• [1]
    Tracy, S.M., and Sherman, I.W. (1972) Purine uptake and utilization by the avian malaria parasite Plasmodium lophurae. J. Protozool. 19, 541549.
  • [2]
    Bungener, W., and Nielsen, G. (1968) Nucleic acid metabolism in experimental malaria. 2. Incorporation of adenosine and hypoxanthine into the nucleic acids of malaria parasites (Plasmodium berghei and Plasmodium vinckei). Z. Tropenmed. Parasitol. 19, 185197.
  • [3]
    Hammond, D.J., and Gutteridge, W.E. (1984) Purine and pyrimidine metabolism in the Trypanosomatidae. Mol. Biochem. Parasitol. 13, 243261.
  • [4]
    Hassan, H.F., and Coombs, G.H. (1988) Purine and pyrimidine metabolism in parasitic protozoa. FEMS Microbiol. Rev. 4, 4783.
  • [5]
    Ullman, B., and Carter, D. (1995) Hypoxanthine–guanine phosphoribosyltransferase as a therapeutic target in protozoal infections. Infect. Agents Dis. 4, 2940.
  • [6]
    Aronov, A.M., Munagala, N.R., Ortiz De Montellano, P.R., Kuntz, I.D., and Wang, C.C. (2000) Rational design of selective submicromolar inhibitors of Tritrichomonas foetus hypoxanthine–guanine–xanthine phosphoribosyltransferase. Biochemistry 39, 46844691.
  • [7]
    Berens, R.L., Krug, E.C., and Marr, J.J. (1995) Purine and pyrimidine metabolism, In: Biochemistry and Molecular Biology of Parasites (Marr, J.J., Muller, M., Eds.), pp. 89117. Academic Press, London .
  • [8]
    De Koning, H.P., Al Salabi, M.I., Cohen, A.M., Coombs, G.H., and Wastling, J.M. (2003) Identification and characterisation of high affinity nucleoside and nucleobase transporters in Toxoplasma gondii. Int. J. Parasitol. 33, 821831.
  • [9]
    Ghosh, M., and Mukherjee, T. (2000) Stage-specific development of a novel adenosine transporter in Leishmania donovani amastigotes. Mol. Biochem. Parasitol. 108, 9399.
  • [10]
    Finley, R.W., Cooney, D.A., and Dvorak, J.A. (1988) Nucleoside uptake in Trypanosoma cruzi: analysis of a mutant resistant to tubercidin. Mol. Biochem. Parasitol. 31, 133140.
  • [11]
    De Koning, H.P., and Jarvis, S.M. (1998) A highly selective, high-affinity transporter for uracil in Trypanosoma brucei brucei: evidence for proton-dependent transport. Biochem. Cell Biol. 76, 853858.
  • [12]
    Cohn, C.S., and Gottlieb, M. (1997) The acquisition of purines by trypanosomatids. Parasitol. Today 13, 231235.
  • [13]
    Carter, N.S., Landfear, S.M., and Ullman, B. (2001) Nucleoside transporters of parasitic protozoa. Trends Parasitol. 17, 142145.
  • [14]
    Davey, R.A., Mayrhofer, G., and Ey, P.L. (1992) Identification of a broad-specificity nucleoside transporter with affinity for the sugar moiety in Giardia intestinalis trophozoites. Biochim. Biophys. Acta 1109, 172178.
  • [15]
    Davey, R.A., Ey, P.L., and Mayrhofer, G. (1991) Characteristics of thymidine transport in Giardia intestinalis trophozoites. Mol. Biochem. Parasitol. 48, 163171.
  • [16]
    Aronow, B., Kaur, K., McCartan, K., and Ullman, B. (1987) Two high affinity nucleoside transporters in Leishmania donovani. Mol. Biochem. Parasitol. 22, 2937.
  • [17]
    Hall, S.T., Odgers, G.A., and Gero, A.M. (1993) Nucleoside transport in Crithidia luciliae. Int. J. Parasitol. 23, 10391044.
  • [18]
    Carter, N.S., and Fairlamb, A.H. (1993) Arsenical-resistant trypanosomes lack an unusual adenosine transporter. Nature 361, 173176.
  • [19]
    De Koning, H.P., and Jarvis, S.M. (1997) Hypoxanthine uptake through a purine-selective nucleobase transporter in Trypanosoma brucei brucei procyclic cells is driven by protonmotive force. Eur. J. Biochem. 247, 11021110.
  • [20]
    De Koning, H.P., and Jarvis, S.M. (1997) Purine nucleobase transport in bloodstream forms of Trypanosoma brucei is mediated by two novel transporters. Mol. Biochem. Parasitol. 89, 245258.
