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Guanine Phosphoribosyltransferase of Helicobacter Pylori As a Potential Therapeutic Target

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Guanine Phosphoribosyltransferase of Helicobacter Pylori As a Potential Therapeutic Target CHARACTERISATION OF THE XANTHINE- GUANINE PHOSPHORIBOSYLTRANSFERASE OF HELICOBACTER PYLORI AS A POTENTIAL THERAPEUTIC TARGET Megan Jane Duckworth A thesis submitted in fulfilment of the requirements of the degree of Doctor of Philosophy School of Medical Sciences, Faculty of Medicine, The University of New South Wales 2008 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: DUCKWORTH First name: MEGAN Other name/s:JANE Abbreviation for degree as given in the University calendar: 1780 School: MEDICAL SCIENCES (PATHOLOGY) Faculty: MEDICINE Title: CHARACTERISATION OF THE XANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE OFHELICOBACTER PYLORI AS A POTENTIAL THERAPEUTIC TARGET Abstract 350 words maximum: (PLEASE TYPE) Helicobacter pylori infects more than half of the global population and causes gastric disorders. The increasing development of antibiotic resistance by the bacterium continues to limit treatment options. The identification and characterisation of novel therapeutic targets are necessary for successful future treatment of the infection. One potential target for therapeutic intervention is the gpt gene encoded by hp0735 (jhp0672) in H. pylori strain 26695 (J99). This gene produces a putative xanthine-guanine phosphoribosyltransferase (XGPRTase), an enzyme of the purine salvage synthesis pathway. This project employed theoretical, molecular and biochemical approaches to investigate features of H. pylori gpt and XGPRTase that will serve to ascertain their therapeutic potential. The production of a functional XGPRTase by H. pylori was investigated in cell-free extracts, and the kinetic parameters of this activity were compared to those of purified rXGPRTase enzyme. The three 6-oxopurine substrates were recognised by rXGPRTase and allosteric kinetics were observed for some substrates of the enzyme in cell-free extracts and for purified enzyme. These observations indicate complex regulation and an influence of cellular interactions on activity. Bioinformatics were employed to analyse XGPRTase phylogeny, and threading techniques used to build a structural model of XGPRTase. The enzyme is significantly divergent from the equivalent mammalian enzyme, and modelling identified specific features of the enzyme. Molecular approaches were utilised to analyse the essential role of gpt in H. pylori survival. These included insertional inactivation of the gpt in wild-type H. pylori strains and in mutants possessing a complementing copy of the gene present at the rdxA locus. No mutants were recovered with inactivated gpt possibly as a result of pleiotropic effects. Plasmid-mediated complementation was attempted employing IPTG-inducible shuttle vectors and did not yield any mutants. Further characterisation of H. pylori XGPRTase was performed by determining the effects of nucleotide monophosphates and purine analogues on enzyme activity. Inhibition by GMP was observed in all cases, however differences in the inhibition by other nucleotide monophosphates were found between cell-free extracts and the recombinant enzyme. Inhibition of rXGPRTase activity was observed by the purine analogue 6-mercaptopurine ribose, a compound that previously has been shown to inhibit H. pylori growth in culture. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). …………………………………………………………… ……………………………………..……………… ……….……………………...……. Signature Witness … Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….............. COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' Signed ……………………………………………........................... Date ……………………………………………........................... AUTHENTICITY STATEMENT ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format.’ Signed ……………………………………………........................... Date ……………………………………………........................... Acknowledgements I would like to express my gratitude to my supervisor Associate Professor George L. Mendz. You support throughout my project at times exceeded my expectations of a supervisor and I am grateful that whenever possible you helped me to see that I was capable of so much more than I thought. To Professor Hazel Mitchell and Dr Jani O’Rourke, your help in the field has been fantastic and greatly appreciated. You both represented everything that was good about the school of Biotechnology and Biomolecular Sciences and when nobody else would provide space or the time of day, you did everything you could. Thanks goes also to Dr Andrew Harris for not only being my very first Microbiology tutor and inspiring me to keep exploring, but also for providing me with technical guidance and support during the early months of my research in the world of Helicobacter. To Dr Zsuzsanna Kovach and Edward Fox, you brought an international flare to the lab and your constant support will never be forgotten. My work would also not have been possible without the support and patience of the staff at the NMR facility, in particular Jim, Graeme and Hilda. You made me feel welcome in your world and never judged me for my microbiologist’s view on chemistry (or lack there of). To the students of lab 301, in particular Nadeem, Sophie, Alfred and Bernice. Your constant friendship and support has made this entire experience tolerable. Nadeem, thank you for the education in music (you tried at least) and the gifts from around the world, you always successfully made me jealous of your travels! To mum and dad; some people believe you are born with science in the blood, so I guess I should be thanking you for my passions and inquisitive nature. Thank you for always nurturing my curiosity. Thank you also for listening even when you didn’t completely understand and for I providing me with more support than I could bring myself to ask for. To Ewan, I envy you for breaking the mould but still displaying interest during dinner conversation. You make me laugh! I would like to dedicate this thesis to my late Grandmother, Edith, who constantly reminded me that education is one of the greatest privileges available and always spurred me to see just how much I could achieve. I hope that I have made you proud. II Publications and Conference Proceedings Duckworth M, Bergey B, Megraud F, Menard A, Mendz G. L. The xanthine-guanine phosphoribosyltransferase of H. pylori: a potential therapeutic target. European Helicobacter Study Group (EHSG) conference, Vienna, Austria, 2004. Helicobacter 9:487-491. Poster presentation. Duckworth M, Bergey B, Megraud F, Menard A, Mendz G. L. The xanthine-guanine phosphoribosyltransferase of H. pylori. Australian Society of Microbiology (ASM)
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