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-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.
Reardon
J E
JE
Graduate Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02254.
Abeles
R H
RH
D000818:Animals; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D002784:Cholesterol / Q000096:biosynthesis*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008798:Mevalonic Acid / Q000031:analogs & derivatives*; D010766:Phosphorylation; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D006845:Hydrocarbons, Fluorinated; D002784:Cholesterol; D002262:Carboxy-Lyases; C022503:pyrophosphomevalonate decarboxylase; D008798:Mevalonic Acid