  • [21]
    Sanchez, M.A., Tryon, R., Pierce, S., Vasudevan, G., and Landfear, S.M. (2004) Functional expression and characterization of a purine nucleobase transporter gene from Leishmania major. Mol. Membr. Biol. 21, 1118.
  • [22]
    Al Salabi, M.I., Wallace, L.J., and De Koning, H.P. (2003) A Leishmania major nucleobase transporter responsible for allopurinol uptake is a functional homolog of the Trypanosoma brucei H2 transporter. Mol. Pharmacol. 63, 814820.
  • [23]
    Hedstrom, L., and Wang, C.C. (1989) Purine base transport in wild-type and mycophenolic acid-resistant Tritrichomonas foetus. Mol. Biochem. Parasitol. 35, 219227.
  • [24]
    Day, R.E., and Gero, A.M. (1997) Stimulated transport of hypoxanthine in Crithidia luciliae: relationship to purine stress. Parasitology 114, 1927.
  • [25]
    Carter, N.S., Drew, M.E., Sanchez, M., Vasudevan, G., Landfear, S.M., and Ullman, B. (2000) Cloning of a novel inosine-guanosine transporter gene from Leishmania donovani by functional rescue of a transport-deficient mutant. J. Biol. Chem. 275, 2093520941.
  • [26]
    Vasudevan, G., Carter, N.S., Drew, M.E., Beverley, S.M., Sanchez, M.A., Seyfang, A., Ullman, B., and Landfear, S.M. (1998) Cloning of Leishmania nucleoside transporter genes by rescue of a transport-deficient mutant. Proc. Natl. Acad. Sci. USA 95, 98739878.
  • [27]
    Sanchez, M.A., Ullman, B., Landfear, S.M., and Carter, N.S. (1999) Cloning and functional expression of a gene encoding a P1 type nucleoside transporter from Trypanosoma brucei. J. Biol. Chem. 274, 3024430249.
  • [28]
    Mäser, P., Sütterlin, C., Kralli, A., and Kaminsky, R. (1999) A nucleoside transporter from Trypanosoma brucei involved in drug resistance. Science 285, 242244.
  • [29]
    Chiang, C.W., Carter, N., Sullivan, W.J. Jr., Donald, R.G., Roos, D.S., Naguib, F.N., El Kouni, M.H., Ullman, B., and Wilson, C.M. (1999) The adenosine transporter of Toxoplasma gondii. Identification by insertional mutagenesis, cloning, and recombinant expression. J. Biol. Chem. 274, 3525535261.
  • [30]
    Carter, N.S., Ben Mamoun, C., Liu, W., Silva, E.O., Landfear, S.M., Goldberg, D.E., and Ullman, B. (2000) Isolation and functional characterization of the PfNT1 nucleoside transporter gene from Plasmodium falciparum. J. Biol. Chem. 275, 1068310691.
  • [31]
    Parker, M.D., Hyde, R.J., Yao, S.Y., McRobert, L., Cass, C.E., Young, J.D., McConkey, G.A., and Baldwin, S.A. (2000) Identification of a nucleoside/nucleobase transporter from Plasmodium falciparum, a novel target for anti-malarial chemotherapy. Biochem. J. 349, 6775.
  • [32]
    Burchmore, R.J., Wallace, L.J., Candlish, D., Al Salabi, M.I., Beal, P.R., Barrett, M.P., Baldwin, S.A., and De Koning, H.P. (2003) Cloning, heterologous expression, and in situ characterization of the first high affinity nucleobase transporter from a protozoan. J. Biol. Chem. 278, 2350223507.
  • [33]
    Henriques, C., Sanchez, M.A., Tryon, R., and Landfear, S.M. (2003) Molecular and functional characterization of the first nucleobase transporter gene from African trypanosomes. Mol. Biochem. Parasitol. 130, 101110.
  • [34]
    Matovu, E., Stewart, M.L., Geiser, F., Brun, R., Mäser, P., Wallace, L.J., Burchmore, R.J., Enyaru, J.C., Barrett, M.P., Kaminsky, R., Seebeck, T., and De Koning, H.P. (2003) Mechanisms of arsenical and diamidine uptake and resistance in Trypanosoma brucei. Eukaryot. Cell 2, 10031008.
  • [35]
    Klenke, B., Stewart, M., Barrett, M.P., Brun, R., and Gilbert, I.H. (2001) Synthesis and biological evaluation of s-triazine substituted polyamines as potential new anti-trypanosomal drugs. J. Med. Chem. 44, 34403452.
