title: F-244 specifically inhibits 3-hydroxy-3-methylglutaryl coenzyme A synthase.
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 micrograms/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 microgram/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 microgram/ml. The effect of analogs of F-244 on HMG-CoA synthase was also investigated.
mesh_terms: D000085:Acetates / Q000378:metabolism; D019342:Acetic Acid; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism; D000818:Animals; D002240:Carbohydrate Sequence; D002460:Cell Line; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000037:antagonists & inhibitors*; D007783:Lactones / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism; D007652:Oxo-Acid-Lyases / Q000037:antagonists & inhibitors*; D051381:Rats; D013261:Sterols / Q000378:metabolism
chemical_list: D000085:Acetates; D005231:Fatty Acids, Unsaturated; D007783:Lactones; D013261:Sterols; C012258:mevastatin; C054282:antibiotic 1233A; D000105:Acetyl Coenzyme A; D008148:Lovastatin; D000101:Acetyl-CoA C-Acetyltransferase; D006904:Hydroxymethylglutaryl-CoA Synthase; D007652:Oxo-Acid-Lyases; D019342:Acetic Acid; D008798:Mevalonic Acid