Drosophila alcohol dehydrogenase polymorphism and carbon-13 fluxes: opportunities for epistasis and natural selection.

The influence of genetic variations in Drosophila alcohol dehydrogenase (ADH) on steady-state metabolic fluxes was studied by means of 13C NMR spectroscopy. Four pathways were found to be operative during 8 hr of ethanol degradation in third instar larvae of Drosophila. Seven strains differed by 18-25% in the ratio between two major pathway fluxes, i.e., into glutamate-glutamine-proline vs. lactate-alanine-trehalose. In general, Adh genotypes with higher ADH activity exhibit a twofold difference in relative carbon flux from malate into lactate and alanine vs. alpha,alpha-trehalose compared to low ADH activity genotypes. Trehalose was degraded by the pentose-phosphate shunt. The pentose-phosphate shunt and malic enzyme could supply NADPH necessary for lipid synthesis from ethanol. Lactate and/or proline synthesis may maintain the NADH/NAD+ balance during ethanol degradation. After 24 hr the flux into trehalose is increased, while the flux into lipids declines in AdhF larvae. In AdhS larvae the flux into lipids remains high. This co-ordinated nature of metabolism and the genotype-dependent differences in metabolic flux may form the basis for various epistatic interactions and ultimately for variations in organismal fitness.