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

Tomoda Hiroshi, Kumagai Hidetoshi, Tanaka Haruo, Omura Satoshi

Research output: Contribution to journalArticle

49 Scopus citations

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 [14C]acetate and [14C]acetyl-CoA into digitonin-precipitable sterol were 50% inhibited by 0.58 βg/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 μg /ml. The effect of analogs of F-244 on HMG-CoA synthase was also investigated.

Original languageEnglish (US)
Pages (from-to)351-356
Number of pages6
JournalBiochimica et Biophysica Acta (BBA)/Lipids and Lipid Metabolism
Volume922
Issue number3
DOIs
StatePublished - Dec 14 1987

Keywords

  • Cholesterol biosynthesis
  • F-244
  • HMG-CoA synthase
  • Hydroxymethylglutaryl-CoA reductase
  • Hydroxymethylglutaryl-CoA synthase
  • Inhibitor
  • β-Lactone

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Endocrinology

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