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Investigation of Cysteine and Methionine Oxidation Using X-Ray

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Investigation of Cysteine and Methionine Oxidation Using X-Ray Investigation of Cysteine and Methionine Oxidation Using X-Ray Absorption Spectroscopy by Anusha Karunakaran B.Sc., Simon Fraser University, 2000 M.Sc., University of Sussex, 2002 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) April 2010 © Anusha Karunakaran, 2010 ABSTRACT Cysteine (Cys) and methionine (Met) are sulfur containing amino acids with various oxidation forms. Oxidation of Cys yields cysteinyl radicals that have been postulated as intermediates in several biological contexts including enzymatic catalysis, long-range electron transfer, peptide post-translational modification and cellular redox signaling. The challenges of detecting sulfur-based radicals with electron paramagnetic resonance (EPR) have led to the development of Sulfur K- edge X-ray absorption spectroscopy (S K-edge XAS) as a spectroscopic tool. The reactivity of sulfur-based radicals was studied in a Pseudomonas aeruginosa azurin protein system to probe the electronic structure of isolated cysteinyl radicals, which are characterized by S 3p ← 1s pre-edge transition. S K-edge XAS has shown to be a sensitive method in detecting these cysteinyl radicals in hydrophobic and hydrophilic protein environments. The pre-edge feature of the cysteinyl radicals in hydrophobic environments was lower in energy than their hydrophilic counterparts due to hydrogen bonding interactions. Additionally, S K-edge XAS was employed to study the redox photochemistry of Met and its oxidized forms methionine sulfoxide (MetSO) and methionine sulfone (MetSO2). Met is easily photooxidized to MetSO and MetSO2 in the presence of O2. In the absence of O2, photoirradiation leads to the one-electron-oxidized Met cation radical (MetS•+), suggesting an alternative mechanism for photooxidation of thioethers through direct oxidation. The photoirradiation of MetSO leads back to Met under both aerobic and anaerobic conditions while MetSO2 is photochemically inert. These findings provide new insights into the formation of age-related cataracts. ii Finally, the metal-induced Met oxidation in amyloid-β (Aβ) peptide was investigated. Much of the research to date has focused on the redox chemistry of 2+ Cu in Aβ peptide with inconsistent findings with regards to the role of Met35 and the oxidation state of the Met35. Findings reported here indicate that in the presence of 2+ 3+ Cu alone, Met35 was oxidized to MetSO, but surprisingly Fe failed to oxidize the Met. These differences in the oxidation behaviour lead to the investigation of the metal binding site in Aβ. Fe3+ found to be in a six-coordinate environment with oxygen-rich ligands while Cu2+ is in a five-coordinate environment with histidine-rich ligands. iii TABLE OF CONTENTS Abstract .................................................................................................................... ii Table of Contents .................................................................................................... iv List of Tables ......................................................................................................... viii List of Figures ......................................................................................................... ix List of Schemes .................................................................................................... xiii List of Equations ................................................................................................... xiv Abbreviations and Symbols .................................................................................. xv Acknowledgements ............................................................................................ xviii Chapter 1: Introduction ........................................................................................ 1 1.1 Thesis Overview .......................................................................................... 1 1.2 The Chemistry of Cysteine and Methionine ................................................. 2 1.3 Reactive Oxygen and Nitrogen Species ...................................................... 4 1.4 Cysteine Oxidation ...................................................................................... 7 1.4.1 Intra- and Intermolecular Disulfides ................................................................... 8 1.4.2 Sulfenic Acids ..................................................................................................14 1.4.3 Sulfinic and Sulfonic Acids ...............................................................................19 1.4.4 S-Nitrosylation..................................................................................................22 1.4.5 Cysteinyl Radical .............................................................................................23 1.5 Methionine Oxidation ................................................................................. 28 1.5.1 Formation and Role of Sulfoxide ......................................................................28 1.5.2 Formation and Role of Sulfone .........................................................................32 1.5.3 Methionine Radical Cation ...............................................................................33 1.6 Implications of Cys and Met Oxidation in Diseases ................................... 35 Chapter 2: X-Ray Absorption Spectroscopy..................................................... 39 2.1 Background and Theory ............................................................................ 39 2.1.1 X-Ray Absorption Near-Edge Structure (XANES) ............................................41 2.1.2 Extended X-Ray Absorption Fine Structure (EXAFS) .......................................44 2.2 Experimental Set-up .................................................................................. 48 2.3 Data Reduction and Analysis ..................................................................... 52 2.3.1 Sulfur K-edge XANES ......................................................................................52 2.3.2 Metal K-edge XANES and EXAFS ...................................................................53 iv Chapter 3: Synthesis and Characterization of Cysteinyl Radicals in Pseudomonas Aeruginosa Azurin ........................................................................ 56 3.1 Introduction ................................................................................................ 56 3.1.1 Implications of Cysteinyl Radicals in Biology ....................................................56 3.1.2 Current Spectroscopic Detection ......................................................................57 3.1.3 Proposed Spectroscopic Detection ..................................................................59 3.1.4 Pseudomonas aeruginosa Azurin.....................................................................61 3.1.5 Cysteines of Interest in Two Distinct Regions of Azurin ....................................62 3.2 Experimental .............................................................................................. 64 3.2.1 Multi Site-directed Mutagenesis .......................................................................64 3.2.2 Sequencing ......................................................................................................65 3.2.3 Protein Expression and Purification ..................................................................65 3.2.4 Synthesis of Rhenium Complex .......................................................................69 3.2.5 Re-labeling Reaction ........................................................................................71 3.2.6 Purification of Labeled Azurins .........................................................................71 3.2.7 The Flash/Quench/Freeze Methodology ..........................................................72 3.2.8 XAS Data Acquisition .......................................................................................73 3.2.9 XAS Data Processing and Analysis ..................................................................73 3.3 Results and Discussion ............................................................................. 75 3.3.1 Re-labeled Azurin mutants ...............................................................................75 3.3.2 Generation of Cysteinyl Radicals .....................................................................77 3.3.3 Characterization of Cysteinyl Radicals by Sulfur K-edge XAS ..........................78 3.4 Conclusions ............................................................................................... 82 Chapter 4: Photochemistry of Methionine, Methionine Sulfoxide, and Methionine Sulfone ................................................................................................ 83 4.1 Introduction ................................................................................................ 83 4.1.1 Methionine Oxidation .......................................................................................83 4.1.2 Age-related Cataracts ......................................................................................84 4.1.3 Photooxidation of Thioether .............................................................................85 4.2 Experimental .............................................................................................. 87 4.2.1
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