(503d) Exploring Novel Pathways and Structures in Sphingolipid Metabolism Using BNICE

Sphingolipids represent an ubiquitous lipid class that can be found in almost all eukaryotes and prokaryotes, and they perform critical roles in cellular structural and signalling. For example, phophosphingolipids are important structural components of the cellular membrane; and sphingomyelin which upon hydrolysis can generate ceramide, an important intracellular signalling molecule. Their significance also appears in regulatory pathways such as cell cycle arrest, apoptosis, senescence and differentiation. There are approximately forty known diseases of sphingolipid metabolism that abnormally store excess amounts of sphingolipids, including the genetic Gauchers Disease, in which fatty lipids accumulate in cells and organs such as the spleen, liver, lungs, brain, and bone marrow. Therefore, understanding their biosynthesis and their degradation pathways would be of utmost importance in discovering new therapies.

In this work, the BNICE computational framework was applied to investigate sphingolipid metabolism, and to predict novel synthesis and biodegradation routes for sphingolipids. Using BNICE, we reproduced all the proposed compounds, synthesis and biodegradation routes observed previously through experiments. Furthermore, our simulations introduced a large number of novel compounds and reactions. We studied the novel pathways for the production and degradration of some sphingolipid compounds in depth using BNICE, together with thermodynamic analysis and pathway search methods.

The results of this work show that BNICE can be used to generate novel pathways for synthesis and biodegradation of sphingolipid compounds and suggest novel methods for inhibiting diseases resulting from perturbations of the sphingolipid metabolism.