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Characterisation of the Biosynthetic Pathway of a Tripyrrolic Secondary Metabolite, Prodigiosin

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Characterisation of the Biosynthetic Pathway of a Tripyrrolic Secondary Metabolite, Prodigiosin Maxime Pierre Fabrice Couturier Substrate elucidation and mutasynthesis: Characterisation of the biosynthetic pathway of a tripyrrolic secondary metabolite, prodigiosin This dissertation is submitted for the degree of Doctor of Philosophy University of Cambridge Clare College September 2019 Preface Declaration I hereby declare that: This thesis is the result of my own work and includes nothing which is the outcome of work done in collaboration except as declared in the Preface and specified in the text. This thesis is not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or qualification at the University of Cambridge or any other University. I further state that no substantial part of my thesis has already been submitted , or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Cambridge or any other University or similar institution. This dissertation does not exceed 60,000 words, including abstract, tables, and footnotes, but excluding table of contents, diagrams, figure captions, list of abbreviations, bibliography, appendices and acknowledgements. Maxime Couturier Cambridge, September 2019 i Preface Abstract Substrate elucidation and mutasynthesis: Characterisation of the biosynthetic pathway of a tripyrrolic secondary metabolite, prodigiosin Maxime Pierre Fabrice COUTURIER A wide variety of biological activity can be found in the realm of secondary metabolites. The tripyrrole prodigiosin illustrates this perfectly with activities ranging from antimicrobial to immunosuppressive and anticancer. Microorganisms producing the red pigment prodigiosin were first isolated more than 150 years ago. Yet, its structure was only elucidated in the 1960s and the biosynthetic pathway remained mainly unknown until the 2000s. This secondary metabolite results from a bifurcated pathway where monopyrrole 2-methyl-3-pentyl-1H-pyrrole (MAP) and bipyrrole 4-methoxy-1H,1'H-2,2'-bipyrrole (MBC) are produced independently before condensation. As MBC is an intermediate in the synthesis of other natural products, the enzymes involved in its formation have been well characterised. In contrast, the three enzymes – PigD, PigE and PigB – involved in the formation of MAP are specific to the biosynthesis of prodigiosin and less is known about them. This thesis focuses on the latter two enzymes. PigE was first described as a transaminase catalysing the transformation of 3-acetyloctanal into 3-acetyloctylamine (which cyclises to form dihydroMAP) and this activity has been confirmed by feeding intermediates to various gene-knockout strains. However, in vitro studies have demonstrated that 3-acetyloctanal could not be the product of PigD. In addition, bioinformatics analysis of its amino acid sequence showed that PigE has two domains: a transaminase C- terminal moiety and an unspecified N-terminal one, which we propose is a thioester reductase that converts a 3-acetyloctanoyl thioester to 3-acetyloctanal. Attempted chemical complementation of a pigD-knockout strain of Serratia using synthetic thioester, carboxylic acid and aldehyde substrates showed that both the thioester and the aldehyde can be used for pigment production, indicating that a thioester reductase is involved in prodigiosin biosynthetic pathway. Furthermore, the PigE protein was expressed in a heterogeneous host, purified and submitted to a number of activity and kinetic assays, which demonstrated that it can reduce a 3-acetyloctanoyl thioester substrate. The oxidation of dihydroMAP to MAP had previously been shown to be catalysed by an FAD- dependent oxidase PigB. The kinetics of HapB, a homologue of PigB had been studied by a previous group member. To take this project further we studied the substrate flexibility of the ii Preface enzyme and used it to form new analogues of prodigiosin by mutasynthesis. Ten analogues of dihydroMAP with modifications either in the C2 or C3 positions were synthesised. Both extensions and truncations in the length of the chain at the C3 position could be accepted, whereas alkyl chains longer than 3 carbons on the C2 position could not be accommodated. Similar results were found in vivo when the analogues were fed to a pigD-knockout strain of Serratia, showing that PigB and the condensing enzyme PigC shared similar flexibility. Eight analogues of prodigiosin were hence obtained and their antimicrobial activities against Gram- positive and Gram-negative bacteria were assessed. iii Preface iv Preface Acknowledgement I would like to take this opportunity to express my gratitude to my supervisor Dr. Finian J. Leeper. Not only did he guide me through these four years, but he also always encouraged me to give my best in everything. I would also like to thank him for the time he spent proof-reading this work and the other reports I submitted over the years. I would also like to thank Prof. George P.C. Salmond for welcoming me in his lab in the Biochemistry Department and useful input all along this project. I am also extremely grateful to the Frances and Augustus Newman foundation and the BBSRC DTP for funding this PhD. Nothing would have been possible without them. A big thanks to the members of both labs for their support and friendship. In particular, I would like to thank Dr Rita Monson, who taught me microbiology and molecular biology with a rare patience and Dr Annabel Murphy for her all her helpful inputs and advice. A great thank you as well to Dr Emma Radoux and Flaviu Bulat who welcomed me in the Leeper lab and took the time to make sure I was starting off on the right foot, and to Danny Parle, Matt Corney and Alex Chan for bearing me in the last year. I also would like to thank my academic mentor, Dr Anthony Coyne who was always there when I needed support or advice. A great thank you also to the technical teams both in the Chemistry and Biochemistry departments: research would not be possible without you! I feel extremely fortunate to have spent the past few years as part of the University of Cambridge and Clare College. This place gathers brilliant minds from all imaginable backgrounds – who would have thought you could do a PhD in music – to form one of the most stimulating environments I have ever encountered. I would also like to take this opportunity to thank Prof. Sam Zard who taught me chemistry in the Ecole Polytechnique and without whom I probably would not be here today. A warm thank you to my family for their constant support. To my parents for always finding ways to motivate me and to put things in perspective. To my brothers, whose role in this project I am still trying to determine, but it was certainly crucial. Finally, a grand merci to Vinny, well, for everything… Pour la patrie, Les sciences Et la gloire v Preface Table of contents Declaration ........................................................................................................................................ i Abstract ............................................................................................................................................ ii Acknowledgement ............................................................................................................................ v Table of contents .............................................................................................................................vi List of abbreviations ........................................................................................................................xi Chapter 1. Prodigiosin: structure, synthesis and biosynthesis ........................................................ 1 1. Structure of prodiginines ...................................................................................................... 1 2. Discovery and elucidation of the structure of prodigiosin .................................................. 3 3. Elucidation of prodigiosin biosynthetic pathway ............................................................... 5 3.1. Biosynthesis of MBC24,31 .................................................................................................7 3.2. Biosynthesis of MAP 9 .................................................................................................. 9 3.3. Biosynthesis of 2-undecylpyrrole 13 ............................................................................. 11 3.4. Condensation: PigC ..................................................................................................... 12 3.5. Formation of cyclized prodiginines ............................................................................ 13 4. Related compounds ............................................................................................................. 13 4.1. Marineosin ................................................................................................................... 13 4.2. Roseophilin .................................................................................................................. 14 4.3. Tambjamines ............................................................................................................... 15 5. Biological properties of prodiginines ................................................................................. 16 5.1. Antimalarial ................................................................................................................. 16 5.2. Antifungal ...................................................................................................................
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