  • [36]
    Tye, C.K., Kasinathan, G., Barrett, M.P., Brun, R., Doyle, V.E., Fairlamb, A.H., Weaver, R., and Gilbert, I.H. (1998) An approach to use an unusual adenosine transporter to selectively deliver polyamine analogues to trypanosomes. Bioorg. Med. Chem. Lett. 8, 811816.
  • [37]
    Soulere, L., Hoffmann, P., Bringaud, F., and Perie, J. (2000) Synthesis and uptake of nitric oxide-releasing drugs by the P2 nucleoside transporter in Trypanosoma equiperdum. Bioorg. Med. Chem. Lett. 10, 13471350.
  • [38]
    Stewart, M.L., Bueno, G.J., Baliani, A., Klenke, B., Brun, R., Brock, J.M., Gilbert, I.H., and Barrett, M.P. (2004) Trypanocidal activity of melamine-based nitroheterocycles. Antimicrob. Agents Chemother. 48, 17331738.
  • [39]
    Wallace, L.J., Candlish, D., and De Koning, H.P. (2002) Different substrate recognition motifs of human and trypanosome nucleobase transporters. Selective uptake of purine antimetabolites. J. Biol. Chem. 277, 2614926156.
  • [40]
    Papageorgiou, I.G., Yakob, L., Diallinas, G., Soteriadou, K.P., and De Koning, H.P. (2004) Identification of the first pyrimidine nucleobase transporter in Leishmania: similarities with the Trypanosoma brucei U1 transporter and antileishmanial activity of uracil analogues. Parasitology 130, 275283.
  • [41]
    Avila, J.L., Rojas, T., Avila, A., Polegre, M.A., and Robins, R.K. (1987) Biological activity of analogs of guanine and guanosine against American Trypanosoma and Leishmania spp. Antimicrob. Agents Chemother. 31, 447451.
  • [42]
    Bacchi, C.J., Nathan, H.C., Yarlett, N., Goldberg, B., McCann, P.P., Bitonti, A.J., and Sjoerdsma, A. (1992) Cure of murine Trypanosoma brucei rhodesiense infections with an S-adenosylmethionine decarboxylase inhibitor. Antimicrob. Agents Chemother. 36, 27362740.
  • [43]
    Bressi, J.C., Verlinde, C.L., Aronov, A.M., Shaw, M.L., Shin, S.S., Nguyen, L.N., Suresh, S., Buckner, F.S., Van Voorhis, W.C., Kuntz, I.D., Hol, W.G., and Gelb, M.H. (2001) Adenosine analogues as selective inhibitors of glyceraldehyde-3-phosphate dehydrogenase of Trypanosomatidae via structure-based drug design. J. Med. Chem. 44, 20802093.
  • [44]
    Rodenko, B. (2004) A new entry to adenosine analogues via purine nitration: Combinatorial synthesis of antiprotozoal agents and adenosine receptor ligands. PhD thesis, University of Amsterdam, The Netherlands .
  • [45]
    Seley, K.L., Schneller, S.W., Rattendi, D., Lane, S., and Bacchi, C.J. (1997) Synthesis and antitrypanosomal activities of a series of 7-deaza-5′-noraristeromycin derivatives with variations in the cyclopentyl ring substituents. Antimicrob. Agents Chemother. 41, 16581661.
  • [46]
    Winstanley, P. (2001) Modern chemotherapeutic options for malaria. Lancet Infect. Dis. 1, 242250.
  • [47]
    Hill, D., and Dubey, J.P. (2002) Toxoplasma gondii: transmission, diagnosis and prevention. Clin. Microbiol. Infect. 8, 634640.
  • [48]
    Derouin, F. (2001) Anti-toxoplasmosis drugs. Curr. Opin. Investig. Drugs 2, 13681374.
  • [49]
    Momeni, A.Z., Reiszadae, M.R., and Aminjavaheri, M. (2002) Treatment of cutaneous leishmaniasis with a combination of allopurinol and low-dose meglumine antimoniate. Int. J. Dermatol. 41, 441443.
  • [50]
    Das, V.N., Ranjan, A., Sinha, A.N., Verma, N., Lal, C.S., Gupta, A.K., Siddiqui, N.A., and Kar, S.K. (2001) A randomized clinical trial of low dosage combination of pentamidine and allopurinol in the treatment of antimony unresponsive cases of visceral leishmaniasis. J. Assoc. Physicians India 49, 609613.
