Isopentenoid synthesis in isolated embryonic Drosophila cells: absolute mevalonic acid utilization and 3-hydroxy-3-methylglutaryl-coenzyme A reductase modulation.

The relationship between absolute isopentenoidogenesis (total and specific) and 3-hydroxy-3-methylglutaryl-coenzyme A suppression in response to increased mevalonate availability is unknown. We determined absolute isopentenoidogenesis values for the nonsterologenic Drosophila Kc cell incubated (2 h) with increasing [3H]mevalonate concentrations. At least 80% of the maximum suppression of 3-hydroxy-3-methyl glutaryl-co-enzyme A activity was achieved when total isopentenoidogenesis was increased only 2-fold. However, a 12-fold increase in total isopentenoidogenesis was achieved at higher exogenous [3H]mevalonate concentrations. Thus, modulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity was coupled to physiological changes in mevalonate/nonsterol isopentenoid availability. In contrast, isopentenoid accumulation, oxidation, and secretion were enhanced with pharmacological increases in mevalonate availability. Furthermore, an apparent constancy of total isopentenoidogenesis values plus increased metabolism of exogenous mevalonate and a significant (35-45%) suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity, in response to exogenous substrate concentrations (less than 150 microM), supported a partial or complete compensatory dimunition in endogenous substrate synthesis. Since these responses occurred within the 2-h study, earlier time periods must be assessed to (i) define the initial nonsterol-mediated regulatory response and (ii) to trap the nonsterol isopentenoid regulatory signal molecule(s).