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Mechanistic Study of Cysteine Dioxygenase, a Non-Heme

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Mechanistic Study of Cysteine Dioxygenase, a Non-Heme MECHANISTIC STUDY OF CYSTEINE DIOXYGENASE, A NON-HEME MONONUCLEAR IRON ENZYME by WEI LI Presented to the Faculty of the Graduate School of The University of Texas at Arlington in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY THE UNIVERSITY OF TEXAS AT ARLINGTON August 2014 Copyright © by Student Name Wei Li All Rights Reserved Acknowledgements I would like to thank Dr. Pierce for your mentoring, guidance and patience over the five years. I cannot go all the way through this without your help. Your intelligence and determination has been and will always be an example for me. I would like to thank my committee members Dr. Dias, Dr. Heo and Dr. Jonhson- Winters for the directions and invaluable advice. I also would like to thank all my lab mates, Josh, Bishnu ,Andra, Priyanka, Eleanor, you all helped me so I could finish my projects. I would like to thank the Department of Chemistry and Biochemistry for the help with my academic and career. At Last, I would like to thank my lovely wife and beautiful daughter who made my life meaningful and full of joy. July 11, 2014 iii Abstract MECHANISTIC STUDY OF CYSTEINE DIOXYGENASE A NON-HEME MONONUCLEAR IRON ENZYME Wei Li, PhD The University of Texas at Arlington, 2014 Supervising Professor: Brad Pierce Cysteine dioxygenase (CDO) is an non-heme mononuclear iron enzymes that catalyzes the O2-dependent oxidation of L-cysteine (Cys) to produce cysteine sulfinic acid (CSA). CDO controls cysteine levels in cells and is a potential drug target for some diseases such as Parkinson’s and Alzhermer’s. Several crystal structures of CDO have been determined and they reveal a ferrous iron active site coordinated by three histidine residues. This feature is divergent from the monoanionic 2-histidine-1-carboxylate coordination typically observed within the non-heme mononuclear iron super family of oxidase/oxygenase enzymes. Furthermore, within 3.3 Å of the CDO active site iron is an unusual covalently crosslinked cysteine-tyrosine pair (C93-Y157). To date, only 3 other enzymes have been identified with a similar Cys-Tyr post-transitional modification and the role of this modification in CDO is still unknown. Due to the lack of structural evidence of oxygen-bound intermediates, the mechanism of CDO remains unclear. In this work, a transient intermediate FeIII-superoxo was discovered by chemical rescue reaction and characterized using UV-vis, EPR and resonance Mossbauer. To probe the influence of second-sphere enzyme-substrate interaction, the steady-state kinetics and iv O2/CSA coupling were measured for wild-type CDO and selected active site variants (Y157F, C93A, H155A). In additional, using CN- as a probe, the influence of the C93- T157 pair to the active site is investigated on EPR. Key substrate-enzyme interaction was also investigated by substrate specificity of CDO. Selected thiol-containing compounds were incubated with CDO for steady-state kinetic analysis using NMR. LC- MS confirmed the presence of products and dioxygenase activity. v Table of Contents Acknowledgements .............................................................................................................iii Abstract .............................................................................................................................. iv List of Illustrations ............................................................................................................... x List of Tables ......................................................................................................................xii Chapter 1 Introduction of Non-heme Mononuclear Iron Enzyme and Cysteine Dioxygenase ....................................................................................................................... 1 Mononuclear Non-heme Iron Containing Enzyme: The 2-His-1- carboxyglate Facial Triad ............................................................................................... 2 Obligated Substrate Binding and Oxygen-activating/substrate-activating Pathway ...................................................................................................................... 3 Enzyme Groups that Contain the 2-His-1-carboxylate Facial Triad ............................... 4 α-Ketoglutarate-dependent Enzymes ......................................................................... 4 Mechanism ............................................................................................................. 5 Extradiol and Intradiol Dioxygenase ........................................................................... 9 Extradiol dioxygenases .......................................................................................... 9 Intradiol dioxygenases ......................................................................................... 12 Rieske Dioxygenases ............................................................................................... 13 Naphthalene dioxygenase (NDO) ........................................................................ 15 Pterin-dependent Hydroxylases ............................................................................... 17 Phenylalanine hydroxylase (PheH) ...................................................................... 18 Isopenicillin N Synthase (IPNS) and 1-aminocyclopropane-1-carboxylic Acid Oxidase (ACCO) ............................................................................................... 21 Isopenicillin N Synthase (IPNS) ........................................................................... 21 1-aminocyclopropane-1-carboxylic acid oxidase (ACCO) ................................... 23 vi Cysteine Dioxygenase .................................................................................................. 26 L-Cysteine ................................................................................................................ 26 Cysteine Dixoygenase .............................................................................................. 35 Early study on CDO ............................................................................................. 35 Structure of CDO .................................................................................................. 36 Characterization ................................................................................................... 38 Mechanism ........................................................................................................... 39 Diseases related to cysteine and CDO ................................................................ 44 Summary ...................................................................................................................... 45 Chapter 2 Single Turnover of Substrate-Bound Ferric Cysteine Dioxygenase with Superoxide Anion: Enzymatic Reactivation, Product Formation, and a Transient Intermediate ...................................................................................................... 46 Introduction ................................................................................................................... 46 Materials and Methods ................................................................................................. 53 Purification of CDO ................................................................................................... 53 TLC CDO Activity Assay........................................................................................... 54 HPLC CDO Activity Assay ........................................................................................ 55 Anaerobic Work ........................................................................................................ 55 II K2IrCl6 Oxidation of Fe -CDO ................................................................................... 56 Addition of Superoxide to Substrate-Bound FeIII-CDO ............................................. 56 Spectroscopy ............................................................................................................ 57 Results .......................................................................................................................... 58 Production of FeIII-CDO (2)....................................................................................... 58 Addition of Superoxide Anion to Substrate-Bound FeIII-CDO (2a) ........................... 63 vii EPR Spectroscopy of Putative Substrate-Bound FeIII-Superoxo CDO (3a) ........................................................................................................................... 67 Discussion .................................................................................................................... 70 Oxidation of CDO Active Site ................................................................................... 70 Putative Ferric-Superoxide Intermediate (3a) of CDO ............................................. 72 Mechanistic Implications........................................................................................... 73 Chapter 3 Second-Sphere Interactions between the C93–Y157 Cross-Link and the Substrate-Bound Fe Site Influence the O2 Coupling Efficiency in Mouse Cysteine Dioxygenase .......................................................................................... 77 Introduction ................................................................................................................... 77 Materials and Methods ................................................................................................
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