Isopentenoid synthesis in eukaryotic cells. An initiating role for post-translational control of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
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.
Giron
M D
MD
Department of Biochemistry and Biophysics, University of California, San Francisco 94143.
Havel
C M
CM
Watson
J A
JA
D002460:Cell Line; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D045782:Hemiterpenes; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000037:antagonists & inhibitors; D007700:Kinetics; D007783:Lactones / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
D005231:Fatty Acids, Unsaturated; D045782:Hemiterpenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D009943:Organophosphorus Compounds; C054282:antibiotic 1233A; C004809:isopentenyl pyrophosphate; D006903:Hydroxymethylglutaryl CoA Reductases; D006904:Hydroxymethylglutaryl-CoA Synthase; D008798:Mevalonic Acid