Inhibition of hydroxymethylglutaryl-coenzyme A synthase by L-659,699.

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Abstract
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-(hydroxymethyl)-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 .mu.M. The enzymes 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 .mu.M, 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 .mu.M L-659,699. The effect of a number of analogs of L-659,699 on HMG-CoA synthase is also discussed.

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