A new screening method for specific inhibitors of mevalonate biosynthesis was established using Vero cells, an animal cell line. The cultures selected were those which inhibited the growth of Vero cells in the Eagle's minimum essential medium supplemented with 2%calf serum (2% CS-MEM) but lacked inhibitory activity against the growth of cells in 2% CS-MEMsupplemented with 1 mM mevalonate. By this screening method, inhibitors of the two enzymes involved in mevalonate biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase and HMG-CoA reductase, were selected from about 1 1,000 soil isolates. The ²-lactone 1233A, a fungal metabolite, was found to be the first naturally occurring compound which inhibits HMG-CoA synthase specifically and strongly. Monacolins K and J, inhibitors of HMG-CoAreductase, were also detected and identified.
ASJC Scopus subject areas
- Drug Discovery