'-4 coupling reaction.",
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