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Understanding and Engineering the Factors That Control Fatty Acid Biosynthesis in Escherichia Coli

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Understanding and Engineering the Factors That Control Fatty Acid Biosynthesis in Escherichia Coli UNDERSTANDING AND ENGINEERING THE FACTORS THAT CONTROL FATTY ACID BIOSYNTHESIS IN ESCHERICHIA COLI DANIELLE GALLAGHER IMPERIAL COLLEGE LONDON, DEPARTMENT OF LIFE SCIENCES THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY OF THE UNIVERSITY OF LONDON, IMPERIAL COLLEGE LONDON 2018 I declare that this thesis is my own work and that it has not been submitted anywhere for any award. Where other sources of information have been used, they have been acknowledged. 1 Copyright Declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work 2 ABSTRACT This research identified and characterised several genetic and environmental factors that contribute to controlling the metabolic flux through fatty acid synthesis (FAS) in Escherichia coli, to enable high yield in production of fatty acids (FA) which can be further processed towards industrially relevant commodity products. Due to their essentiality to growth, high energy and carbon investment, E. coli have evolved several mechanisms that tightly coordinate FAS with phospholipid synthesis and the energy status of the cell. This makes the outcome of systematic engineering manipulations difficult to predict, but is an area of research that benefits greatly from computationally driven solutions that can be gained from modelling metabolism. In order to model metabolism effectively, parameters of the kinetic system must be obtained and enable subsequent associations with in vivo metabolism and physiology. To adequately make this association, mathematical formulas describing biochemical pathways must account for the control and regulation the system is subject to, so that metabolic engineers can design towards specific phenotypes and product yield. This work investigated FAS regulation under a range of perturbations and how the system responds in vivo to these changes, to gain insight into the control and regulations that are in place during fluctuating conditions. Furthermore, the experiments of this study found adaptive evolution to FA to be a promising strategy in complementing a directed engineering approach in E. coli, in order to adapt to the burden that presents itself during FA overproduction. As a directed approach towards FA overproduction, three novel bypass routes to malonyl-CoA production were also investigated, and found to improve in vivo rates of malonyl-CoA. However, improving this rate-limiting step alone was not sufficient for to overcome the native regulatory and energetic limitations that are present in FAS. The bypass routes were therefore combined with specific process optimisations identified during this research, which was found to improve yield compared to non-optimised cultivations. 3 ACKNOWLEDGEMENTS First and foremost, I would like to thank my supervisor Dr Patrik Jones, for giving me the opportunity to work in the MME lab, for his collaboration and the discussions that went into shaping this research and for the support it took to complete. Thanks to Paulina for the lab chats, Queenie for being a kind and funny bench mate, John and Ian for reading and giving valuable feedback on the thesis and being supportive in answering many questions over the years. My thanks also go to James Mansfield for his support and guidance during the work conducted at the bioreactor suite, and Mark Bennet for technical support of the LC-MS work. I am thankful to my PRP panel Prof Anne Dell and Prof Mark Isalan for their invaluable feedback in the beginning and throughout the milestones of this PhD. To my student supervisions over the last three years for their invaluable discussions around this research. Special thanks to Dr. Danielle Belgrave for being a wonderful mentor and friend to me at Imperial, and for the inspiring lunch time retreats. I am thankful for my family who have shaped me as a person, and given me my perspective on life. Páidín, Mícheál and Alex, thank you for the happy memories and the humour that kept me going here. I am so lucky and proud to have you as my brothers. My mother Mary, thank you for everything you’ve given and done for me over my whole life, for supporting, guiding and consoling me over the last three years - for being my friend and for motivating me. My father Danny, thank you for always encouraging my interests, for not letting me give up, and for giving me a healthy dose of ambition my whole life. I could never thank you enough for giving me the foundations to pursue this career. To my other family, my framily in London and Ireland, thank you for the canal cans, Toy Shows, critical masses, emergency pints, birthdays, Christmas curries, soul- soothing brunches and stitch and bitch nights. Thanks for keeping it light and for simply being around over the years. Your friendships have meant the world to me. Thanks to Lia my furry writing companion for the cuddles and scratches. 4 Finally, an infinite gratitude and love to Jimmer, mo chroí, mo solas ’s mo shaol. Thank you for brightening my life and bringing me so much joy. I could not have finished this PhD without you. The words of this thesis are dedicated to you, our life together and our future. Is tú mo chúis <3 5 TABLE OF CONTENTS Abstract .............................................................................................................................. 3 Acknowledgements ............................................................................................................ 4 Table of contents ................................................................................................................ 6 List of figures .................................................................................................................... 10 List of tables ..................................................................................................................... 17 Abbreviations ................................................................................................................... 17 1 General Introduction ..................................................................................................... 20 1.1 Motivation and background .................................................................................... 20 1.2 Microbial commodity chemical production ............................................................. 26 1.3 Renewable fatty acid synthesis ............................................................................... 29 1.4 Fatty acid biosynthesis and degradation pathways in E. coli .................................... 31 1.5 The regulation of fatty acid synthesis in E. coli ........................................................ 35 1.6 Phospholipid and cell membrane synthesis ............................................................. 41 1.7 The contribution of central carbon metabolism toward fatty acid synthesis ........... 43 1.8 The use of predictive modelling to guide and inform fatty acid research ................. 46 1.9 Current practices and yields in engineering E. coli for fatty acid overproduction ..... 49 1.10 Objective of research ............................................................................................ 53 2 Materials and Methods ................................................................................................. 55 2.1 Media preparation and buffers ............................................................................... 55 2.2 Microbiological techniques ..................................................................................... 56 Sterile technique ............................................................................................................... 56 Frozen glycerol stocks ....................................................................................................... 56 Strains ............................................................................................................................... 56 Batch cultivation conditions ............................................................................................. 57 Continuous cultivation in 1.5L bioreactor ........................................................................ 58 Continuous cultivation in turbidostats ............................................................................. 59 Preparation of competent cells ........................................................................................ 60 Transformation of E. coli .................................................................................................. 60 6 Quantification of cell culture density ............................................................................... 60 Growth assays ................................................................................................................... 61 2.3 Molecular biological techniques .............................................................................. 61 Plasmids ............................................................................................................................ 61 Primers .............................................................................................................................
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