Method of search for microbial inhibitors of mevalonate biosynthesis using animal cells.
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-MEM supplemented 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 11,000 soil isolates. The beta-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-CoA reductase, were also detected and identified.
Kumagai
H
H
Kitasato Institute and School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
Tomoda
H
H
Omura
S
S
D000192:Actinomycetales / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005658:Fungi / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000037:antagonists & inhibitors*; D007783:Lactones / Q000494:pharmacology; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism*; D015394:Molecular Structure; D009281:Naphthalenes / Q000494:pharmacology; D007652:Oxo-Acid-Lyases / Q000037:antagonists & inhibitors*; D012988:Soil Microbiology; D014709:Vero Cells
D000900:Anti-Bacterial Agents; D005231:Fatty Acids, Unsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D009281:Naphthalenes; C012258:mevastatin; C054282:antibiotic 1233A; D008148:Lovastatin; D006904:Hydroxymethylglutaryl-CoA Synthase; D007652:Oxo-Acid-Lyases; C045376:monacolin J; D008798:Mevalonic Acid