  • [51]
    De Koning, H.P., Anderson, L.F., Stewart, M., Burchmore, R.J., Wallace, L.J., and Barrett, M.P. (2004) The trypanocide diminazene aceturate is accumulated predominantly through the TbAT1 purine transporter: additional insights on diamidine resistance in African trypanosomes. Antimicrob. Agents Chemother. 48, 15151519.
  • [52]
    De Koning, H.P. (2001) Transporters in African trypanosomes: role in drug action and resistance. Int. J. Parasitol. 31, 512522.
  • [53]
    De Koning, H.P., and Jarvis, S.M. (1999) Adenosine transporters in bloodstream forms of Trypanosoma brucei brucei: substrate recognition motifs and affinity for trypanocidal drugs. Mol. Pharmacol. 56, 11621170.
  • [54]
    Suswam, E.A., Taylor, D.W., Ross, C.A., and Martin, R.J. (2001) Changes in properties of adenosine transporters in Trypanosoma evansi and modes of selection of resistance to the melaminophenyl arsenical drug, Mel Cy. Vet. Parasitol. 102, 193208.
  • [55]
    Suswam, E.A., Ross, C.A., and Martin, R.J. (2003) Changes in adenosine transport associated with melaminophenyl arsenical (Mel CY) resistance in Trypanosoma evansi: down-regulation and affinity changes of the P2 transporter. Parasitology 127, 543549.
  • [56]
    Ross, C.A., and Barns, A.M. (1996) Alteration to one of three adenosine transporters is associated with resistance to cymelarsan in Trypanosoma evansi. Parasitol. Res. 82, 183188.
  • [57]
    Barrett, M.P., Zhang, Z.Q., Denise, H., Giroud, C., and Baltz, T. (1995) A diamidine-resistant Trypanosoma equiperdum clone contains a P2 purine transporter with reduced substrate affinity. Mol. Biochem. Parasitol. 73, 223229.
  • [58]
    James, D.M., and Born, G.V. (1980) Uptake of purine bases and nucleosides in African trypanosomes. Parasitology 81, 383393.
  • [59]
    Okochi, V.I., Abaelu, A.M., and Akinrimisi, E.O. (1983) Studies on the mechanism of adenosine transport in Trypanosoma vivax. Biochem. Int. 6, 129139.
  • [60]
    Sanchez, G., Knight, S., and Strickler, J. (1976) Nucleotide transport in African trypanosomes. Comp Biochem. Physiol B 53, 419421.
  • [61]
    Stein, A., Vaseduvan, G., Carter, N.S., Ullman, B., Landfear, S.M., and Kavanaugh, M.P. (2003) Equilibrative nucleoside transporter family members from Leishmania donovani are electrogenic proton symporters. J. Biol. Chem. 278, 3512735134.
  • [62]
    Legros, D., Ollivier, G., Gastellu-Etchegorry, M., Paquet, C., Burri, C., Jannin, J., and Buscher, P. (2002) Treatment of human African trypanosomiasis–present situation and needs for research and development. Lancet Infect. Dis. 2, 437440.
  • [63]
    Barrett, M.P., and Fairlamb, A.H. (1999) The biochemical basis of arsenical-diamidine crossresistance in African trypanosomes. Parasitol. Today 15, 136140.
  • [64]
    Carter, N.S., Berger, B.J., and Fairlamb, A.H. (1995) Uptake of diamidine drugs by the P2 nucleoside transporter in melarsen-sensitive and -resistant Trypanosoma brucei brucei. J. Biol. Chem. 270, 2815328157.
  • [65]
    De Koning, H.P., Watson, C.J., and Jarvis, S.M. (1998) Characterization of a nucleoside/proton symporter in procyclic Trypanosoma brucei brucei. J. Biol. Chem. 273, 94869494.
  • [66]
    Witola, W.H., Inoue, N., Ohashi, K., and Onuma, M. (2004) RNA-interference silencing of the adenosine transporter-1 gene in Trypanosoma evansi confers resistance to diminazene aceturate. Exp. Parasitol. 107, 4757.
  • [67]
    Sanchez, M.A., Tryon, R., Green, J., Boor, I., and Landfear, S.M. (2002) Six related nucleoside/nucleobase transporters from Trypanosoma brucei exhibit distinct biochemical functions. J. Biol. Chem. 277, 2149921504.
  • [68]
    De Koning, H.P., Watson, C.J., Sutcliffe, L., and Jarvis, S.M. (2000) Differential regulation of nucleoside and nucleobase transporters in Crithidia fasciculata and Trypanosoma brucei brucei. Mol. Biochem. Parasitol. 106, 93107.
  • [69]
    Kidder, G.W., Dewey, V.C., and Nolan, L.L. (1978) Transport and accumulation of purine bases by Crithidia fasciculata. J. Cell Physiol. 96, 165170.
