(404b) Study of Yeast Sphingolipid Metabolism with a Detailed Kinetic Model

Sphingolipids have recently emerged as important bioactive molecules in addition to being critical structural components of cellular membranes. Beside their structural function, these molecules have been implicated in regulating cell growth and fundamental cell processes such as differentiation, migration, and apoptosis. On the organism level, sphingolipids play roles in physiological processes including inflammation and vasculogenesis. We developed a kinetic model of the sphingolipid metabolism in yeast with the aim to identify the critical key parameters responsible for the regulation of the sphingolipid metabolism and its interaction with the global cell metabolism. The mechanistic model allows for an accurate description of the kinetics of each reaction and of enzyme saturation. In particular, we have investigated the effects of the competition of multiple substrates for a single enzyme on the distribution of fluxes and on the steady state concentrations. Sphingolipids in yeast are present in five hydroxylation states, which have been shown to interact differently with other lipids, as for example ergosterol, to form cell membrane structures. Our model describes the hydroxylation states and it is able to reproduce their experimental profiles. We performed a detailed sensitivity analysis of the steady-state concentrations and fluxes and we identified the key parameters that determine the function of the sphingolipid pathway and the distribution of the hydroxylation states. We further discuss how the model can be extended to include larger portions of the lipid and carbon biosynthesis pathways. Knowledge acquired from the yeast model can be readily applied to other organisms, since the spingolipid pathways is highly conserved in eukaryotes.