antibiotic-1233a and isopentenyl-pyrophosphate

Using insect (Drosophila) and rodent mammalian cell cultures we demonstrate that acute mevalonate-mediated suppression of 3-hydroxy-3-methylglutaryl coenzyme A was initiated in the absence of protein synthesis. In addition, insect and mammalian cells depleted (1 h) of putative regulatory post-isopentenyl-1-pyrophosphate metabolites by incubation with an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A synthase (L-659,699) accumulated 3-hydroxy-3-methylglutaryl coenzyme A reductase enzyme units. This accumulation resulted primarily from a decrease in the loss of 3-hydroxy-3-methylglutaryl coenzyme A reductase enzyme units rather than from an increase in enzyme synthesis. These observations suggest that the initial phase of mevalonate-mediated suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity was governed primarily by post-translational processes. An unknown rapidly turning over post-isopentenyl-1-pyrophosphate metabolite(s) is proposed as the agonist for these post-translational processes.

Topics: Cell Line; Fatty Acids, Unsaturated; Hemiterpenes; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxymethylglutaryl-CoA Synthase; Kinetics; Lactones; Mevalonic Acid; Organophosphorus Compounds; Protein Processing, Post-Translational