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  • Journal article
    Wright MH, Clough B, Rackham MD, Kaveri R, Brannigan J, Grainger M, Moss DK, Bottrill AR, Heal WP, Broncel M, Serwa RA, Brady D, Mann DJ, Leatherbarrow RJ, Tewari R, Wilkinson AJ, Holder AA, Tate EWet al., 2013,

    Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach

    , Nature Chemistry, Vol: 6, Pages: 112-121, ISSN: 1755-4349

    Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase.

  • Journal article
    Poulin B, Patzewitz E-M, Brady D, Silvie O, Wright MH, Ferguson DJP, Wall RJ, Whipple S, Guttery DS, Tate EW, Wickstead B, Holder AA, Tewari Ret al., 2013,

    Unique apicomplexan IMC sub-compartment proteins are early markers for apical polarity in the malaria parasite

    , Biology Open, Vol: 2, Pages: 1160-1170, ISSN: 2046-6390

    The phylum Apicomplexa comprises over 5000 intracellularprotozoan parasites, including Plasmodium and Toxoplasma,that are clinically important pathogens affecting humans andlivestock. Malaria parasites belonging to the genusPlasmodium possess a pellicle comprised of a plasmalemmaand inner membrane complex (IMC), which is implicated inparasite motility and invasion. Using live cell imaging andreverse genetics in the rodent malaria model P. berghei, welocalise two unique IMC sub-compartment proteins (ISPs)and examine their role in defining apical polarity duringzygote (ookinete) development. We show that these proteinslocalise to the anterior apical end of the parasite where IMCorganisation is initiated, and are expressed at alldevelopmental stages, especially those that are invasive.Both ISP proteins are N-myristoylated, phosphorylated andmembrane-bound. Gene disruption studies suggest that ISP1is likely essential for parasite development, whereas ISP3 isnot. However, an absence of ISP3 alters the apical localisationof ISP1 in all invasive stages including ookinetes andsporozoites, suggesting a coordinated function for theseproteins in the organisation of apical polarity in the parasite.

  • Journal article
    Alibhai D, Kelly DJ, Warren S, Kumar S, Margineau A, Serwa RA, Thinon E, Alexandrov Y, Murray EJ, Stuhmeier F, Tate EW, Neil MAA, Dunsby C, French PMWet al., 2013,

    Automated fluorescence lifetime imaging plate reader and its application to Forster resonant energy transfer readout of Gag protein aggregation

    , Journal of Biophotonics, Vol: 6, Pages: 398-408, ISSN: 1864-0648

    Fluorescence lifetime measurements can provide quantitativereadouts of local fluorophore environment andcan be applied to biomolecular interactions via Fo¨ rsterresonant energy transfer (FRET). Fluorescence lifetimeimaging (FLIM) can therefore provide a high contentanalysis (HCA) modality to map protein-protein interactions(PPIs) with applications in drug discovery, systemsbiology and basic research. We present here an automatedmultiwell plate reader able to perform rapid unsupervisedoptically sectioned FLIM of fixed and livebiological samples and illustrate its potential to assayPPIs through application to Gag protein aggregationduring the HIV life cycle. We demonstrate both heteroFRETand homo-FRET readouts of protein aggregationand report the first quantitative evaluation of a FLIMHCA assay by generating dose response curves throughaddition of an inhibitor of Gag myristoylation. Z0 factorsexceeding 0.6 are realised for this FLIM FRET assay.Fluorescence lifetime plate map with representativeimages of high and low FRET cells and correspondingdose response plot.

  • Journal article
    Tate EW, Bell AS, Rackham MD, Wright AHet al., 2013,

    N- Myristoyltransferase as a potential drug target in malaria and leishmaniasis

    , Parasitology, Vol: 141, Pages: 37-49, ISSN: 1469-8161

    Infections caused by protozoan parasites are among the most widespread and intractable transmissible diseases affecting the developing world, with malaria and leishmaniasis being the most costly in terms of morbidity and mortality. Although new drugs are urgently required against both diseases in the face of ever-rising resistance to frontline therapies, very few candidates passing through development pipelines possess a known and novel mode of action. Set in the context of drugs currently in use and under development, we present the evidence for N-myristoyltransferase (NMT), an enzyme that N-terminally lipidates a wide range of specific target proteins through post-translational modification, as a potential drug target in malaria and the leishmaniases. We discuss the limitations of current knowledge regarding the downstream targets of this enzyme in protozoa, and our recent progress towards potent cell-active NMT inhibitors against the most clinically-relevant species of parasite. Finally, we outline the next steps required in terms of both tools to understand N-myristoylation in protozoan parasites, and the generation of potential development candidates based on the output of our recently-reported high-throughput screens.

