Computational modeling of sphingolipid metabolism.
BACKGROUND
As suggested by the origin of the word, sphingolipids are mysterious molecules with various roles in antagonistic cellular processes such as autophagy, apoptosis, proliferation and differentiation. Moreover, sphingolipids have recently been recognized as important messengers in cellular signaling pathways. Notably, sphingolipid metabolism disorders have been observed in various pathological conditions such as cancer and neurodegeneration.


RESULTS
The existing formal models of sphingolipid metabolism focus mainly on de novo ceramide synthesis or are limited to biochemical transformations of particular subspecies. Here, we propose the first comprehensive computational model of sphingolipid metabolism in human tissue. Contrary to the previous approaches, we use a model that reflects cell compartmentalization thereby highlighting the differences among individual organelles.


CONCLUSIONS
The model that we present here was validated using recently proposed methods of model analysis, allowing to detect the most sensitive and experimentally non-identifiable parameters and determine the main sources of model variance. Moreover, we demonstrate the usefulness of our model in the study of molecular processes underlying Alzheimer's disease, which are associated with sphingolipid metabolism.
Institute of Computer Science Polish Academy of Sciences, Warsaw, Poland. wwro@biol.uw.edu.pl.
Weronika
W
Wronowska
Faculty of Biology University of Warsaw, Warsaw, Poland. a.charzynska@phd.ipipan.waw.pl.|Bioinformatics Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. a.charzynska@phd.ipipan.waw.pl.
Agata
A
Charzyńska
Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland. k.nienaltowski@sysbiosig.org.
Karol
K
Nienałtowski
Institute of Informatics, University of Warsaw, Warsaw, Poland. aniag@mimuw.edu.pl.
Anna
A
Gambin
D000544:Alzheimer Disease / Q000378:metabolism; D055162:Biocatalysis; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D003198:Computer Simulation; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D010766:Phosphorylation; D015203:Reproducibility of Results; D013107:Sphingolipids / Q000096:biosynthesis / Q000378:metabolism*
D013107:Sphingolipids