  • [70]
    Hall, S.T., Hillier, C.J., and Gero, A.M. (1996) Crithidia luciliae: regulation of purine nucleoside transport by extracellular purine concentrations. Exp. Parasitol. 83, 314321.
  • [71]
    Alleman, M.M., and Gottlieb, M. (1996) Enhanced acquisition of purine nucleosides and nucleobases by purine-starved Crithidia luciliae. Mol. Biochem. Parasitol. 76, 279287.
  • [72]
    Gottlieb, M. (1985) Enzyme regulation in a trypanosomatid: effect of purine starvation on levels of 3′-nucleotidase activity. Science 227, 7274.
  • [73]
    Gero, A.M. (1998) Purine stress in Crithidia: adaptation of a parasite to environmental stress. Parasitol. Today 14, 277281.
  • [74]
    Gero, A.M., Day, R.E., and Hall, S.T. (1997) Stimulated transport of adenosine, guanosine and hypoxanthine in Crithidia luciliae: metabolic machinery in which the parasite has a distinct advantage over the host. Int. J. Parasitol. 27, 241249.
  • [75]
    Sanchez, M.A., Drutman, S., Van Ampting, M., Matthews, K., and Landfear, S.M. (2004) A novel purine nucleoside transporter whose expression is up-regulated in the short stumpy form of the Trypanosoma brucei life cycle. Mol. Biochem. Parasitol. 136, 265272.
  • [76]
    Marr, J.J., Berens, R.L., and Nelson, D.J. (1978) Purine metabolism in Leishmania donovani and Leishmania braziliensis. Biochim. Biophys. Acta 544, 360371.
  • [77]
    Hansen, B.D., Perez-Arbelo, J., Walkony, J.F., and Hendricks, L.D. (1982) The specificity of purine base and nucleoside uptake in promastigotes of Leishmania braziliensis panamensis. Parasitology 85, 271282.
  • [78]
    Goldberg, B., Yarlett, N., Sufrin, J., Lloyd, D., and Bacchi, C.J. (1997) A unique transporter of S-adenosylmethionine in African trypanosomes. FASEB J. 11, 256260.
  • [79]
    Phelouzat, M.A., Basselin, M., Lawrence, F., and Robert-Gero, M. (1995) Sinefungin shares AdoMet-uptake system to enter Leishmania donovani promastigotes. Biochem. J. 305, 133137.
  • [80]
    Iovannisci, D.M., Kaur, K., Young, L., and Ullman, B. (1984) Genetic analysis of nucleoside transport in Leishmania donovani. Mol. Cell Biol. 4, 10131019.
  • [81]
    Ogbunude, P.O., al Jaser, M.H., and Baer, H.P. (1991) Leishmania donovani: characteristics of adenosine and inosine transporters in promastigotes of two different strains. Exp. Parasitol. 73, 369375.
  • [82]
    Baer, H.P., Serignese, V., Ogbunude, P.O., and Dzimiri, M. (1992) Nucleoside transporters in Leishmania major: diversity in adenosine transporter expression or function in different strains. Am. J. Trop. Med. Hyg. 47, 8791.
  • [83]
    Seyfang, A., and Landfear, S.M. (1999) Substrate depletion upregulates uptake of myo-inositol, glucose and adenosine in Leishmania. Mol. Biochem. Parasitol. 104, 121130.
  • [84]
    Klamo, E.M., Drew, M.E., Landfear, S.M., and Kavanaugh, M.P. (1996) Kinetics and stoichiometry of a proton/myo-inositol cotransporter. J. Biol. Chem. 271, 1493714943.
  • [85]
    Baldwin, S.A., Beal, P.R., Yao, S.Y., King, A.E., Cass, C.E., and Young, J.D. (2004) The equilibrative nucleoside transporter family, SLC29. Pflugers Arch. 447, 735743.
  • [86]
    Gray, J.H., Owen, R.P., and Giacomini, K.M. (2004) The concentrative nucleoside transporter family, SLC28. Pflugers Arch. 447, 728734.
  • [87]
    De Koning, H.P., and Diallinas, G. (2000) Nucleobase transporters (review). Mol. Membr. Biol. 17, 7594.
  • [88]
    Mohlmann, T., Mezher, Z., Schwerdtfeger, G., and Neuhaus, H.E. (2001) Characterisation of a concentrative type of adenosine transporter from Arabidopsis thaliana (ENT1, At). FEBS Lett. 509, 370374.
