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Selenium in Thioredoxin Reductase: Resistance to Oxidative Inactivation, Oxidation States, and Reversibility of Chemical Reactions Drew Barber University of Vermont

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Selenium in Thioredoxin Reductase: Resistance to Oxidative Inactivation, Oxidation States, and Reversibility of Chemical Reactions Drew Barber University of Vermont University of Vermont ScholarWorks @ UVM Graduate College Dissertations and Theses Dissertations and Theses 2018 Selenium In Thioredoxin Reductase: Resistance To Oxidative Inactivation, Oxidation States, And Reversibility Of Chemical Reactions Drew Barber University of Vermont Follow this and additional works at: https://scholarworks.uvm.edu/graddis Part of the Biochemistry Commons Recommended Citation Barber, Drew, "Selenium In Thioredoxin Reductase: Resistance To Oxidative Inactivation, Oxidation States, And Reversibility Of Chemical Reactions" (2018). Graduate College Dissertations and Theses. 943. https://scholarworks.uvm.edu/graddis/943 This Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks @ UVM. It has been accepted for inclusion in Graduate College Dissertations and Theses by an authorized administrator of ScholarWorks @ UVM. For more information, please contact [email protected]. SELENIUM IN THIOREDOXIN REDUCTASE: RESISTANCE TO OXIDATIVE INACTIVATION, OXIDATION STATES, AND REVERSIBILITY OF CHEMICAL REACTIONS A Dissertation Presented by Drew Barber to The Faculty of the Graduate College of The University of Vermont In Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy Specializing in Biochemistry October, 2018 Defense Date: July 5, 2018 Dissertation Examination Committee: Robert Hondal, Ph.D., Advisor Albert van der Vliet, Ph.D., Chairperson Stephen Everse, Ph.D. Matthew Poynter, Ph.D. Cynthia J. Forehand, Ph.D., Dean of the Graduate College Abstract Selenium is a required trace element which was originally discovered by the Swedish chemist Jons Jacob Berzelius in 1817. It was initially believed to be a toxin as it was identified as being the cause of hoof maladies and excessive hair loss in horses that feed upon plants with high selenium content. It wasn’t until 1957 that the potential contributions of selenium to physiology were first demonstrated. Selenium is now known to play a critical role in the maintenance of human health. Interestingly, unlike other trace metals/semi-metals, selenium is directly incorporated into proteins in the form of the amino acid selenocysteine (Sec) in a very complicated and energetically costly fashion. Though rare, being found in only 25 human proteins, Sec proteins are involved in numerous vital biological processes including maintenance of redox homeostasis and anti-oxidant defense. Even though Sec is essential, the reason that Sec replaces its structural analog cysteine (Cys) in only 25 proteins is not widely agreed upon. A previous model suggests that the replacement of Cys with Sec provides enzymes with a type of catalytic advantage. The presence of Cys-containing orthologs of mammalian Sec- enzymes in other eukaryotes argues against this model. A newer model to explain the use of Sec is that the gain of function imparted to an enzyme by replacing Cys with Sec is the ability of Sec to impart chemical reversibility. Building on previous results from our lab demonstrating the ability of Sec to confer proteins with the ability to resist over oxidation we have elucidated the mechanism by which Sec containing thioredoxin reductase (TrxR) resists over oxidation. The ability of Sec-TrxR to resist oxidative inactivation is due to the greater electrophilicity of Sec relative to Cys. This allows for quicker resolution and prevents over oxidation. Based on these findings we also investigate the utility of the alkylating agent dimedone to probe the oxidation state of Sec. Interestingly, it was discovered that dimedone will react with seleneninic acid with the resulting adduct being labile. Additonally it was discovered that dimedone will also react with seleninic acid, resulting in the formation of a dimedone dimer. These results call into question the usefulness of dimedone in deteremining the oxidation state of Sec. Finally, we provide evidence that Sec-TrxR enzymes are able to catalyze single electron reductions. This is most likely due to the formation of a stable Sec radical intermediate. As a whole this project provides support for the theory that Sec was selected for due to its ability to convey chemical reversiablity to proteins. Citations Material from this dissertation has been accepted for publication in Protein Science in 2018 in the following forms: Payne N.P., Barber D.R., Ruggles E.L., Hondal R.J.. (2018). Can Dimedone be Used to Study Selenoproteins? An Investigation of the Reactivity of Dimedone Towards Oxidized Forms of Selenocysteine. Protein Science Barber D.R., Hondal RJ.. (2018). Gain of function conferred by selenocysteine: