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Insights Into the Role of PFKFB3 in Cancer Minsuh Seo Louisiana State University and Agricultural and Mechanical College

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Insights Into the Role of PFKFB3 in Cancer Minsuh Seo Louisiana State University and Agricultural and Mechanical College Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 2012 Insights into the role of PFKFB3 in cancer Minsuh Seo Louisiana State University and Agricultural and Mechanical College Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_dissertations Recommended Citation Seo, Minsuh, "Insights into the role of PFKFB3 in cancer" (2012). LSU Doctoral Dissertations. 608. https://digitalcommons.lsu.edu/gradschool_dissertations/608 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please [email protected]. ISIGHTS ITO THE ROLE OF PFKFB3 I CACER A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy In The Department of Biological Sciences by Minsuh Seo B.S., Kyungpook National University, Korea, 2007 December 2012 ACKOWLEDGMETS I would like to express deepest gratitude to my advisor, Dr. Yong-Hwan Lee for his guidance, encouragement and support in all stages of this work. Without your endless patience and caring advice, this work would not have been possible. I have really enjoyed my time in the lab and have learned invaluable lessons that will serve me in all of my future endeavors. I would also like to thank the members of my committee, Dr. Marcia Newcomer, Dr. Grover Waldrop, Dr. Huangen Ding, for all advice and guidance on improving my research project. I thank Dr. Norimoto Murai for participating as the Dean’s representative on my committee. I also wish to thank Dr. Sue Bartlett and all members of Structural Biology Group for the valuable discussions and suggestions. I would also like to thank the members of the Lee lab: Blake Crochet, Dr. Michael Cavalier, and Dr. Jeong-Do Kim for being tolerant, helpful, and friendly. I would like to give special thanks to Dr. Young-Sun Yim for your encouragement, support and friendship that helped me through this process. I'll never forget the wonderful times we shared together. I thank the 5 th year students and all my colleagues in Choppin hall for being always friendly, cheerful and helpful. I also thank my friends for providing continuous support and friendship and I would not be where I am today without them. Finally, my most heartfelt thanks to my parent, Kilsu Seo and Mal-Sun Min and my brother, Jeong-Ui Seo, for all support and encouragement that help me pursue my academic goals. I also offer a special thanks to my aunt, Pil Zinkhen, and my cousin, Patrick Zinkhen, who have been supportive and caring. I would not get through the toughest times without the endless love, care, and prayer of my family and aunt. And to my grandmother, ii all your love and kindness have held me steady throughout my life. Your love and memories will always remain with me. iii TABLE OF COTETS ACKNOWLEDGMENTS ............................................................................................................. ii LIST OF TABLES ....................................................................................................................... vii LIST OF FIGURES .................................................................................................................... viii LIST OF ABBREVIATIONS ........................................................................................................xi ABSTRACT ................................................................................................................................ xii CHAPTER 1: REVIEW OF LITERATURE …………………………………...........................1 Glycolysis ...........................................................................................................................1 Fructose-2,6-Bisphosphate .................................................................................................1 Bifunctional Enzyme, PFKFB ............................................................................................4 The Liver Isoform (PFKFB1) .............................................................................................7 The Heart Isoform (PFKFB2) ………………………………............…………………….7 The Testis Isoform (PFKFB4) ............................................................................................9 The Cancer Isoform (PFKFB3) ......................................................................................... 9 Tumor Metabolism, Warburg Effect ...............................................................................12 PFKFB3 and Cancer Metabolism .....................................................................................15 PFKFB3 as a Target in Cancer Therapeutics …………...............……….........................16 Oxidative Stress ……………….....................................................................................17 ROS and Cancer ……........................................................................................................21 Glutathione …….............................................................................................................24 S-Glutathionylation, a Post-Translational Modification ...................................................27 CHAPTER 2: STRUCTURE-BASED DEVELOPMENT OF SMALL MOLECULE PFKFB3 INHIBITORS: A FRAMEWORK FOR POTENTIAL CANCER THERAPEUTI C AGENT TARGETING THE WARBURG EFFECT ..............31 iv Introduction ......................................................................................................................31 Results ...............................................................................................................................33 Overall Strategy for Inhibitor Screening and Improvement .................................33 Inhibitor Screening and Binding Properties ..........................................................34 Effects of N4A and YN1 on the Fru-2,6-P2 levels, Glycolysis, and Cell Growth …………………………………………………37 Structure of the PFKFB3-N4A complex ............................................................43 YN1 and YZ9 from the exploration of N4A scaffold ...........................................47 Discussion .........................................................................................................................49 Materials and Methods ………..........................................................................................51 CHAPTER 3: PFKFB3 REGULATES OXIDATIVE STRESS HOMEOSTASIS VIA ITS S-GLUTATHIONYLATION IN CANCER ..........................................58 Introduction .......................................................................................................................58 Results ...............................................................................................................................59 Identification of S-glutathionylation of PFKFB3 ………….................................59 Effects of reversible S-glutathionylation of PFKFB3 on Enzymatic Activity......61 PFKFB3 Undergoes S-glutathionylation under in Vivo Conditions Associated with Increased Cellular Oxidative Stress ……………...……………63 Functional Consequences of PFKFB3 S-glutathionylation on Metabolic Alteration and ROS Regulation ...........................................................65 Glutathionylation of PFKFB3 Supports Cancer Cell Survival .............................67 v Discussion .......................................................................................................................68 Materials and Methods ......................................................................................................70 CHAPTER 4: CONCLUSIONS ...................................................................................................79 REFERENCES ...........................................................................................................................82 VITA ............................................................................................................................................96 vi LIST OF TABLES Table 2.1 The kinetic and biological properties the PFKFB3 inhibitors …………………..........40 Table 2.2 Interactions between the inhibitors and PFKFB3 ..............….......................................46 Table 2.3 Statistics of reflection data and structure refinements (PFKFB3•inhibitor complex) ..............….....................................................................57 Table 3.1 Statistics of reflection data and structure refinements (PFKFB3•SSG) .......................78 vii LIST OF FIGURES Figure 1.1 Glucose metabolism ......................................................................................................2 Figure 1.2 The most potent allosteric activator of glycolysis, Fructose-2,6-Bisphosphate.............3 Figure 1.3 The enzymatic reactions of PFKFB, which are responsible for the synthesis and degradation of Fructose-2,6-Bisphosphate .............................................................5 Figure 1.4 The P-loop is involved in binding of ATP ....................................................................6 Figure 1.5 The crystal structures of PFKFB isoforms.....................................................................8 Figure 1.6 Regulation of PFKFB activities by Phosphorylation ..................................................10 Figure 1.7 Substrate binding
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