  • Journal article
    Storck EM, Serwa RA, Tate EW, 2013,

    Chemical proteomics: a powerful tool for exploring protein lipidation

    , Biochemical Society Transactions, Vol: 41, Pages: 56-61, ISSN: 1470-8752

    The study of post-translational modifications such as protein lipidation is a non-trivial challenge of the post-genomic era. In recent years the field of chemical proteomics has greatly advanced our ability to identify and quantify protein lipidation. In the present review, we give a brief overview of the tools available to study protein acylation, prenylation and cholesterylation, and their application in the identification and quantification of protein lipidation in health and disease.

  • Journal article
    Rackham MD, Brannigan JA, Moss DK, Yu Z, Wilkinson AJ, Holder AA, Tate EW, Leatherbarrow RJet al., 2013,

    Discovery of Novel and Ligand-Efficient Inhibitors of <i>Plasmodium falciparum</i> and <i>Plasmodium vivax N</i>-Myristoyltransferase

    , JOURNAL OF MEDICINAL CHEMISTRY, Vol: 56, Pages: 371-375, ISSN: 0022-2623
  • Journal article
    Douse CH, Green JL, Salgado PS, Simpson PJ, Thomas JC, Langsley G, Holder AA, Tate EW, Cota Eet al., 2012,

    Regulation of the Plasmodium motor complex: phosphorylation of myosin A tail-interacting protein (MTIP) loosens its grip on MyoA.

    , Journal of Biological Chemistry, Vol: 287, Pages: 36968-36977, ISSN: 1083-351X

    Background: Recent phosphoproteome data reveal the extent of post-translational phosphorylation in selected apicomplexanparasites.Results: Binding site mutants that mimic the effect of MTIP phosphorylation in vivo severely decrease MyoA binding.Conclusion: Phosphorylation of selected binding site residues modulates the activity of the actomyosin motor.Significance: Study of Apicomplexa phosphosites can inform on the regulation of functions involved in pathogenesis.

  • Journal article
    Yu Z, Brannigan JA, Moss DK, Brzozowski AM, Wilkinson AJ, Holder AA, Tate EW, Leatherbarrow RJet al., 2012,

    Design and Synthesis of Inhibitors of Plasmodium falciparum N-Myristoyltransferase, A Promising Target for Antimalarial Drug Discovery

    , Journal of Medicinal Chemistry, Vol: 55, Pages: 8879-8890, ISSN: 0022-2623

    Design of inhibitors for N-myristoyltransferase (NMT), an enzyme responsible for protein trafficking in Plasmodium falciparum, the most lethal species of parasites that cause malaria, is described. Chemistry-driven optimization of compound 1 from a focused NMT inhibitor library led to the identification of two early lead compounds 4 and 25, which showed good enzyme and cellular potency and excellent selectivity over human NMT. These molecules provide a valuable starting point for further development.

  • Journal article
    Thinon E, Mann D, Tate EW, 2012,

    Targeting N-myristoyl transferase-1 in cancer using peptide microarrays

    , Journal of Peptide Science, Vol: 18, Pages: S75-S75, ISSN: 1099-1387
  • Journal article
    Price HP, Hodgkinson MR, Wright MH, Tate EW, Smith BA, Carrington M, Stark M, Smith DFet al., 2012,

    A role for the vesicle-associated tubulin binding protein ARL6 (BBS3) in flagellum extension in Trypanosoma brucei

    , Biochimica et Biophysica Acta-Molecular Cell Research, Vol: 1823, Pages: 1178-1191, ISSN: 0167-4889

    The small GTPase Arl6 is implicated in the ciliopathic human genetic disorder Bardet–Biedl syndrome, actingat primary cilia in recruitment of the octomeric BBSome complex, which is required for specific traffickingevents to and from the cilium in eukaryotes. Here we describe functional characterisation of Arl6 in the flagellatedmodel eukaryote Trypanosoma brucei, which requires motility for viability. Unlike human Arl6 whichhas a ciliary localisation, TbARL6 is associated with electron-dense vesicles throughout the cell body followingco-translational modification by N-myristoylation. Similar to the related protein ARL-3A in T. brucei, modulationof expression of ARL6 by RNA interference does not prevent motility but causes a significant reductionin flagellum length. Tubulin is identified as an ARL6 interacting partner, suggesting that ARL6 may act as ananchor between vesicles and cytoplasmic microtubules. We provide evidence that the interaction betweenARL6 and the BBSome is conserved in unicellular eukaryotes. Overexpression of BBS1 leads to translocationof endogenous ARL6 to the site of exogenous BBS1 at the flagellar pocket. Furthermore, a combination ofBBS1 overexpression and ARL6 RNAi has a synergistic inhibitory effect on cell growth. Our findings indicatethat ARL6 in trypanosomes contributes to flagellum biogenesis, most likely through an interaction with theBBSome

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