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Inhibition and Reaction Mechanism of Mycobacterium Tuberculosis Anthranilate Phosphoribosyltransferase

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Inhibition and Reaction Mechanism of Mycobacterium Tuberculosis Anthranilate Phosphoribosyltransferase Inhibition and reaction mechanism of Mycobacterium tuberculosis anthranilate phosphoribosyltransferase A potential target for novel drug design Preeti Kundu A thesis submitted to Victoria University of Wellington in fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry Supervisor: Prof. Emily Parker Co-supervisor: Prof. Peter Tyler 2020 2 Abstract Tuberculosis (TB), which is estimated to affect 2 billion individuals worldwide, is an infection predominately caused by Mycobacterium tuberculosis (M. tuberculosis). Of particular concern is the increasing prevalence of TB, which is becoming resistant to the treatments currently available. Anthranilate phosphoribosyltransferase (AnPRT) catalyses the formation of N-(5’- phosphoribosyl)anthranilate (PRA) from 5-phospho-α-ribose-1-diphosphate (PRPP) and anthranilate and plays an important role in the synthesis of an essential amino acid in M. tuberculosis. A strain with a genetic knockout of the trpD gene, which encodes for the AnPRT enzyme, was unable to cause disease, even in immune-deficient mice. Therefore, this enzyme is a potential drug target for the development of new treatments against TB and other infectious diseases. This research explores the synthesis of different substrates and potential transition state analogues in order to understand catalysis and inhibition of AnPRT enzymes to aid novel drug design. The first part of this study utilises “bianthranilate-like” phosphonate inhibitors that display effective inhibition of the AnPRT enzyme, with the lowest Ki value being 1.3 μM. It was found strong enzymatic inhibition increases with an increased length of the phosphonate linker that occupies multiple anthranilate binding sites within the anthranilate binding channel of the enzyme. Crystal studies of the enzyme in complex with the inhibitors were carried out in order to expose the binding interactions. The second part of this study investigates several new compounds that target the active site of M. tuberculosis AnPRT, based on a virtual screening approach. This approach identified a strong AnPRT inhibitor, which displays an apparent Ki value of 7.0 ± 0.4 μM with respect to both substrates. This study also exposed a conformational change at the active site of the enzyme that occurs on inhibitor binding. The observed conformational changes of the enzyme active site diminish the binding of the substrate PRPP. These pieces of information provide future inhibitor design strategies to aid the development of novel anti-TB agents that target the AnPRT enzyme. To elucidate the reaction mechanism of M. tuberculosis AnPRT, the third part of this study explores the substrate binding sites in detail. This study uses structural analysis, i complemented by differential scanning fluorimetry (DSF) and isothermal titration calorimetry (ITC), to reveal detailed information of the substrate and inhibitor binding sites. The final part of this thesis presents the synthesis of various PRPP analogues and potential transition state mimics that were designed based on the likely reaction mechanism of the enzyme. This set of inhibitors includes a number of iminoribitol analogues that were developed to capture the geometry of the flattened ribose ring and include a nitrogen atom within the ring to mimic the positive charge characteristics that are expected in the oxocarbenium-ion-like transition state predicted for M. tuberculosis AnPRT. Additionally, we were able to solve the structure of M. tuberculosis AnPRT in complex with one of the potential transition state mimics, which was observed to bind at the active site of the enzyme. This structure provides new insight into the catalytic mechanism of the enzyme and creates an opportunity to develop more specific inhibitors against the M. tuberculosis AnPRT enzyme. ii Acknowledgements Many people need to be acknowledged for their unique, direct or indirect, contributions to the work presented in this thesis. First and foremost, I would like to thank Professor Emily Parker for believing in me and for giving me the opportunity to work with you. I have been very grateful for your guidance and support during the toughest time of my life. Thank you for always having an open door when I needed your help with any issues, science and unrelated. Your passion, hard work and dedication to science is really inspiring. In addition, I would like to thank my co-supervisor, Professor Peter Tyler, for your support, calmly chat and your knowledge of anything related to the synthesis of transition state analogues. Thank you to past and present members of the Parker research group, particularly to Dr Gerard Johan Moggré (GJ) whose work this thesis builds upon in many places. Thank you, GJ for the knowledgeable chat and teaching me the ways of the synthetic chemistry laboratory. To Dr Yu Bai, thank you for making the biochemistry lab a fun place to work with your music. I value your ability to critically discuss results and general insightful discussions of science, history, country and many other interesting topics in coffee breaks. A big thank you to Dr Wanting Jiao for introducing me docking and providing reviews and valuable advice. Many thanks to Dr Oliver Sterritt for the detailed review of my thesis, introducing me to the Australian Synchrotron and for taking my samples there. Many thanks to Rudranuj Bundela (Rudy) for all of our pleasant or unpleasant debates about research and other subjects, which really has broadened my perspective. Calling me “big sister” means a lot to me. You have helped me a lot to get through the difficult times by discussing issues and providing me with valuable advice. An enormous thank you to Parastoo and Mohammad for all the special memories, help and chat. It has been fantastic to have gone through the PhD experience with both of you. Thank you, Leyla and Candice for making the lab a pleasant place to work. Thank you, Davey Lim, Govind Pratap, Effie, Sarah Kessans, Nicky, Kyle, Rose, Gerd Mittelstädt and Rosannah Cameron for all of your help and insightful discussion. I would also like thank to Amelia, Matt, iii Wayne, Marie and Ian, the technicians from the University of Canterbury and Victoria University of Wellington. Thank you to the Biomolecular Interaction Centre, Department of Chemical and Physical Science at the University of Canterbury for financial support and Victoria University of Wellington for my doctoral scholarship and travel funding to attend conferences. Also, to the Ferrier Research Institute for proving all of the facilities required to carry out this work. To my family and friends, thank you for the support you have given me. In particular, this thesis would not have been here without the continuing support of my husband Sandeep. Thank you for motivating me and believing in me when the science and times were hard. Your encouragement brings out the best in me! Lots of love to my lovely kids Pari and Samar Veer. Pari used to say to me “I hope mama you will finish your PhD soon so then you can play with me”. Finally, the day has come, thanks for being so kind. Lastly, I want to dedicate my thesis to my father and brother. Losing both of them in the last two years has been an incalculable lasting blow. They will be forever missed. iv Table of content Abstract ............................................................................................................................ i Acknowledgements ......................................................................................................... iii Table of content ............................................................................................................... v List of Figures ................................................................................................................. xii List of Tables ................................................................................................................. xvii Abbreviations ................................................................................................................. xix Chapter 1 Introduction .................................................................................................... 1 1.1 Enzymes ........................................................................................................................... 2 1.2 Mycobacterium tuberculosis ........................................................................................... 2 1.3 Tuberculosis ..................................................................................................................... 3 1.4 New anti-TB drugs ........................................................................................................... 5 1.4.1 SQ109 ......................................................................................................................... 5 1.4.2 TMC207 ...................................................................................................................... 6 1.4.3 OPC-67683 ................................................................................................................. 6 1.5 Amino acid biosynthesis as a drug target........................................................................ 7 1.6 Tryptophan biosynthesis ................................................................................................. 9 1.7 Classification of the phosphoribosyltransferase family ................................................ 10 1.8 Anthranilate phosphoribosyltransferase .....................................................................
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