  • [89]
    Xiao, G., Wang, J., Tangen, T., and Giacomini, K.M. (2001) A novel proton-dependent nucleoside transporter, CeCNT3, from Caenorhabditis elegans. Mol. Pharmacol. 59, 339348.
  • [90]
    Loewen, S.K., Ng, A.M., Mohabir, N.N., Baldwin, S.A., Cass, C.E., and Young, J.D. (2003) Functional characterization of a H+/nucleoside co-transporter (CaCNT) from Candida albicans, a fungal member of the concentrative nucleoside transporter (CNT) family of membrane proteins. Yeast 20, 661675.
  • [91]
    Landfear, S.M., Ullman, B., Carter, N.S., and Sanchez, M.A. (2004) Nucleoside and nucleobase transporters in parasitic protozoa. Eukaryot. Cell 3, 245254.
  • [92]
    Liu, W., Arendt, C.S., Gessford, S.K., Ntaba, D., Carter, N.S., and Ullman, B. (2005) Identification and characterization of purine nucleoside transporters from Crithidia fasciculata. Mol. Biochem. Parasitol. 140, 112.
  • [93]
    Alleman, M.M., Mann, V.H., Bacchi, C.J., Yarlett, N., Gottlieb, M., and Dwyer, D.M. (1995) Crithidia luciliae: effect of purine starvation on S-adenosyl-L-methionine uptake and protein methylation. Exp. Parasitol. 81, 519528.
  • [94]
    Gero, A.M., and O'Sullivan, W.J. (1990) Purines and pyrimidines in malarial parasites. Blood Cells 16, 467484.
  • [95]
    Walsh, C.J., and Sherman, I.W. (1968) Purine and pyrimidine synthesis by the avian malaria parasite, Plasmodium lophurae. J. Protozool. 15, 763770.
  • [96]
    Webster, H.K., Whaun, J.M., Walker, M.D., and Bean, T.L. (1984) Synthesis of adenosine nucleotides from hypoxanthine by human malaria parasites (Plasmodium falciparum) in continuous erythrocyte culture: inhibition by hadacidin but not alanosine. Biochem. Pharmacol. 33, 15551557.
  • [97]
    Polet, H., and Barr, C.F. (1968) DNA, RNA, and protein synthesis in erythrocytic forms of Plasmodium knowlesi. Am. J. Trop. Med. Hyg. 17, 672679.
  • [98]
    Gutteridge, W.E., and Trigg, P.I. (1970) Incorporation of radioactive precursors into DNA and RNA of Plasmodium knowlesi in vitro. J. Protozool. 17, 8996.
  • [99]
    Bungener, W., and Nielsen, G. (1967) Nucleic acid metabolism in experimental malaria. 1. Studies on the incorporation of thymidine, uridine, and adenosine in the malaria parasite (Plasmodium berghei and Plasmodium vinckei). Z. Tropenmed. Parasitol. 18, 456462.
  • [100]
    Van Dyke, K., Tremblay, G.C., Lantz, C.H., and Szustkiewicz, C. (1970) The source of purines and pyrimidines in Plasmodium berghei. Am. J. Trop. Med. Hyg. 19, 202208.
  • [101]
    Scott, H.V., Gero, A.M., and O'Sullivan, W.J. (1986) In vitro inhibition of Plasmodium falciparum by pyrazofurin, an inhibitor of pyrimidine biosynthesis de novo. Mol. Biochem. Parasitol. 18, 315.
  • [102]
    Hammond, D.J., Burchell, J.R., and Pudney, M. (1985) Inhibition of pyrimidine biosynthesis de novo in Plasmodium falciparum by 2-(4-t-butylcyclohexyl)-3-hydroxy-1,4-naphthoquinone in vitro. Mol. Biochem. Parasitol. 14, 97109.
  • [103]
    Plagemann, P.G., Wohlhueter, R.M., and Woffendin, C. (1988) Nucleoside and nucleobase transport in animal cells. Biochim. Biophys. Acta 947, 405443.
  • [104]
    Domin, B.A., Mahony, W.B., and Zimmerman, T.P. (1988) Purine nucleobase transport in human erythrocytes. Reinvestigation with a novel “inhibitor-stop” assay. J. Biol. Chem. 263, 92769284.
  • [105]
    Cabantchik, Z.I. (1990) Properties of permeation pathways induced in the human red cell membrane by malaria parasites. Blood Cells 16, 421432.
  • [106]
    Upston, J.M., and Gero, A.M. (1995) Parasite-induced permeation of nucleosides in Plasmodium falciparum malaria. Biochim. Biophys. Acta 1236, 249258.
