F-244 SPECIFICALLY INHIBITS 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A SYNTHASE

  • 14 December 1987
    • journal article
    • research article
    • Vol. 922  (3) , 351-356
Abstract
A .beta.-lactone isolated from Scopulariopsis sp. shows a potent inhibition of cholesterogenesis. The structure of this .beta.-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 .mu.g/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 [14C]acetate and [14C]acetyl-CoA into digitonin-precipitable sterol were 50% inhibited by 0.58 .mu.g/ml of F-244. The incorporation of [14C]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 IC50 value of 0.065 .mu.g/ml. The effect of analogs of F-244 on HMG-CoA synthase was also investigated.

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