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Reengineering Butyrylcholinesterase for the Catalytic Degradation of Organophosphorus Compounds DISSERTATION Presented in Partia

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Reengineering Butyrylcholinesterase for the Catalytic Degradation of Organophosphorus Compounds DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Kevin Garrett McGarry, Jr. Ohio State University Biochemistry Program The Ohio State University 2019 Dissertation Committee David W. Wood, Ph.D. Thomas J. Magliery, Ph.D. Hannah S. Shafaat, Ph.D. Patrice P. Hamel, Ph.D. Christopher M. Hadad, Ph.D. Copyrighted by Kevin Garrett McGarry, Jr. 2019 Abstract Chemical warfare nerve agents (CWNAs) present a global threat to both military and civilian populations. The acute toxicity of CWNAs stems from their ability to strongly inhibit cholinesterases – specifically acetylcholinesterase (AChE). This inhibition can lead to uncontrolled cholinergic cellular signaling, resulting in a cholinergic crisis and, ultimately, death. While the current FDA-approved standard of care is moderately effective when administered early, development of novel treatment strategies is necessary and was the goal that was set forth upon joining Dr. Wood’s laboratory six years ago. Butyrylcholinesterase (BChE) is an enzyme which displays a high degree of structural homology to AChE. Unlike AChE, BChE appears to be a non-essential enzyme. In vivo, BChE primarily serves as a bioscavenger of toxic esters due to its ability to accommodate a wide variety of substrates within its active site. Like AChE, BChE is readily inhibited by CWNAs. Due to its high affinity for binding CWNAs and that null-BChE yields no apparent health effects, exogenous BChE has been explored as a candidate therapeutic for CWNA intoxication. Despite years of research, minimal strides have been made to develop BChE (or any other enzyme) as a therapeutically relevant catalytic bioscavenger of CWNAs. BChE is, however, in early clinical trials as a ii stoichiometric bioscavenger of CWNAs. Unfortunately, as a stoichiometric bioscavenger, large quantities of the protein must be administered to combat CWNA toxicity. Throughout this work are described various platforms to produce recombinant butyrylcholinesterase; an enzyme comparison study across multiple, commonly-used large animal models for organophosphate (OP) research; ultimately, culminating in previously unidentified mutations of BChE that confer catalytic degradation of the CWNA, sarin. These exciting mutations, along with corresponding future efforts, may finally lead to a novel, catalytic therapeutic to combat CWNA intoxication. iii Dedication I would like to dedicate this dissertation to some very special people in my life: First, I dedicate this work to my wife, Stephanie and our new son, Riley. Riley, you don’t understand this now, but one day, I hope that the work I’ve done here makes you proud of your daddy. Steph, thank you for supporting me in my desire to return to school, dealing with me being in the lab late in the evenings, having to come in to the lab with me before and/or after football games, or even when I have been home and I am working or thinking about science, as well as the many “Fend for Yourself (FFYN)” dinner nights as a result! Over these last few months, as well, I truly appreciate all you do as a new mother! Riley and I are so lucky to have you! Steph, I could not have done this without you being there for me and listening to all of my scientific ramblings – even if you didn’t always understand it! I love you. Next, I would like to recognize my parents, Kathy and Kevin. Mom and Dad, you always believed in me and supported me in everything I have done, and, to this day, you continue to challenge me to do better in everything. Mom and Dad, your faith in me never wavered, and for that I am eternally grateful. Mom, thank you for always proofreading my writings -- from grade school through this dissertation. (In theory, this should be the last one!). iv My brother, Brian, who, for the past 34+ years I have competed with in everything. The drive to challenge and better each other from the basketball court on mom and dad’s driveway, to our education, careers, and lives in general is something I continue to grow from daily. Continue challenging me, Brian, it is appreciated. I would also like to dedicate this work to Dr. Juan Alfonzo who, in 2004, decided to take a very persistent undergraduate into his lab (if only so I would quit asking if I could join his lab). Juan, what I learned in your lab lit the research fire within me and has ultimately led to my career in science. The friendship we still have to this day is a bond that will last forever. Finally, I would like to dedicate this dissertation to my adviser, Dr. David Wood. I truly appreciate Dr. Wood’s openness to try something that, to our knowledge, has never been done before in the sciences at Ohio State; nor is it something that most professors would want to undertake. Without Dr. Wood’s willingness to take a chance on me and allowing me to join his lab while still maintaining full-time employment at Battelle, this would never have been possible, and for that I am forever grateful. Dr. Wood even established a co-appointment so that he could serve as my advisor and for this I am especially grateful. Thank you. v Acknowledgments I would like to acknowledge my co-workers at Battelle who have supported me throughout these last six years. I would especially like to recognize Dr. Jill Harvilchuck who initially approached me about the idea of returning to graduate school to pursue a doctorate in biochemistry. I would also like to recognize Tom Snider, who recently passed away but was always willing to lend an ear and to provide valuable insight into anything I was working on or just wanted to discuss. Dr. Bob Moyer, thank you for your guidance during your time at Battelle and willingness to listen to the often unsolicited OSU research news I inundated you with over the years. To all of the members of the biochemistry team (past and present) at Battelle who have helped me out along the way to get where I am today, thank you. Lastly, I would like to acknowledge all of my committee members (both past and present), your input and guidance over the last several years has led to some very interesting ideas, discussions, and scientific breakthroughs. I have learned a great deal from you, and I hope that the relationships we have developed will continue as scientific collaborations over the course of our careers. Thank you all. vi Vita 2000 – 2004........................................Bachelor of Science in Microbiology The Ohio State University, Columbus, OH 2005 – 2007........................................Master of Science in Microbiology The Ohio State University, Columbus, OH 2007 – Present ....................................Researcher in Health, Highly Toxic Materials Battelle Biomedical Research Center, West Jefferson, OH 2013 – Present ....................................Graduate Student, Candidate, Doctor of Philosophy Ohio State Biochemistry Program The Ohio State University, Columbus, OH vii Publications Moyer, R. A., McGarry, K. G., Jr., Babin, M. C., Platoff, G. E., Jr., Jett, D. A., and Yeung, D. T. (2018) Kinetic analysis of oxime-assisted reactivation of human, Guinea pig, and rat acetylcholinesterase inhibited by the organophosphorus pesticide metabolite phorate oxon (PHO), Pestic Biochem Physiol 145, 93-99. Snider, T. H., McGarry, K. G., Jr., Babin, M. C., Jett, D. A., Platoff, G. E., Jr., and Yeung, D. T. (2016) Acute toxicity of phorate oxon by oral gavage in the Sprague- Dawley rat, Fundam Toxicol Sci 3, 195-204. Brittain, M. K., McGarry, K. G., Moyer, R. A., Babin, M. C., Jett, D. A., Platoff, G. E., Jr., and Yeung, D. T. (2016) Efficacy of Recommended Prehospital Human Equivalent Doses of Atropine and Pralidoxime Against the Toxic Effects of Carbamate Poisoning in the Hartley Guinea Pig, International journal of toxicology 35, 344-357. McGarry, K. G., Bartlett, R. A., Machesky, N. J., Snider, T. H., Moyer, R. A., Yeung, D. T., and Brittain, M. K. (2013) Evaluation of HemogloBind treatment for preparation of samples for cholinesterase analysis, Adv Biosci Biotechnol 4, 1020-1023. viii McGarry, K. G., Walker, S. E., Wang, H., and Fredrick, K. (2005) Destabilization of the P site codon-anticodon helix results from movement of tRNA into the P/E hybrid state within the ribosome, Molecular cell 20, 613-622. Fields of Study Major Field: Ohio State Biochemistry Program ix Table of Contents Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iv Acknowledgments.............................................................................................................. vi Vita .................................................................................................................................... vii Publications ...................................................................................................................... viii List of Tables .................................................................................................................... xv List of Figures .................................................................................................................. xvi Chapter 1. Introduction ......................................................................................................
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  • Butyrylcholinesterase Inhibitors

