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Mass Spectrometry Method Development for the Discovery and Characterization of Secondary Metabolites

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Mass Spectrometry Method Development for the Discovery and Characterization of Secondary Metabolites University of Kentucky UKnowledge Theses and Dissertations--Chemistry Chemistry 2021 MASS SPECTROMETRY METHOD DEVELOPMENT FOR THE DISCOVERY AND CHARACTERIZATION OF SECONDARY METABOLITES Zachary Kelley University of Kentucky, [email protected] Author ORCID Identifier: https://orcid.org/0000-0002-7076-5450 Digital Object Identifier: https://doi.org/10.13023/etd.2021.282 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Kelley, Zachary, "MASS SPECTROMETRY METHOD DEVELOPMENT FOR THE DISCOVERY AND CHARACTERIZATION OF SECONDARY METABOLITES" (2021). Theses and Dissertations--Chemistry. 143. https://uknowledge.uky.edu/chemistry_etds/143 This Doctoral Dissertation is brought to you for free and open access by the Chemistry at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Chemistry by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Zachary Kelley, Student Dr. Bert Lynn, Major Professor Dr. Yinan Wei, Director of Graduate Studies MASS SPECTROMETRY METHOD DEVELOPMENT FOR THE DISCOVERY AND CHARACTERIZATION OF SECONDARY METABOLITES ________________________________________ DISSERTATION ________________________________________ A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Arts and Sciences at the University of Kentucky By Zachary David Kelley Lexington, Kentucky Director: Dr. Bert C. Lynn, Professor of Chemistry Lexington, Kentucky 2021 Copyright © Zachary David Kelley 2021 https://orcid.org/0000-0002-7076-5450 ABSTRACT OF DISSERTATION MASS SPECTROMETRY METHOD DEVELOPMENT FOR THE DISCOVERY AND CHARACTERIZATION OF SECONDARY METABOLITES Secondary metabolites are organic compounds produced by an organism for reasons other than growth and development. In plants, secondary metabolites generally act as defense agents produced to deter predators and inhibit other competitive species. For humans, these compounds can often have a beneficial effect and are pursued and utilized as natural pharmaceuticals. The development of sensitive, high-throughput analytical screening methods for plant derived metabolites is crucial for natural pharmaceutical product discovery and plant metabolomic profiling. Here, metabolomic profiling methods were developed using a microfluidic capillary zone electrophoresis device and evaluated against traditional separation approaches. An alkaloid screening assay was constructed to analyze transgenic mutant plant extracts for novel metabolites. Putatively identified novel features were detected, elucidated, and then isolated and purified for pharmaceutical evaluation. Additionally, methods for the analysis of polyphenolic plant-derived secondary metabolites, such as cannabinoids, were also developed and evaluated. In this case, the occurrence of cross-instrumental variation was addressed, given the tight legal restrictions regarding commercialization the products in question. Lastly, the microfluidic CZE-MS methods were further applied for both primary and secondary metabolite profiling in a DMPK assay. This assay was developed to inclusively monitor metabolic changes as a response to varying concentrations of a therapeutic in circulation. The metabolomic methods developed and evaluated in this work displayed high sensitivity, efficiency, and accuracy and can be utilized across a wide variety of applications. KEYWORDS: Mass Spectrometry, Capillary Electrophoresis, Alkaloids, Secondary Metabolites, Metabolomics Zachary Kelley (Name of Student) 7/16/2021 Date MASS SPECTROMETRY METHOD DEVELOPMENT FOR THE DISCOVERY AND CHARACTERIZATION OF SECONDARY METABOLITES By Zachary David Kelley Dr. Bert C. Lynn Director of Dissertation Dr. Yinan Wei Director of Graduate Studies 07/16/2021 Date Dedicated to Amanda, Barry, and my family, My never-ending sources of love, support, and encouragement throughout this voyage. ACKNOWLEDGMENTS First of all, I would like to sincerely thank my advisor, Dr. Bert C. Lynn, for his patience, guidance, encouragement, and friendship throughout the last five years. Through his thought-provoking teachings and constant push for me to continuously ask “why?”, I truly feel that I have immensely grown as both a scientist and as a person. I have no doubts in my mind that I picked the perfect advisor for my graduate program and will be forever grateful for my time in his research group. I look forward to continuing our relationship as colleagues and catching up in the future at the annual ASMS meetings. I would also like to thank my committee members, Dr. Mark A. Lovell, Dr. Stephen M. Testa, and Dr. Brian C. Rymond for their support and constructive feedback through-out the years. Even through a project change and the challenges of a pandemic, they always took the time to help guide me in the right direction and push me to widen my scientific skillset. Additionally, many thanks to everyone at Naprogenix LLC, especially Dr. John Littleton and Dr. Trent Rogers, for supporting me with a research assistantship throughout most of my graduate career. My time with the company has been invaluable and has opened the doors to so many opportunities already. I am also very thankful for my colleagues in the Lynn lab, both past and present, for their friendship and support. From teaching each other and learning about our cultural differences to working through complicated experiments and instrumental issues, I will also look back on our time together with fondness and I can’t wait to see what the future has in store for everyone. Special thanks to my other graduate school colleagues and the iii Chemistry Department faculty and staff for further enriching my time in the program as well. I will also be forever thankful for my wonderful family and friends. Between the early morning calls with my mom, Laura, during our morning commutes to the weekly Tuesday night chats with my dad, Stephen, I never felt far from my family or unsupported, despite the long distance between us. To all of my siblings, both by birth and by marriage, for the laughs when I needed them most and their advice during the tough decisions. To my friends for making Kentucky feel like home and always making me feel welcomed and appreciated. I am extremely fortunate to have so many wonderful people in my life and I truly cherish all of you. Lastly, I would like to thank my partner through it all, Amanda. Graduate school is challenging, but she made it is so much easier through her constant encouragement, understanding, and love. She believed in me every day, even when I didn’t believe in myself, and gave me a reason to keep pushing on when I wanted to quit. I am truly blessed to have such a wonderful partner and will be eternally grateful for everything that she has done and sacrificed for me to help me through this journey. Having her by my side is one of the main reasons that I have made it this far and I can’t wait to see what adventures the future has in store for us next. iv TABLE OF CONTENTS ACKNOWLEDGMENTS ................................................................................................. iii LIST OF TABLES ........................................................................................................... viii LIST OF FIGURES ........................................................................................................... ix LIST OF ABBREVIATIONS AND SYMBOLS ............................................................ xiv CHAPTER 1. Introduction ................................................................................................. 1 Background ..................................................................................................................... 1 Secondary Metabolites and Metabolomics ..................................................................... 2 Mass Spectrometry .......................................................................................................
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