Modeling sphingomyelin synthase 1 driven reaction at the Golgi apparatus can explain data by inclusion of a positive feedback mechanism.

Here we present a minimal mathematical model for the sphingomyelin synthase 1 (SMS1) driven conversion of ceramide to sphingomyelin based on chemical reaction kinetics. We demonstrate via mathematical analysis that this model is not able to qualitatively reproduce experimental measurements on lipid compositions after altering SMS1 activity. We prove that a positive feedback mechanism from the products to the reactants of the reaction is one possible model extension to explain these specific experimental data. The proposed mechanism in fact exists in vivo via protein kinase D and the ceramide transfer protein CERT. The model is further evaluated by additional observations from the literature.

[1]  Heikki Haario,et al.  DRAM: Efficient adaptive MCMC , 2006, Stat. Comput..

[2]  Satoshi Yasuda,et al.  Molecular machinery for non-vesicular trafficking of ceramide , 2003, Nature.

[3]  Martin Hermansson,et al.  Both Sphingomyelin Synthases SMS1 and SMS2 Are Required for Sphingomyelin Homeostasis and Growth in Human HeLa Cells* , 2007, Journal of Biological Chemistry.

[4]  K. Pfizenmaier,et al.  Regulation of secretory transport by protein kinase D–mediated phosphorylation of the ceramide transfer protein , 2007, The Journal of cell biology.

[5]  F. Maxfield,et al.  SMS overexpression and knockdown: impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis Published, JLR Papers in Press, November 2, 2007. , 2008, Journal of Lipid Research.

[6]  G. Meer,et al.  Membrane lipids: where they are and how they behave , 2008, Nature Reviews Molecular Cell Biology.

[7]  V. Malhotra,et al.  Role of the Second Cysteine-rich Domain and Pro275 in Protein Kinase D2 Interaction with ADP-Ribosylation Factor 1, Trans-Golgi Network Recruitment, and Protein Transport , 2010, Molecular biology of the cell.

[8]  Soichi Wakatsuki,et al.  Structural basis for specific lipid recognition by CERT responsible for nonvesicular trafficking of ceramide , 2008, Proceedings of the National Academy of Sciences.

[9]  SchmidtHenning,et al.  Systems Biology Toolbox for MATLAB , 2006 .

[10]  Yusuf A. Hannun,et al.  Principles of bioactive lipid signalling: lessons from sphingolipids , 2008, Nature Reviews Molecular Cell Biology.

[11]  S. Carrasco,et al.  Diacylglycerol, when simplicity becomes complex. , 2007, Trends in biochemical sciences.

[12]  Elisabet Sarri,et al.  Phospholipid Synthesis Participates in the Regulation of Diacylglycerol Required for Membrane Trafficking at the Golgi Complex* , 2011, The Journal of Biological Chemistry.

[13]  Gareth O. Roberts,et al.  Convergence assessment techniques for Markov chain Monte Carlo , 1998, Stat. Comput..

[14]  Mats Jirstrand,et al.  Systems biology Systems Biology Toolbox for MATLAB : a computational platform for research in systems biology , 2006 .

[15]  S. Lev Non-vesicular lipid transport by lipid-transfer proteins and beyond , 2010, Nature Reviews Molecular Cell Biology.

[16]  A. Cornish-Bowden Fundamentals of Enzyme Kinetics , 1979 .

[17]  M. Hussain,et al.  Mechanisms involved in cellular ceramide homeostasis , 2012, Nutrition & Metabolism.

[18]  Peter Storz,et al.  Protein kinase D regulates vesicular transport by phosphorylating and activating phosphatidylinositol-4 kinase IIIβ at the Golgi complex , 2005, Nature Cell Biology.

[19]  C. Luberto,et al.  Sphingomyelin Synthases Regulate Protein Trafficking and Secretion , 2011, PloS one.

[20]  J. Brouwers,et al.  Identification of a family of animal sphingomyelin synthases , 2004, The EMBO journal.

[21]  V. Malhotra,et al.  The formation of TGN-to-plasma-membrane transport carriers. , 2006, Annual review of cell and developmental biology.

[22]  A. Hindmarsh,et al.  CVODE, a stiff/nonstiff ODE solver in C , 1996 .

[23]  M. Del Poeta,et al.  Sphingomyelin synthases regulate production of diacylglycerol at the Golgi. , 2008, The Biochemical journal.

[24]  K. Hanada,et al.  Intracellular trafficking of ceramide by ceramide transfer protein , 2010, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[25]  V. Litvak,et al.  Maintenance of the diacylglycerol level in the Golgi apparatus by the Nir2 protein is critical for Golgi secretory function , 2005, Nature Cell Biology.

[26]  J. Holthuis,et al.  Tales and mysteries of the enigmatic sphingomyelin synthase family. , 2010, Advances in experimental medicine and biology.

[27]  Stephen P. Brooks,et al.  Assessing Convergence of Markov Chain Monte Carlo Algorithms , 2007 .

[28]  Mano Ram Maurya,et al.  Integration of lipidomics and transcriptomics data towards a systems biology model of sphingolipid metabolism , 2011, BMC Systems Biology.

[29]  David B. Dunson,et al.  Bayesian Data Analysis , 2010 .

[30]  Darren J. Wilkinson Stochastic Modelling for Systems Biology , 2006 .