Inhibition of cholesterol biosynthesis by fluorinated mevalonate analogues

The conversion of mevalonate to cholesterol in rat liver homogenates (IC50 = 0.01-1.0 mM) is inhibited by 6- (I), 6,6-di- (II), and 6,6,6-trifluoromevalonate (III), as well as 4,4-difluoromevalonate (IV). Addition of compound I, III, or IV to rat liver homogenates results in the accumulation of 5-ph...

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Veröffentlicht in:Biochemistry (Easton) Jg. 26; H. 15; S. 4717
Hauptverfasser: Reardon, J E, Abeles, R H
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 28.07.1987
Schlagworte:
Animals
Carboxy-Lyases - antagonists & inhibitors
Carboxy-Lyases - isolation & purification
Cholesterol - biosynthesis
Hydrocarbons, Fluorinated - pharmacology
Kinetics
Liver - metabolism
Male
Mevalonic Acid - analogs & derivatives
Phosphorylation
Rats
Rats, Inbred Strains
Structure-Activity Relationship
ISSN:0006-2960
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Zusammenfassung:The conversion of mevalonate to cholesterol in rat liver homogenates (IC50 = 0.01-1.0 mM) is inhibited by 6- (I), 6,6-di- (II), and 6,6,6-trifluoromevalonate (III), as well as 4,4-difluoromevalonate (IV). Addition of compound I, III, or IV to rat liver homogenates results in the accumulation of 5-phospho- and 5-pyrophosphomevalonate. The conversion of isopentenyl pyrophosphate to cholesterol is not inhibited by the fluorinated analogues. It thus appears likely that the decarboxylation of mevalonate 5-pyrophosphate is inhibited. Rat liver homogenates catalyze the phosphorylation of I and III. The inhibition of the decarboxylation of mevalonate 5-pyrophosphate by I and III was demonstrated directly with partially purified decarboxylase. Compound I is a remarkably effective inhibitor of the decarboxylation (Ki = 10 nM). Similar results were reported by Nave et al. [Nave, J. F., d'Orchymont, H., Ducep, J. B., Piriou F., & Jung, M. J. (1985) Biochem. J. 227, 247]. It is likely that the phosphorylated or pyrophosphorylated forms of all inhibitors tested are responsible for inhibition. We also describe a chemical method for the synthesis of mevalonate 5-pyrophosphate.
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ISSN:0006-2960
DOI:10.1021/bi00389a018