Isoprenoid synthesis in isolated embryonic Drosophila cells. Sterol-independent regulatory signal molecule is distal to isopentenyl 1-pyrophosphates.
Embryonic Drosophila cells (Kc cells) were used to further characterize sterol-independent modulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity. 3-Methyl-3-5-dihydroxyvalerate (mevalonate), 3-fluoromethyl-3,5-dihydroxyvalerate (fluoromevalonate), and 3-ethyl-3,5-dihydroxyvalerate (homomevalonate) were tested as modulators. Although mevalonate caused a rapid, reversible suppression of reductase activity, fluoro- and homomevalonate increased activity; fluoromevalonate was more effective than homomevalonate. Mevalonate, added simultaneously with fluoromevalonate, blocked the analogue's effect on Kc cell reductase activity. However, mevalonate did not suppress an established fluoromevalonate increase in HMG-CoA reductase activity. Fluoromevalonate blocked [1-14C, 5-3H]mevalonate conversion to 14CO2- and 3H-labeled lipids and [3H] mevalonate 5-pyrophosphate accumulated. Neither protein nor RNA synthesis were required for mevalonate-mediated suppression of reductase activity. However, fluoromevalonate's effect on reductase activity required protein synthesis. Furthermore, in the absence of protein synthesis, fluoromevalonate-stabilized Kc cell HMG-CoA reductase activity. We have concluded that mevalonate, fluoromevalonate, homomevalonate, and compactin (mevinolin) modulated HMG-CoA reductase activity because they altered isoprenoid carbon flow to a post-isopentenyl 1-pyrophosphate regulatory, signal molecule.
D000818:Animals; D002460:Cell Line; D004330:Drosophila / Q000201:enzymology*; D045782:Hemiterpenes; D006358:Hot Temperature; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007700:Kinetics; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000378:metabolism*; D011106:Polyisoprenyl Phosphates / Q000096:biosynthesis*; D014176:Protein Biosynthesis
D045782:Hemiterpenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009943:Organophosphorus Compounds; D011106:Polyisoprenyl Phosphates; C004809:isopentenyl pyrophosphate; C031073:homomevalonic acid; C047102:3-fluoromevalonate; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid