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Modeling Sphingolipid Metabolism in Yeast

Cells, whether free-living or as components of an organism, are regularly exposed to stimuli and perturbations to which they have to respond in a coordinated fashion. Such responses may vary widely in the numbers and types of identifiable steps that begin with sensing the stimulus and end with a change in biochemistry or physiology, but always require one or several mechanisms of signal transduction. In eukaryotes, some of this signaling is accomplished with sphingolipids, which are known to be instrumental in stress responses, differentiation, cell cycle arrest, and apoptosis. The goal of this project is to design, test, validate and apply mathematical models of sphingolipid metabolism in yeast. Our current model permits the simulation of the effects of acute and long-term perturbations in metabolites, enzyme activities and precursors of sphingolipids. Some of the predictions have been successfully validated with experiments.


Selected References:

[1] Alvarez-Vasquez, F., K.J. Sims, Y.A. Hannun, and E.O. Voit: Integration of kinetic information on yeast sphingolipid metabolism in dynamical pathway models. J. Theor. Biol. 226, 265-291, 2004.

[2] Alvarez-Vasquez, F., K. J. Sims, Y. Okamoto, E. O. Voit, and Y. A. Hannun. Simulation and Evaluation of de novo Sphingolipid Fluxes in S. cerevisiae. Nature Jan 27; 433(7024): 425-430, 2005.

[3] Alvarez-Vasquez, F., K. J. Sims, E.O. Voit, and Y.A. Hannun: Coordination of the dynamics of yeast sphingolipid metabolism during the diauxic shift. Theoretical Biology and Medical Modelling 4(1), 42, 2007.

[4] Voit, E.O., F. Alvarez-Vasquez, and Y.A. Hannun: Computational Analysis of Sphingolipid Pathway Systems. Computational analysis of sphingolipid pathway systems. Adv Exp Med Biol. 688: 264-275, 2010.

[5] Alvarez-Vasquez, F., H. Riezman, E. O. Voit, and Y. A. Hannun. Mathematical modeling and validation of the ergosterol pathway in Saccharomyces cerevisiae. PLoS One 6(12): e28344, 2011.

[6] Fonseca, L.L., P.W. Chen, and E.O. Voit: Canonical modeling of the multi-scale regulation of the heat stress response in yeast. Metabolites 2(1), 221-241, 2012.

[7] Chen, P.-W., L.L. Fonseca, Y.A. Hannun, and E.O. Voit: Coordination of rapid sphingolipid responses to heat stress in yeast (submitted).

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Simulation and Evaluation of de novo Sphingolipid Fluxes in S. cerevisiae Simulation and Evaluation of de novo Sphingolipid Fluxes in S. cerevisiae
from [2] from [2; Suppl.]