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 isopentenoid and sterol regulatory signal molecules. A primary target of this multivalent control process is the enzyme which catalyzes mevalonate synthesis: 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (EC 1.1.1.34). In this report Staphylococcus aureus alpha-toxin perforated Chinese hamster ovary cells were used to facilitate the identification of isopentenoidogenic reactions and metabolites required for mevalonate-mediated loss of HMG-CoA reductase activity. alpha-Toxin-perforated cells retained the capacity to decrease, upon demand, HMG-CoA reductase activity and protein in response to mevalonate or isopentenoid pyrophosphate esters. Also, it was deduced with highly specific metabolic inhibitors, that conversion of farnesyl 1-diphosphate to squalene was required for mevalonate-mediated suppression of reductase activity. Since squalene (2 microM) did not downregulate reductase activity, pre-squalene pyrophosphate or a derivative, or polyprenyl-1-pyrophosphate-generated inorganic pyrophosphate, or a combination of these metabolites are proposed as candidate regulatory nonsterol isopentenoid signal molecules.
Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0448.
M D
MD
Giron
C M
CM
Havel
J A
JA
Watson
D000818:Animals; D016466:CHO Cells; D002463:Cell Membrane Permeability; D002999:Clone Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007700:Kinetics; D008798:Mevalonic Acid / Q000378:metabolism* / Q000494:pharmacology*; D008954:Models, Biological; D015398:Signal Transduction; D013185:Squalene / Q000494:pharmacology; D013211:Staphylococcus aureus; D010738:Type C Phospholipases / Q000494:pharmacology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013185:Squalene; D006903:Hydroxymethylglutaryl CoA Reductases; D010738:Type C Phospholipases; D008798:Mevalonic Acid