Computational analysis of sphingolipid pathway systems.

Sphingolipid metabolism constitutes a complex pathway system that includes biosynthesis of different types of sphingosines and ceramides, the formation and recycling of complex sphingolipids and the supply of materials for remodeling. Many of the metabolites have several roles, for instance, as substrates and as modulators of reactions in other parts of the system. The large number of sphingolipid compounds and the different types of nonlinear interactions among them render it difficult to predict responses of the sphingolipid pathway system to perturbations, unless one utilizes mathematical models. The sphingolipid pathway system not only invites modeling as a useful tool, it is also a very suitable test bed for developing detailed modeling techniques and analyses, due to several features. First, the reaction network is relatively well understood and many of the steps have been characterized, at least in vitro. Second, sphingolipid metabolism constitutes a relatively closed system, such that most reactions occur within the system rather than between the system and other pathways. Third, the basic structure of the pathway is conserved throughout evolution, but some of the details vary among differentspecies. This degree of similarity permits comparative analyses and may one day elucidate the gradual evolution toward superior system designs. We discuss here some reasons that make sphingolipid modeling an appealing companion to experimental researchand sketch out applications of sphingolipid models that are different from typical model uses.