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Metabolite Transport Pathways of Plasmodium Falciparum

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Metabolite Transport Pathways of Plasmodium Falciparum METABOLITE TRANSPORT PATHWAYS OF PLASMODIUM FALCIPARUM Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor in Philosophy by Susan Elizabeth Beveridge May 2012 DECLARATION This thesis is the result of my own work. The material contained in the thesis has not been presented, nor is currently being presented, either wholly or in part for any other degree or other qualification Susan E. Beveridge This research was canied out in the Department of Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, The University of Liverpool rr ACKNOWLEDGEMENTS I would like to thank my supervisors Dr. Pat Bray, Prof. Steve Ward and Dr. Giancarlo Biagini for their support and guidance throughout my work. The work canied out in this thesis would not have been possible without the technical help and valuable advice provided by Dr. Enrique Salcedo Sora. I would also like to thank the staff and students of the Molecular and Biochemical Parasitology group for then advice and support during my hours spent in the lab. This work was supported by a BBSRC doctoral training grant. ABSTRACT Susan Beveridge - Metabolite Transport Pathways of Plasmodium falciparum Metabolite transport pathways of the malaria parasite, Plasmodium falciparum, are an important area for study in order to further the understanding of the parasite’s biology. Identification and characterisation of the transporters involved in these pathways may also provide potential novel drug targets or drug delivery mechanisms. This is especially valuable as chemotherapy remains one of the main management strategies in the fight against malaria and the usefulness of the current range of antimalarial drugs is seriously threatened by the emergence and spread of resistance. In this thesis the Xenopus laevis oocyte heterologous expression system was used to functionally characterise a gene-specific cDNA library of 48 putative membrane proteins and the previously annotated putative amino acid transporter PFF1430c for the uptake of several amino acids. This screening failed to identify any definite amino acid transport by the cDNA library or PFF 1430c, however tins could have been due to the fact that uptake of a relatively narrow range of amino acids was tested and these were used at concentrations lower than found physiologically. Inherent issues with the X. laevis expression system may also have been an issue, including the expression of endogenous transporters for the substrates being investigated. The uptake of methionine by intact infected RBCs and free P. falciparum parasites was also characterised. No increase in uptake by infected RBCs compared to uninfected RBCs was found, however this is an unexpected iv result compared to other nutrients and further experiments need to be carried out before any conclusion can be made. Methionine was found to be transported across the parasite plasma membrane via one or more saturable systems showing partial similarity to the vertebrate systems L- methionine influx into the free parasites was inhibited most effectively by cysteine and to a lesser degree by lysine and histidine. The whole cell membrane transport of substrates related to folate and methionine metabolism was studied using a pharmacological approach. pABA was the only folate substrate to antagonise sulphadoxine and pyrimethamine at physiological concentrations and growth assays with E. coli ApabA/AabgT expressing P. falciparum folate transporters PfFTl or PfFT2 also showed pABA to be the most efficient folate substrate at increasing bacterial growth. These results suggest that the folate precursor pABA may be the relevant natural folate intennediate substrate for the intraerythrocytic malaria parasite. This is an interesting observation as pABA is not significantly utilised or synthesised in humans making pABA salvage a potential target for chemotherapy. v CONTENTS ACKNOWLEDGEMENTS III ABSTRACT IV CONTENTS VI LIST OF FIGURES X LIST OF TABLES XIV PUBLICATIONS XV ABBREVIATIONS XVI CHAPTER I 1 INTRODUCTION 1 1.1 Malaria 1 1.1.1 Discovery of the Malaria Parasite 2 1.1.2 The Life Cycle of the Malaria Parasite 4 1.2 Malaria Management Strategies 6 1.2.1 Vector Control 6 1.2.2 Vaccine Development 8 1.2.3 Malaria Chemotherapy 10 1.3 P. falciparum Folate Pathway and Antimalarial Antifolates 19 1.3.1 De novo Folate Biosynthesis in P. falciparum 21 1.3.2 Folate Salvage by P. falciparum 24 1.3.3 Role of Folates in Pfalciparum 26 1.3.4 Antimalarial Antifolates 28 1.4 Membrane Transport Pathways of P. falciparum 34 1.4.1 Currently Identified P. falciparum Membrane Transporters 42 1.4.2 P. falciparum Membrane Transport Pathways as Drug Targets 48 1.4.3 P. falciparum Membrane Transport Pathways