Mechanism of the inhibition of cholesterol biosynthesis by 6-fluoromevalonate

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Abstract
6-Fluoromevalonate blocks the incorporation of mevalonic acid, but not that of isopentenyl pyrophosphate, into non-saponifiable lipids in a rat liver multienzyme system. With 3H-labeled 6-fluoromevalonate, it was found that 6-fluoromevalonate is converted to its phospho and pyrophospho derivatives in this system. The kinetics of the 2 kinases were studied. 6-Fluoromevalonate 5-pyrophosphate is a potent competitive inhibitor of pyrophosphomevalonate decarboxylase (K1 = 37 nM). In the multienzyme assay for cholesterol biosynthesis, there is accumulation of mevalonate 5-phosphate and mevalonate 5-pyrophosphate in the presence of 5 .mu.M-6-fluoromevalonate, and 6-fluoromevalonate 5-pyrophosphate is more effective than 6-fluoromevalonate in inhibiting cholesterol biosynthesis. 6-Fluoromevalonate blocks cholesterol biosynthesis at the level of pyrophosphomevalonate decarboxylase after being pyrophosphorylated. [Hypercholesterolemia is a major risk factor in coronary artery disease.].