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Reengineering Butyrylcholinesterase for the Catalytic Degradation of Organophosphorus Compounds

McGarry, Kevin G, Jr.
http://orcid.org/0000-0003-2591-3992
http://rave.ohiolink.edu/etdc/view?acc_num=osu1555481894515424

Abstract Details

2019, Doctor of Philosophy, Ohio State University, Biochemistry Program, Ohio State.
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 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.
David Wood, Ph.D. (Advisor)
Thomas Magliery, Ph.D. (Committee Member)
Hannah Shafaat, Ph.D. (Committee Member)
Patrice Hamel, Ph.D. (Committee Member)
Christopher Hadad, Ph.D. (Committee Member)
193 p.
Biochemistry; Biomedical Engineering
acetylcholinesterase; butyrylcholinesterase; cholinesterase; chemical and biological weapons; organophosphates

Recommended Citations

Citations

  • McGarry, Jr., K. G. (2019). Reengineering Butyrylcholinesterase for the Catalytic Degradation of Organophosphorus Compounds [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555481894515424

    APA Style (7th edition)

  • McGarry, Jr., Kevin. Reengineering Butyrylcholinesterase for the Catalytic Degradation of Organophosphorus Compounds . 2019. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1555481894515424.

    MLA Style (8th edition)

  • McGarry, Jr., Kevin. "Reengineering Butyrylcholinesterase for the Catalytic Degradation of Organophosphorus Compounds ." Doctoral dissertation, Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555481894515424

    Chicago Manual of Style (17th edition)

osu1555481894515424
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© 2019, some rights reserved.Creative Commons License Reengineering Butyrylcholinesterase for the Catalytic Degradation of Organophosphorus Compounds by Kevin G McGarry Jr. is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.