MEVALONATE-MEDIATED SUPPRESSION OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE FUNCTION IN ALPHA-TOXIN-PERFORATED CELLS

The regulation of mevalonic acid synthesis requires both nonsterol iso pentenoid and sterol regulatory signal molecules. A primary target of this multivalent control process is the enzyme which catalyzes mevalon ate synthesis: 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reducta se (EC 1.1.1.34). In this report Staphylococcus aureus alpha-toxin per forated Chinese hamster ovary cells were used to facilitate the identi fication of isopentenoidogenic reactions and metabolites required for mevalonate-mediated loss of HMG-CoA reductase activity. alpha-Toxin-pe rforated cells retained the capacity to decrease, upon demand, HMG-CoA reductase activity and protein in response to mevalonate or isopenten oid pyrophosphate esters. Also, it was deduced with highly specific me tabolic inhibitors, that conversion of farnesyl 1-diphosphate to squal ene was required for mevalonate-mediated suppression of reductase acti vity. Since squalene (2 mu M) did not downregulate reductase activity, pre-squalene pyrophosphate or a derivative, or polyprenyl-1-pyrophosp hate-generated inorganic pyrophosphate, or a combination of these meta bolites are proposed as candidate regulatory nonsterol isopentenoid si gnal molecules.