as Antimalarial Resistance Mediation Targets 51 1.4.4 Amino Acid Transport 52 vi 1.4.5 Amino Acid Transporter Gene Families 55 1.5 Aims of Thesis 72 CHAPTER 2 73 MATERIALS AND METHODS 73 2.1 Culturing of P. falciparum parasites in vitro 73 2.1.1 Prep aration o f Red Blood Cells 74 2.1.2 Preparation of Culture Media 74 2.1.3 Examination of Parasites and Calculation of Parasitaemia Using Giemsa Stained Slides 75 2.1.4 Synchronisation o f P arasite Cultures 76 2.1.5 Gassing o f Parasite Cultures 77 2.1.6 Cryopreservation of Parasites 77 2.1.7 Retrieval of Cryopreserved Parasites 77 2.2 Total ENA Extraction from P. falciparum Cultures 78 2.3 cDNA Synthesis from Total P. falciparum RNA 80 2.4 Genomic DNA Extraction from P. falciparum Cultures 81 2.5 Agarose Gel Electrophoresis 82 CHAPTER 3 84 XENOPUS LAEVIS OOCYTE SCREENING OF PUTATIVE P. FALCIPARUM AMINO ACID TRANSPORTERS 84 3.1 Introduction 84 3.2 Materials and Methods 90 3.2.1 Chemicals 90 3.2.2 Bioinformatics 90 3.2.3 Gene Specific cDNA Library 91 3.2.4 Cloning of PFF1430c, PFL0420w, PFL1515c, PFB0435c} PFE0775c, PF11_0334 101 3.2.5 X Laevis Oocyte Expression System 114 3.2.6 Statistical Analysis o f Results 122 3.3 Results 123 3.3.1 Functional characterisation of the gene-specific cDNA Library 123 3.3.2 Cloning of PFF1430c? PFL0420w, PFL1515c, PFB0435c, PFE0775C, PF11 _0334 141 vii 3.3.3 Functional characterisation of PFF1430c 145 3.4 Discussion 148 3.4.1 Critical Assessment 152 CHAPTER 4 163 METHIONINE TRANSPORT IN THE P. FALCIPARUM PARASITE 163 4.1 Introduction 163 4.2 Materials and Methods 165 4.2.1 Parasite Cultivation 165 4.2.2 Transport Assays In P. falciparum Parasitised Red Blood Cells 165 4.2.3 Transport Assays in Free P. falciparum Parasites 168 4.2.4 Statistical Analysis of Results 171 4.3 Results 172 4.3.1 Uptake of Methionine by P. falciparum Parasitised Human Red Blood Cells 172 4.3.2 Uptake of Methionine by free P. falciparum parasites 173 4.4 Discussion 182 4.4.1 Critical Assessment 186 CHAPTERS 192 ANTAGONISM OF THE NATURAL FOLATE PRECURSOR PARA-AMINOBENZOIC ACID ON THE ACTION OF ANTICANCER AND ANTIM ALARIAL ANTIFOLATES 192 5.1 Introduction 192 5. 2 Materials and Methods 198 5.2.1 Parasite Cultivation 198 5.2.2 Stocks of Inhibitors 199 5.2.3 Stocks of Folate Pathway Substrates 199 5.2.4 Parasite Inocula Preparation 200 52.5 In Vitro Sensitivity Assay 200 5.2.6 Determination of IC50 202 5.2.7 E. coli expression of PfFTl and PfFT2 and growth assays 203 5.2.8 Statistical Analysis of Results 205 5.3 Results 206 viii 5.3.1 Sulphadoxine Antagonism by Folate Substrates 206 5.3.2 Pyrimethamine Antagonism by Folate Substrates 208 5.3.3 Methotrexate Antagonism by Folate Substrates 210 5.3.4 Expression of PfFTl and PfFT2 in E. coli and Growth Rescue Experiments with Folate Substrates 212 5.4 Discussion 215 5.4.1 Critical Assessment 218 CHAPTER 6 221 6.1 GENERAL DISCUSSION 221 6.2 Future Work 231 REFERENCES 234 ix LIST OF FIGURES Figure 1.1 The spatial distribution of P. falciparum malaria 2 endemicity in 2007. Figure 1.2 The life cycle of the malaria parasite. 5 Figure 1.3 Structures of the 4-aminoquinolines, chloroquine (1) 13 and amodiaquine (2). Figure 1.4 Structures of the quinoline methanols, quinine (1) 15 and mefloquine (2). Figure 1.5 Structure of the bisquinoline, piperaquine. 17 Figure 1.6 Structures of artemisinin and the first generation 19 artemisinin analogues. Figure 1.7 Structures of folic acid (1), pteridine (2), pABA (3) 21 and glutamic acid (4). Figure 1.8 P. falciparum de novo folate biosynthesis pathway 25 and possible salvage routes. Figure 1.9 Folate-dependent reactions in P. falciparum. 27 Figure 1.10 Structures of DHFR inhibitors proguanil (1), 30 cycloguanil (2) and pyrimethamine (3). Figure 1.11 Structures of the DHPS inhibitors sulphadoxine (1) 32 and dapsone (2). Figure 1.12 Schematic illustration of the classes of transport 37 proteins and examples of parasite and host transport processes in Plasmodium infected RBCs. Figure 3.1 Schematic illustration of the Xenopus laevis oocyte 121 expression system. X Figure 3.2 Uptake of radiolabelled methionine, isoleucine and 126- leucine (A), glutamic acid, taurine and pantothenic 128 acid (B), and choline chloride and folic acid (C) in water-injected and group 1 to 6 cRNA injected oocytes. Figure 3.3 Uptake of radiolabelled methionine, isoleucine, and 130 taurine in water-injected and group 1 individual cRNA injected oocytes. Figure 3.4 Uptake of radiolabelled methionine plus competition 133 with 0.2 mM unlabelled methionine hi water-injected and gene 41 and gene 49 injected oocytes. Figure 3.5 Time course uptake of radiolabelled methionine in 134 water-injected and gene 41 cRNA injected oocytes. Figure 3.6 Uptake of radiolabelled glutamic acid, taurine and 136 pantothenic acid in water-injected and group 4 individual cRNA injected oocytes.
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