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Novel Intrinsic and Extrinsic Approaches to Selectively Regulate Novel Intrinsic and Extrinsic Approaches to Selectively Regulate Glycosphingolipid Metabolism by Mustafa Ali Kamani A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Biochemistry University of Toronto © Copyright by Mustafa Ali Kamani 2013. Novel Intrinsic and Extrinsic Approaches to Selectively Regulate Glycosphingolipid Metabolism. Doctor of Philosophy, 2013. Mustafa Ali Kamani Department of Biochemistry University of Toronto Abstract Glycosphingolipid (GSL) metabolism is a complex process involving proteins and enzymes at distinct locations within the cell. Mammalian GSLs are typically based on glucose or galactose, forming glucosylceramide (GlcCer) and galactosylceramide (GalCer). Most GSLs are derived from GlcCer, which is synthesized on the cytosolic leaflet of the Golgi, while all subsequent GSLs are synthesized on the lumenal side. We have utilized both pharamacological and genetic manipulation approaches to selectively regulate GSL metabolism and better understand its mechanistic details. We have developed analogues of GlcCer and GalCer by substituting the fatty acid moiety with an adamanatane frame. The resulting adamantylGSLs are more water- soluble than their natural counterparts. These analogues selectively interfere with GSL metabolism at particular points within the metabolic pathway. At 40 µM, adaGlcCer prevents synthesis of all GSLs downstream of GlcCer, while also elevating GlcCer levels, by inhibiting lactosylceramide (LacCer) synthase and glucocerebrosidase, respectively. AdaGalCer specifically reduces synthesis of globotriaosylceramide (Gb3) and downstream globo-series GSLs. AdaGalCer also increases Gaucher disease N370S glucocerebrosidase expression, lysosomal localization and activity. AdaGSLs, therefore, have potential as novel therapeutic ii agents in diseases characterized by GSL anomalies and as tools to study the effects of GSL modulation. Two predominant theories have been developed to explain how GlcCer accesses the Golgi lumen: one involving direct translocation from the cytosolic-to-lumenal leaflet of the Golgi by the ABC transporter P-glycoprotein (P-gp, ABCB1, MDR1), and the other involving retrograde transport of GlcCer by FAPP2 to the ER, followed by entry into the vesicular transport system for Golgi lumenal access. To examine the in vivo involvement of P-gp in GSL metabolism, we generated a knockout model by crossbreeding the Fabry disease mouse with the P-gp knockout mouse. HPLC analyses of tissue Gb3 levels revealed a tissue-specific reduction in MDR1/Fabry mice. TLC analyses, however, did not show such reduction. In addition, we performed a gene knockdown study using siRNA against P-gp and FAPP2. Results show these siRNA to have distinct effects on GSL levels that are cell-type specific. These results give rise to the prospect of unique therapeutic approaches by targeting P-gp or FAPP2 for synthesis inhibition of particular GSL pathways. iii In the name of God, the most Kind, the most Merciful Acknowledgements I would like to thank my supervisor, Dr. Clifford Lingwood for giving me the opportunity to work in his lab. Dr. Lingwood, you entrusted me with a truly fascinating project with considerable potential. You were always available to discuss the outcomes of my experiments and the necessary future directions. At the same time, you instilled within me the confidence to work independently. I would like to thank my supervisory committee members, Dr. Roy Baker and Dr. Jeffrey Medin, for their input and guidance throughout my research. I want to thank Dr. Robert K. Yu for agreeing to serve as the external examiner and for his detailed appraisal of this thesis. I also want to thank all other members of my examining committee, Dr. Trevor Moraes, Dr. Christine Bear and Dr. Thierry Mallevaey, not only for agreeing to serve on the committee, but also for their constructive feedback to further advance my research. I want to thank the collaborators and contributors to my projects, including Dr. Jeffrey Medin, Dr. Don Mahuran, Dr. Brigitte Rigat, Dr. Natalia Pacienza and Sayuri Yonekawa. I would like to extend my sincere gratitude to Beth Binnington and Dr. Murugesapillai Mylvaganam. Beth, you provided me with the technical training necessary to carry out all my experiments and helped me troubleshoot through the many challenges that would arise. I knew I could always count on you for help when needed. Myl, without your chemical genius, my iv project would never have expanded in the way it did. You have been a great friend, teacher and mentor. Your passion for chemistry and for instilling an appreciation for this subject in students is unparalleled. Thanks also to Mrs. Shirley Thompson, and all the Lingwood lab members, past and present. Most of all, I would like to thank my family, without whose support I would never have reached this stage. Their unconditional love and support, and their words of encouragement and wisdom when times were good and during periods of frustration kept me afloat to achieve this milestone. It is to them that I dedicate this thesis. v Table of Contents Abstract .......................................................................................................................................... ii Acknowledgements....................................................................................................................... iv Table of Abbreviations ................................................................................................................. xi List of Tables .............................................................................................................................. xiii List of Schemes........................................................................................................................... xiv List of Figures .............................................................................................................................. xv Chapter 1: Introduction .................................................................................................................. 1 1.1 Glycosphingolipids: The Beginning .................................................................................... 1 1.2 Glycosphingolipid Structure ................................................................................................ 1 1.3 Metabolism .......................................................................................................................... 4 1.3.1 Ceramide Synthesis ...................................................................................................... 5 1.3.2 Phosphosphingolipids ................................................................................................... 7 1.3.3 Glycosphingolipids ....................................................................................................... 9 1.4 Lipid Flippase .................................................................................................................... 12 1.4.1 ABC Transporters ....................................................................................................... 13 1.4.2 P-glycoprotein (P-gp) ................................................................................................. 14 1.4.3 ABC Transporters and Lipid Transport ...................................................................... 17 1.5 FAPP2 ................................................................................................................................ 20 1.6 LacCer................................................................................................................................ 22 1.7 Glycosyltransferase knockout ............................................................................................ 23 1.8 Complex GSL Synthesis .................................................................................................... 24 1.8.1 Lacto-series ................................................................................................................. 25 1.8.2 Globo-series ................................................................................................................ 26 1.8.3 Stage-specific embryonic antigens ............................................................................. 27 1.8.4 Blood Group Determinant GSLS................................................................................ 28 1.8.5 Ganglio-series ............................................................................................................. 29 1.8.6 Gangliosides ............................................................................................................... 29 1.8.7 Fucolipids ................................................................................................................... 31 1.8.8 Glycosyltransferase Complexes.................................................................................. 32 1.8.9 Pathway after LacCer ................................................................................................. 33 1.8.10 Multiple Locations of Glycosyltransferases ............................................................. 34 1.8.11 Regulation of Glycosyltransferases .......................................................................... 35 1.9 GSL synthesis by the recycling pathway ........................................................................... 37 1.10 GSL Catabolism .............................................................................................................
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