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Non-Heme Iron Oxygenases: an Investigation of the Protein Ligand Effects on the Chemical Reactivity In

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Non-Heme Iron Oxygenases: an Investigation of the Protein Ligand Effects on the Chemical Reactivity In Non-Heme Iron Oxygenases: An Investigation of the Protein Ligand Effects on the Chemical Reactivity in MiaE and Cysteamine Dioxygenase by Philip Palacios Presented to the Faculty of the Graduate School of The University of Texas-Arlington in Partial Fulfillment of the requirements of the Degree of DOCTOR OF PHILOSOPHY THE UNIVERSITY OF TEXAS-ARLINGTON August 2019 Copyright © by Philip Palacios 2019 All Rights Reserved Acknowledgements Firstly, I want to express my sincere gratitude to my P.I. and friend, Dr. Brad Pierce, for his patience and support throughout these five years. It has been greatest honor to have worked under your guidance. I want to also thank my thesis committee members Dr. Rasika Dias, Dr. Robin Macaluso, and Dr. Jongyun Heo for their feedback throughout my graduate career. I want to thank all my coworkers that I’ve had the pleasure of working with throughout my graduate career; Josh, Sinjinee, Nick, Jared, Pender, Bender and the rest of the group. All of you made the experience of going to work enjoyable. We started out as lab mates and ended up as lifelong friends. I cannot think of a more perfect group of delinquents to spend these past five years with. Lastly, I want to thank my family and friends. To my family, you’ve always been a huge support of my dreams and I am not the person I am today without all that you have done and continue to do for me today. To my wonderful girlfriend, Diane, you’ve been the greatest gift in my life. I am not here without all your love and support throughout these years. You’ve pushed me to be better and always encouraged me to do what I love. September 3rd, 2019 Table of Contents Abstract ......................................................................................................................................................... 1 Chapter 1 Introduction ................................................................................................................................. 4 Analytical applications of Electron Paramagnetic Resonance .................................................................. 4 A look into the Mononuclear Non-Heme Metalloproteins....................................................................... 6 The non-heme iron enzyme family ........................................................................................................... 7 Non-heme iron enzymes with the 2-His-1-carboxylate moiety ................................................................ 9 The Catechol Dioxygenase Enzymes ....................................................................................................... 10 The α-ketoglutarate-depedent enzymes ................................................................................................ 11 The newly discovered 3-His facial triad .................................................................................................. 13 Non-heme iron enzymes involved in sulfur catabolism .......................................................................... 14 The non-heme diiron proteins ................................................................................................................ 18 Chapter 2 Mutation in tRNA-modifying monooxygenase, MiaE, leads to viable enzymatic model for arylamine oxidation. ................................................................................................................................... 23 Introduction ............................................................................................................................................ 23 Materials and Methods ........................................................................................................................... 27 Results ..................................................................................................................................................... 31 Discussion................................................................................................................................................ 39 Chapter 3 The steady-state kinetics and spectroscopic features of the mammalian thiol dioxygenase, cysteamine dioxygenase ............................................................................................................................. 43 Introduction ............................................................................................................................................ 43 Materials and Methods ........................................................................................................................... 46 Results ..................................................................................................................................................... 51 Discussion................................................................................................................................................ 62 Chapter 4 Collaboration Works with Analytical EPR ................................................................................... 65 Spectroscopic and solid-state evaluations of tetra-aza macrocyclic cobalt complexes with parallels to the classic cobalt(II) chloride equilibrium ............................................................................................... 65 Contribution in collaboration .............................................................................................................. 65 Isolation and identification of the pre-catalyst in iron-catalyzed direct arylation of pyrrole with phenylboronic acid .................................................................................................................................. 81 Contribution to collaboration ............................................................................................................. 81 Structural and Electronic Responses to the Three Redox Levels of Fe(NO)N2S2-Fe(NO)2 .................... 103 Contribution to the collaboration ..................................................................................................... 103 Nitroxyl Modified Tobacco Mosaic Virus as a Metal-Free High-Relaxivity MRI and EPR Active Superoxide Sensor ................................................................................................................................ 118 Contribution to the collaboration ..................................................................................................... 118 Appendix ................................................................................................................................................... 142 References ................................................................................................................................................ 148 Figure 1.1 X-ray crystal structures of Fe-bound active sites for the heme and non-heme iron oxygenase. 8 Figure 1.2 X-ray crystal structure of the Fe(II)/α-ketoglutarate dependent enzyme TauD from Myobacterium marinum (PDB: 3SWT)22 ............................................................................................... 9 Figure 1.3 Structure of the α-ketoglutarate cofactor. ................................................................................ 11 Figure 2.1 X-ray crystal structures of two diiron oxygenases, MiaE and AurF. .......................................... 26 Figure 2.2 Classification of non-heme diiron enzymes by structural arrangement of first-coordination sphere ligands and net change in extent of oxidation by bound histidine residues in active-site. .... 26 Figure 2.3 A) UV-vis comparison of as-isolated wt MiaE and L199H variant. ............................................. 32 Figure 2.4 Representative chromatogram of aniline oxidation in L199H reaction (product detected spectrophotometrically at 268 nm).. .................................................................................................. 37 Figure 2.5 Representative chromatogram of nitrosobenzene oxidation in L199H reaction (product detected spectrophotometrically at 268 nm). .................................................................................... 39 Figure 3.1 X-ray crystal structures of CDO and TauD. ................................................................................. 44 Figure 3.2 Steady-state kinetics of Mm ADO-catalyzed ca (A, black circle) and cys (B, white circle) consumption.. ..................................................................................................................................... 53 Figure 3.3 pH dependence of kcat and kcat/KM for the ADO-catalyzed reactions with ca (A and B) and cys (C and D) at 22°C. .......................................................................................................................... 55 Figure 3.4 A) NMR spectrum of cysteamine and hypotaurine representing the α- and β-carbon protons. ............................................................................................................................................................ 58 Figure 3.5 Inhibitory effects by NO on the ADO-catalyzed reaction with ca. The kcat values observed were fit to an exponential decay function.. ................................................................................................. 59 Figure 3.6 Comparative X-band EPR of Av MDO, Mm CDO, and Mm ADO of ES-NO complex.. ................ 61 Figure 4.1 Comparison of the electronic absorption spectra of (a) 1a and 1b and (b) cobalt(ii) chloride in water vs. dmf. ....................................................................................................................................
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