Tomoda Hiroshi

F-244 specifically inhibits 3-hydroxy-3-methylglutaryl coenzyme A synthase.

Abstract A β-lactone isolated from Scopulariopsis sp. shows a potent inhibition of cholesterogenesis. The structure of this β-lactone, termed F-244, is 3,5,7-trimethyl-12-hydroxy-13-hydroxymethyl-2,4-tetradecadiendioic acid 12,14-lactone. The inhibition site of F-244 in cholesterol synthesis was studied. The growth of Vero cells was inhibited at 6.25–12.5 μg/ml of F-244. The inhibition of growth was overcome by the addition of mevalonate to the culture medium, but not by the addition of acetate. In a rat liver enzyme system, the incorporations of [ 14 C]acetate and [ 14 C]acetyl-CoA into digitonin-precipitable sterol were 50% inhibited by 0.58 βg/ml of F-244. The incorporation of [ 14 C]mevalonate was not affected. Studies on the effects of F-244 on the three enzymes involved in mevalonate biosynthesis demonstrated that the drug specifically inhibits HMG-CoA synthase with IC 50 value of 0.065 μg /ml. The effect of analogs of F-244 on HMG-CoA synthase was also investigated.