  • [107]
    Kirk, K. (2001) Membrane transport in the malaria-infected erythrocyte. Physiol Rev. 81, 495537.
  • [108]
    Desai, S.A., Krogstad, D.J., and McCleskey, E.W. (1993) A nutrient-permeable channel on the intraerythrocytic malaria parasite. Nature 362, 643646.
  • [109]
    Desai, S.A., and Rosenberg, R.L. (1997) Pore size of the malaria parasite's nutrient channel. Proc. Natl. Acad. Sci. USA 94, 20452049.
  • [110]
    Hansen, B.D., Sleeman, H.K., and Pappas, P.W. (1980) Purine base and nucleoside uptake in Plasmodium berghei and host erythrocytes. J. Parasitol. 66, 205212.
  • [111]
    Manandhar, M.S.P., and Van Dyke, K. (1975) Detailed purine salvage metabolism in and outside the free malarial parasite. Exp. Parasitol. 37, 138146.
  • [112]
    Reyes, P., Rathod, P.K., Sanchez, D.J., Mrema, J.E., Rieckmann, K.H., and Heidrich, H.G. (1982) Enzymes of purine and pyrimidine metabolism from the human malaria parasite, Plasmodium falciparum. Mol. Biochem. Parasitol. 5, 275290.
  • [113]
    Berman, P.A., Human, L., and Freese, J.A. (1991) Xanthine oxidase inhibits growth of Plasmodium falciparum in human erythrocytes in vitro. J. Clin. Invest 88, 18481855.
  • [114]
    Penny, J.I., Hall, S.T., Woodrow, C.J., Cowan, G.M., Gero, A.M., and Krishna, S. (1998) Expression of substrate-specific transporters encoded by Plasmodium falciparum in Xenopus laevis oocytes. Mol. Biochem. Parasitol. 93, 8189.
  • [115]
    Rager, N., Mamoun, C.B., Carter, N.S., Goldberg, D.E., and Ullman, B. (2001) Localization of the Plasmodium falciparum PfNT1 nucleoside transporter to the parasite plasma membrane. J. Biol. Chem. 276, 4109541099.
  • [116]
    Rathod, P.K., and Reyes, P. (1983) Orotidylate-metabolizing enzymes of the human malarial parasite, Plasmodium falciparum, differ from host cell enzymes. J. Biol. Chem. 258, 28522855.
  • [117]
    Schwab, J.C., Beckers, C.J., and Joiner, K.A. (1994) The parasitophorous vacuole membrane surrounding intracellular Toxoplasma gondii functions as a molecular sieve. Proc. Natl. Acad. Sci. USA 91, 509513.
  • [118]
    Ngô, H.M., Ngô, E.O., Bzik, D.J., and Joiner, K.A. (2000) Toxoplasma gondii: are host cell adenosine nucleotides a direct source for purine salvage?. Exp. Parasitol. 95, 148153.
  • [119]
    Asai, T., Miura, S., Sibley, L.D., Okabayashi, H., and Takeuchi, T. (1995) Biochemical and molecular characterization of nucleoside triphosphate hydrolase isozymes from the parasitic protozoan Toxoplasma gondii. J. Biol. Chem. 270, 1139111397.
  • [120]
    Bermudes, D., Peck, K.R., Afifi, M.A., Beckers, C.J., and Joiner, K.A. (1994) Tandemly repeated genes encode nucleoside triphosphate hydrolase isoforms secreted into the parasitophorous vacuole of Toxoplasma gondii. J. Biol. Chem. 269, 2925229260.
  • [121]
    Sibley, L.D., Niesman, I.R., Asai, T., and Takeuchi, T. (1994) Toxoplasma gondii: secretion of a potent nucleoside triphosphate hydrolase into the parasitophorous vacuole. Exp. Parasitol. 79, 301311.
  • [122]
    Schwab, J.C., Afifi, A.M., Pizzorno, G., Handschumacher, R.E., and Joiner, K.A. (1995) Toxoplasma gondii tachyzoites possess an unusual plasma membrane adenosine transporter. Mol. Biochem. Parasitol. 70, 5969.
  • [123]
    Silverman, J.A., Qi, H., Riehl, A., Beckers, C., Nakaar, V., and Joiner, K.A. (1998) Induced activation of the Toxoplasma gondii nucleoside triphosphate hydrolase leads to depletion of host cell ATP levels and rapid exit of intracellular parasites from infected cells. J. Biol. Chem. 273, 1235212359.
  • [124]
    Nakaar, V., Beckers, C.J., Polotsky, V., and Joiner, K.A. (1998) Basis for substrate specificity of the Toxoplasma gondii nucleoside triphosphate hydrolase. Mol. Biochem. Parasitol. 97, 209220.