Catalytic enhancement of one-electron transfer reactions by thioredoxin reductase. Protein Science. ii Dedication I would like to dedicate this dissertation to my parents, Peggy and Darrell and to my brother Luke. You have all provided me with support and encouragement throughtout my life. Without you guys things would be much more difficult. I would also like to dedicate this dissertation to my other family; Gunther, Maxim, and Nic. You make everything significantly more interesting. iii Acknowledgments I would like to thank my advisor Dr. Robert Hondal for his scientific and professional guidance. I would also like to thank the members of the Hondal lab with special thanks to Conor Payne for collaborating on the dimedone project. I would also like to thank Dr. Stephen Everse for his advice and assistance and Dr. Robert Kelm for his support. iv Table of Contents CITATIONS………………………………………………………………………………ii DEDICATION……………………………………………………………………………iii ACKNOWLEDGMENTS………………………………………………………………..iv LIST OF TABLES……………………………………………………………………...viii LIST OF FIGURES………………………………………………………………………ix CHAPTER 1: Selenocysteine: The 21st Proteinogenic Amino Acid……………………...1 Selenium and Physiology……………………………………………………………….2 Selenocysteine Vs Cysteine…………………………………………………………….5 Thioredoxin Reductase and the Thioredoxin System…………………………………13 Thioredoxin Reductase: Selenium Vs Sulfur………………………………………….17 Specific Aims………………………………………………………………………….24 CHAPTER 2: The Mechanism by Which Mamalian Thioredoxin Reductase Resists Oxidative Inactivation…………………………………………………………………....35 Mamalian Thioredoxin Reductases Ability to Resist Oxidative Inactivation is Depedent Upon the Electrophilic Character of Sec…………………………………...36 Sec Confers Resistance to Oxidative Inactivation…………………………………….37 Methods…………………………………………………………………………………..40 Peptide Synthesis……………………………………………………………………...40 Enzyme Production……………………………………………………………………40 Detection of Oxidative Modifications………………………………………………...42 Inactivation of Truncated Enzymes…………………………………………………...42 Hypobromous Acid Inactivation of TrxR…………………………………………..…43 Inactivation of Insertion Enzymes…………………………………………………….43 Hydrogen Peroxide Inactivation of TrxR……………………………………………..43 Results……………………………………………………………………………………44 Purposed Model of Resistance………………………………………………………...44 Switching Postions of Cys and Sec in mTrxR2…………………………………….…45 Inactivation of Truncated Enzymes…………………………………………………...46 Detection of Oxidative Modifications………………………………………………...47 Discussion………………………………………………………………………………..48 Method of Reisstance………………………………………………………………….48 Switching Positions of Cys and Sec in mTrxR2………………………………………50 Inactivation of mTrxR2………………………………………………………………..51 Conclusions…………………………………………………………………….………...51 CHAPTER 3: Detection of Sec Oxdiation States with Dimedone..……………………..51 Can Dimedone be Used to Study Selenoproteins? An Investigation of the Reactivity of Dimedone Towards the Oxidized Forms of Selenocysteine………………………..62 Use of Dimedone to Detect Sec Oxidation……………………………………………63 Methods…………………………………………………………………………………..65 General Methods………………………………………………………………………65 Production of Thioedoxin Reductase by Semisynthesis……………………………....67 v Attempt to Inhibit Thioredixn Reductase with Dimedone Treatment ..........................67 Peptide Synthesis……………………………………………………………………...67 Labeling of Model Sec-Containing Peptides With Dimedone……………………..…68 Demonstrating the lability of the Sec-Dimedone label………………………………..69 77 Se NMR Time Course Reactions Between Dimedone and Seleninic Acid….……...69 LCMS Analysis of Reaction Between Dimedone and PhSeO2H……………………..69 Attempt of Purify Dimedone Byproducts of Reaction Between Dimedone and PhSeO2H……………………………………………………………………………....70 Formation and Detection of Dimedone Species (1a) Upon Reaction of Mutant Peptide with H2O2……………………………………………………….……...…70 Results……………………………………………………………………………………70 Attempting to Inhibit Thioredoxin Reductase by Dimedone Treatment in the Presence of H2O2……………………………………………….………….………….70 Labeling of Model Sec-Containing Peptides With Dimedone………………………..71 Demonstrating the Lability of the Sec Dimedone Label…………………………...…73 Reaction of Dimedone with Model Seleninic Acids…………………………………..75 The Presence of 1a as a Chemical Signature of Selenininc Acid in a Model Peptide...78 Discussion………………………………………………………………………………..78 Dimedone and Sec-Selenenic Acids………………………………………………..…80 Dimedone and Sec-Seleninic Acids…………………………………………………...82 Conclusions………………………………………………………………………………83 CHAPTER 4: Sec and Thioredoxin Reductase: One Electron Reductions…………103 Gain of function conferred by selenocysteine: Catalytic enhancement of one-electron transfer reactions by thioredoxin reductase………..…………………..104 Sec: A Gain of Function……………………………………………………………..105 Methods…………………………………………………………………………………107 Enzyme Production…………………………………………………………………..107 Reduction of Cytochrome C by TrxR………………………………………………..109 Reduction of the Ascorbyl Radical by
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