    Butyrylcholinesterase Inhibitors

    DOI: 10.1002/cbic.200900309 hChAT: A Tool for the Chemoenzymatic Generation of Potential Acetyl/ Butyrylcholinesterase Inhibitors Keith D. Green,[a] Micha Fridman,[b] and Sylvie Garneau-Tsodikova*[a] Nervous system disorders, such as Alzheimer’s disease (AD)[1] and schizophrenia,[2] are believed to be caused in part by the loss of choline acetyltransferase (ChAT) expression and activity, which is responsible for the for- mation of the neurotransmitter acetylcholine (ACh). ACh is bio- synthesized by ChAT by acetyla- tion of choline, which is in turn biosynthesized from l-serine.[3] ACh is involved in many neuro- logical signaling pathways in the Figure 1. Bioactive acetylcholine analogues. parasympathetic, sympathetic, and voluntary nervous system.[4] Because of its involvement in many aspects of the central nerv- Other reversible AChE inhibitors, such as edrophonium, neo- ous system (CNS), acetylcholine production and degradation stigmine, pyridostigmine, and ecothiopate, have chemical has become the target of research for many neurological disor- structures that rely on the features and motifs that compose ders including AD.[5] In more recent studies, a decrease in ace- acetylcholine (Figure 1). They all possess an alkylated ammoni- tylcholine levels, due to decreases in ChAT activity,[6] has been um unit similar to that of acetylcholine. Furthermore, all of the observed in the early stages of AD.[7–9] An increase in butyryl- compounds have an oxygen atom that is separated by either cholinesterase (BChE) has also been observed in AD.[6] Depend- two carbons from the ammonium group, as is the case in ace- ing on the location in the brain, an increase and decrease of tylcholine, or three carbons.