Abstract
BackgroundAs 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.ResultsThe 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0176-9) contains supplementary material, which is available to authorized users.
Highlights
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
Model of sphingolipid metabolism Our model captures all essential elements of the complex network of sphingolipid metabolism excluding de novo ceramide synthesis which has been described by Vasquez et al [26]
It is worth highlighting that most of these molecules [i.e. CER, SM and glycosphingolipids (GSL)] are restricted to biological membranes. These can be transported between organelles only in the form of complexes with lipid transfer proteins [34], e.g. the CER transfer (CERT) protein binds to CER
Summary
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. Sphingolipids (SL) are a class of complex lipids with a sphingoid base (Sph) [1]. Modifications of this basic structure that consist in the addition of an amide-linked fatty acid or phosphorylation lead to the formation of bioactive sphingolipids such as ceramide (CER), ceramide-1-phosphate (C1P), sphingosine-1-phosphate (S1P) or sphingomyelin (SM) [2, 3]. Ceramides can form through the breakdown of complex sphingolipids that are broken down into sphingosine in the acidic environment of the lysosome. In this pathway, known as salvage pathway, sphingosine is reused, it is reacetylated to form ceramide
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