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Altering Enzyme Activities Using Chemical Modification

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Altering Enzyme Activities Using Chemical Modification Altering enzyme activities using chemical modification Claire Louise Windle Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds Astbury Centre for Structural Molecular Biology September 2015 The candidate confirms that the submitted work is her own and that the appropriate credit has been given within the thesis where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from this thesis may be published without proper acknowledgement. © 2015 The University of Leeds and Claire Louise Windle Jointly Authored Publications Throughout this thesis the work directly attributable to the candidate is as follows: i) Literature research and compilation of the manuscript stated above. ii) The candidate performed all the experimental work and data analysis unless otherwise stated. The candidate confirms that the work submitted is her own, except where work which has formed part of jointly authored publications has been included. The contribution of the candidate and the other authors to this work has been explicitly indicated below. The candidate confirms that appropriate credit has been given within the thesis where reference has been made to the work of others. Details of jointly authored publications and the contributions of other authors to these manuscripts: Chapter 3 contains work from the following publication Timms, N., Windle, C. L., Polyakova, A., Ault, J. R., Trinh, C. H., Pearson, A. R., Nelson, A. & Berry, A. (2013) Structural insights into the recovery of aldolase activity in n-acetylneuraminic acid lyase by replacement of the catalytically active lysine with gamma-thialysine by using a chemical mutagenesis strategy. Chembiochem, 14, 474-81 In this work, I carried out the chemical modification of the wild-type S. aureus NAL (saNAL) into K165-γ-thialysine saNAL and performed analysis of mass spectrometry data, size exclusion chromatography, kinetic assays, pH profiles and circular dichroism experiments, I also carried out crystalisation of the K165C saNAL, data processing for K165C saNAL, K165-γ-thialysine apo saNAL and K165-γ-thialysine saNAL incomplex with pryuvate, model building and refinement for wild-type saNAL, wild-type saNAL in complex with pyruvate, K165C saNAL, K165-γ-thialysine apo saNAL and K165-γ-thialysine saNAL incomplex with pryuvate. Dr Nicole Timms developed and optimised the system for the chemical modification procedure for use in E. coli and S. aureus NAL, performed chemical modification of saNAL and analysed mass i spectrometry data, carried out kinetic assays and refolding assays of the modified protein. Anna Polyakova perfomed optimisation of crystallisation conditions for the wild-type saNAL, crystallisation of wild-type saNAL, data collection and data processing for the wild-type apo saNAL and wild-type in complex with pyruvate saNAL. Dr James Ault performed the mass spectrometry of the chemical modification. Dr Chi Trinh supervised and aided with all X-ray crystallographic aspects of the project; crystallisation, data collection, data processing and refinement. Dr Arwen Pearson provided scientific discussion of the X-ray crystallographic aspects. Prof. Adam Nelson and Prof. Alan Berry provided the project concept and aided with scientific discussion, data interpretation and manuscript preparation. ii Acknowledgements Firstly I would like to thank my supervisors, Professor Alan Berry, Professor Adam Nelson and Professor Arwen Pearson for all their encouragement and guidance. Alan has been a great supervisor; he has always been enthusiastic about my project and provided continuous support. Thank you to Adam for his brilliant supervision and for explaining organic chemistry to me, and thank you to Arwen for the motivation and help with crystallography! I would like to thank Dr James Ault for all the mass spectrometry work that he has carried out for me, and for always being friendly and having the time for a good chat. A huge thanks has to go to Dr Chi Trinh for all his endless help with crystallography, you definitely made data collection more bearable! Over the last four years the most important thing I have learnt, is that the best way to get through a PhD is to make wonderful friends who will always make you laugh and take you for a drink when science seems to hate you. To the Berrys, Radfords and Mass spec you’ve all made the Astbury Centre an amazing place to work. Thanks to Sasha, Rachel, Sophie, Jan and Lydia for all the cocktails and dancing, and thanks to all the Monday night people Paul, Patrick, Tom and Rob for providing much needed distraction from thesis writing. Finally I’d like to thank my family, my Mum and Dad, Sister and Grandparents without you I would not be the person that I am today. Thank you for always supporting the decisions that I make and encouraging me to do what makes me happy. I hope I have made you proud! iii Abstract In Nature there are twenty proteogenic amino acid ‘building blocks’, from which proteins and enzymes are constructed. These proteogenic amino acids confer activity to enzymes; however there are many instances where the chemistries provided by these ‘building blocks’ are expanded upon. Nature recruits an array of cofactors, post-translational modifications and post-translationally generated cofactors, all which help to provide function or activity. Until recently the protein engineer was restricted to the use of the twenty proteogenic amino acids, and so access to this increased chemical diversity was highly challenging. In this thesis, chemical modification has been used to insert a variety of non-canonical amino acids (ncAAs) throughout the active site of the enzyme N-acetylneuraminic acid lyase (NAL). This modification method incorporates ncAAs site-specifically into a protein, via a dehydroalanine intermediate and conjugate addition with a thiol compound. Initial work using this method replaced the catalytic lysine at position 165 with the non-canonical analogue γ-thialysine. It was possible to obtain homogenously modified protein in high yields for detailed kinetic and X-ray crystallographic studies, and therefore possible to elucidate the catalytic and structural consequences of this modification. The work to replace Lys165 with a non-canonical analogue provided a starting point to expand the incorporation of ncAAs into NAL. A total of thirteen different non-canonical side chains were incorporated, individually, at thirteen different positions within the active site of NAL. These modified enzymes were then screened for activity with ten different substrates to determine the effects of ncAA incorporation. It was seen that the ncAAs were well tolerated by the enzyme, as active modified enzymes were produced. By incorporating ncAAs it was possible to alter the substrate specificity of the enzyme. The modified enzyme F190Dpc, containing a dihydroxypropyl cysteine side chain, was found to have an increased activity with an altered substrate, erythrose. This activity was higher than the wild-type enzyme with both the altered substrate and the wild-type substrate, and the non-canonical Dpc side chain outperformed any of the proteogenic amino acids when inserted at the same position in the protein, for the substrate erythrose. This research begins to explore the possibilities of what may be achieved by use of ncAAs. Facile incorporation of ncAAs will allow protein engineers to take inspiration from Nature and expand the chemistries provided by the proteogenic amino acids, hopefully to engineer novel activities or catalysis. iv Contents Acknowledgements iii Abstract iv Contents v List of Figures ix Abbreviations xiii Chapter 1 Introduction .................................................................................................. 2 1.1 Amino acid library extension ............................................................................... 5 1.1.1 21st and 22nd amino acids .......................................................................... 5 1.1.2 Cofactors and post-translational modifications ........................................ 7 1.1.3 Post-translationally generated cofactors ................................................ 10 1.2 Incorporation of non-canonical amino acids..................................................... 15 1.2.1 Auxotrophic incorporation ...................................................................... 16 1.2.2 tRNA suppressor technology ................................................................... 18 1.2.3 Chemical modification of proteins .......................................................... 21 1.3 Catalysis with non-canonical amino acids ......................................................... 25 1.4 Aldolases............................................................................................................ 29 1.4.1 N-Acetylneuraminic acid lyase ................................................................ 34 1.4.2 Protein engineering of N-acetylneuraminic acid lyase ............................ 37 1.5 Thesis aims and objectives ................................................................................ 40 1.5.1 To determine structural and functional effects of replacing the catalytic lysine at position 165 with the ncAA γ-thialysine. .................... 40 1.5.2 Develop methods for high-throughput incorporation of ncAAs by chemical modification, and screening of modified variants. .................. 40 1.5.3 To characterise
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