Inhibition of hydroxymethylglutaryl-coenzyme A synthase by L-659,699.
A beta-lactone isolated from Fusarium sp. has been shown to be a potent specific inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase [(S)-3-hydroxy-3-methylglutaryl-CoA acetoacetyl-CoA-lyase (CoA-acetylating), EC, 4.1.3.5] from rat liver. The structure of this beta-lactone, termed L-659,699, is (E,E)-11-[3-(hydroxy-methyl)-4-oxo-2-oxytanyl]-3,5,7-trimethyl-2,4 - undecadienenoic acid. A partially purified preparation of cytoplasmic HMG-CoA synthase from rat liver was inhibited by L-659,699 with an IC50 of 0.12 microM. The enzyme HMG-CoA reductase, beta-ketoacyl-CoA thiolase, acetoacetyl-CoA synthetase, and fatty acid synthase were not inhibited to any extent by this compound. In cultured Hep G2 cells, the compound inhibited the incorporation of [14C]acetate into sterols with an IC50 of 6 microM, while incorporation of [3H]mevalonate into sterols in these cells was not affected. The activity of HMG-CoA reductase in the cultured Hep G2 cells was induced in a dose-dependent manner by incubation with L-659,699. A 37-fold increase in reductase was observed after a 24-hr incubation with 62 microM L-659,699. The effect of a number of analogs of L-659,699 on HMG-CoA synthase is also discussed.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005670:Fusarium; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D007700:Kinetics; D007783:Lactones / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology*; D007652:Oxo-Acid-Lyases / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D005231:Fatty Acids, Unsaturated; D007783:Lactones; C054282:antibiotic 1233A; D006904:Hydroxymethylglutaryl-CoA Synthase; D007652:Oxo-Acid-Lyases