Inhibition by 6-fluoromevalonate demonstrates that mevalonate or one of the mevalonate phosphates is necessary for lymphocyte proliferation.

摘要: The sterol synthesis inhibitor 6-fluoromevalonate (Fmev) was used to explore the role of mevalonate products in lymphocyte proliferation. Fmev blocks isopentenyl pyrophosphate and all more distal pathway. When cells were cultured lipoprotein-deficient medium, (200 microM) completely inhibited mitogen-stimulated human proliferation, quantified by measuring DNA synthesis. addition low density lipoprotein (LDL) restored responses normal, whereas totally ineffective. Similar results obtained with concentrations up 1 mM. These contrast those observed when biosynthesis blocked lovastatin, an 3-hydroxy-3-methylglutaryl coenzyme A reductase. proliferation lovastatin (5 microM), either high or LDL together required restore responses. In contrast, neither nor alone able cultures 5 microM lovastatin. effect on capacity exogenous lovastatin-blocked lymphocytes directly examined. had no plus lymphocytes, indicating that necessary factor from unaltered Fmev. profoundly endogenous synthesis, decreasing incorporation radiolabeled acetate into digitonin-precipitable sterols 98%. did not alter block possibility allowed shunting essential lipid assessed examining mevalonate. lipids, including ubiquinone, dolichol, other non-sterol lipids 98%, this altered LDL. Furthermore, suppressed protein 97%. data confirm a product is for cell However, indicate synthesized phosphates rather than isoprenoid metabolite.