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Structural Characterization and Therapeutic Utility of the Proton-Coupled Folate Transporter

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Structural Characterization and Therapeutic Utility of the Proton-Coupled Folate Transporter Wayne State University Wayne State University Dissertations 1-1-2016 Structural Characterization And Therapeutic Utility Of The rP oton-Coupled Folate Transporter Michael Roy Wilson Wayne State University, Follow this and additional works at: http://digitalcommons.wayne.edu/oa_dissertations Part of the Biochemistry Commons, Oncology Commons, and the Pharmacology Commons Recommended Citation Wilson, Michael Roy, "Structural Characterization And Therapeutic Utility Of The rP oton-Coupled Folate Transporter" (2016). Wayne State University Dissertations. 1670. http://digitalcommons.wayne.edu/oa_dissertations/1670 This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. STRUCTURAL CHARACTERIZATION AND THERAPEUTIC UTILITY OF THE PROTON-COUPLED FOLATE TRANSPORTER by MICHAEL ROY WILSON DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2016 MAJOR: CANCER BIOLOGY Approved By: ____________________________________ Advisor Date ___________________________________ ____________________________________ ____________________________________ ____________________________________ DEDICATION This dissertation is dedicated to my family, who have given me so much love and support throughout my life and throughout my career. To my grandmother, Sue, who has survived chronic lymphoblastic leukemia and non-Hodgkin’s lymphoma, and to my grandfather, Lee, who lost his battle with metastatic prostate cancer. They have been my inspiration to research new cancer therapies. To my siblings, Marissa and Lucas, who have always been my biggest fans and best friends. To my fiancé, Shannon, who has provided so much encouragement, patience and love. To my father, Roy, who was my first mentor and role model. He gave me the work ethic and ambition that has been so vital to my career. And to my mother, Jill, who was my first teacher. She gave me the thirst for knowledge that has always driven me. They have always believed in me, and I owe them so much. This path in life would never have been possible without them. ii ACKNOWLEDGEMENTS I would like to thank my mentor, Dr. Larry Matherly, without whom this project would not have been possible. Dr. Matherly has helped me to think both critically and creatively in science. He has dedicated countless hours to my education and to my career, despite so many other obligations. Dr. Matherly has always encouraged me to learn new methods and to test every idea. Without his expertise and ambition, my graduate studies could not have been so successful. I feel that wherever my career takes me, Dr. Matherly has prepared me for it. I would like to thank Dr. Zhanjun Hou, who has taught me so many scientific techniques. Zhanjun has taught me to think carefully and critically when it comes to experimental design, and has consulted on nearly every experiment I performed. Without his patience in teaching me and his eye for detail, I could not have produced such quality work. I would like to thank the past and present members of the Matherly lab, including Christina George, Steve Orr, Dr. Sita Kugel, Dr. Eric Hales, Erika Etnyre, Jenny Huang, Lucas Wilson, Dr. Leda Gattoc, Aamod Dekhne, Carrie O’Connor, and Adrianne Wallace-Povirk, who have all been extremely helpful and kind throughout my time in the lab. I would like to thank Dr. Aleem Gangjee and his laboratory for the synthesis of the antifolate compounds studied in this dissertation project. I would like to thank Dr. Lisa Polin, Juiwanna Kushner and Kathryn White for the many hours they spent teaching me to work with mice. I would like to thank my committee members, Dr. Manohar Ratnam, Dr. George Brush, Dr. Zengquan Yang, and Dr. Bharati Mitra, who have provided much insight and guidance. Finally, I would like to thank my funding, T-32 CA009531 from the NIH and the Rumble Fellowship from Wayne State University. iii TABLE OF CONTENTS Dedication ...................................................................................................................................... ii Acknowledgements ...................................................................................................................... iii List of Tables ..................................................................................................................................x List of Figures ............................................................................................................................... xi List of Abbreviations ................................................................................................................. xiii CHAPTER 1 – Introduction .........................................................................................................1 1.1 Indroduction to Folate Biology ..........................................................................................1 1.2 Reduced Folate Carrier ......................................................................................................6 1.3 Folate Receptors ................................................................................................................10 1.4 Proton-Coupled Folate Transporter ...............................................................................11 1.4.1 PCFT Tissue Expression ..........................................................................................11 1.4.2 Hereditary Folate Malabsorption ............................................................................12 1.4.3 PCFT Function ..........................................................................................................12 1.4.4 PCFT Structure .........................................................................................................14 1.4.5 PCFT Oligomerization .............................................................................................20 1.5 The Metabolic Role of Folates .........................................................................................22 1.5.1 One-Carbon Metabolism ..........................................................................................23 1.5.2 Purine Biosynthesis ...................................................................................................25 1.5.3 Polyglutamylation of Folates ....................................................................................27 1.6 Antifolate Treatment of Cancer ......................................................................................28 1.6.1 DHFR Inhibitors .......................................................................................................29 1.6.2 TS Inhibitors .............................................................................................................31 iv 1.6.3 Inhibitors of De Novo Purine Biosynthesis .............................................................33 1.6.4 Multitargeted Antifolate ...........................................................................................35 1.6.5 Antifolate Resistance ................................................................................................37 1.6.6 Utility of FRα Overexpression in Cancer for Therapy and Imaging ...................38 1.6.7 Tumor Targeted Antifolates with PCFT and FR Selectivity ................................40 CHAPTER 2- Proton-Coupled Folate Transporter Transmembrane Domain 2-3 Connecting Region Forms Reentrant Loop Structure ....................................46 2.1 Introduction .......................................................................................................................46 2.2 Materials and Methods .....................................................................................................47 2.2.1 Reagents .....................................................................................................................47 2.2.2 Generation of Cys-less hPCFT and Single-substitution Mutants ........................48 2.2.3 Cell Culture ...............................................................................................................48 2.2.4 Membrane Transport ...............................................................................................49 2.2.5 Surface Biotinylation with MTSEA-biotin .............................................................49 2.2.6 Western Blotting .......................................................................................................51 2.2.7 Statistical Analysis ....................................................................................................51 2.3 Results ................................................................................................................................51 2.3.1 Alanine-scanning Mutagenesis of TMD2 and the TMD2-3 Loop Region of hPCFT....................................................................................................................51 2.3.2 Cys-scanning Mutagenesis and Cys Accessibilities to Biotinylation with MTSEA-biotin for TMD2 and the TMD2-3 Loop Region of hPCFT ..................53 2.3.3 Impact of hPCFT Substrate on Biotinylation and Transport Inhibition by Biotinylation ..............................................................................................................62 2.4 Discussion ..........................................................................................................................63
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