  • [125]
    Krug, E.C., Marr, J.J., and Berens, R.L. (1989) Purine metabolism in Toxoplasma gondii. J. Biol. Chem. 264, 1060110607.
  • [126]
    Schwartzman, J.D., and Pfefferkorn, E.R. (1982) Toxoplasma gondii: purine synthesis and salvage in mutant host cells and parasites. Exp. Parasitol. 53, 7786.
  • [127]
    Chaudhary, K., Darling, J.A., Fohl, L.M., Sullivan, W.J. Jr., Donald, R.G., Pfefferkorn, E.R., Ullman, B., and Roos, D.S. (2004) Purine salvage pathways in the apicomplexan parasite Toxoplasma gondii. J. Biol. Chem. 279, 3122131227.
  • [128]
    Al Safarjalani, O.N., Naguib, F.N., and El Kouni, M.H. (2003) Uptake of nitrobenzylthioinosine and purine beta-L-nucleosides by intracellular Toxoplasma gondii. Antimicrob. Agents Chemother. 47, 32473251.
  • [129]
    Fox, B.A., and Bzik, D.J. (2002) De novo pyrimidine biosynthesis is required for virulence of Toxoplasma gondii. Nature 415, 926929.
  • [130]
    Ey, P.L., Davey, R.A., and Duffield, G.A. (1992) A low-affinity nucleobase transporter in the protozoan parasite Giardia intestinalis. Biochim. Biophys. Acta 1109, 179186.
  • [131]
    Baum, K.F., Berens, R.L., and Marr, J.J. (1993) Purine nucleoside and nucleobase cell membrane transport in Giardia lamblia. J. Eukaryot. Microbiol. 40, 643649.
  • [132]
    Wang, C.C., and Aldritt, S. (1983) Purine salvage networks in Giardia lamblia. J. Exp. Med. 158, 17031712.
  • [133]
    Heyworth, P.G., Gutteridge, W.E., and Ginger, C.D. (1982) Purine metabolism in Trichomonas vaginalis. FEBS Lett. 141, 106110.
  • [134]
    Miller, R.L., and Lindstead, D. (1983) Purine and pyrimidine metabolizing activities in Trichomonas vaginalis extracts. Mol. Biochem. Parasitol. 7, 4151.
  • [135]
    Munagala, N., and Wang, C.C. (2002) The purine nucleoside phosphorylase from Trichomonas vaginalis is a homologue of the bacterial enzyme. Biochemistry 41, 1038210389.
  • [136]
    Munagala, N.R., and Wang, C.C. (2003) Adenosine is the primary precursor of all purine nucleotides in Trichomonas vaginalis. Mol. Biochem. Parasitol. 127, 143149.
  • [137]
    Afifi, M.A., el Wakil, H.S., and Abdel-Ghaffar, M.M. (2000) A novel chemotherapeutic combination for Trichomonas vaginalis targeting purine salvage pathways of the parasite. J. Egypt. Soc. Parasitol. 30, 735746.
  • [138]
    Heyworth, P.G., and Gutteridge, W.E. (1978) Further studies on the purine and pyrimidine metabolism in Trichomonas vaginalis. J. Protozool. 25, 9b.
  • [139]
    Wang, C.C., and Cheng, H.W. (1984) Salvage of pyrimidine nucleosides by Trichomonas vaginalis. Mol. Biochem. Parasitol. 10, 171184.
  • [140]
    Harris, D.I., Beechey, R.B., Linstead, D., and Barrett, J. (1988) Nucleoside uptake by Trichomonas vaginalis. Mol. Biochem. Parasitol. 29, 105116.
  • [141]
    Wang, C.C., Verham, R., Rice, A., and Tzeng, S. (1983) Purine salvage by Tritrichomonas foetus. Mol. Biochem. Parasitol. 8, 325337.
  • [142]
    Somoza, J.R., Skillman, A.G. Jr., Munagala, N.R., Oshiro, C.M., Knegtel, R.M., Mpoke, S., Fletterick, R.J., Kuntz, I.D., and Wang, C.C. (1998) Rational design of novel antimicrobials: blocking purine salvage in a parasitic protozoan. Biochemistry 37, 53445348.
  • [143]
    Hedstrom, L., Cheung, K.S., and Wang, C.C. (1990) A novel mechanism of mycophenolic acid resistance in the protozoan parasite Tritrichomonas foetus. Biochem. Pharmacol. 39, 151160.
  • [144]
    Matias, C., Nott, S.E., Bagnara, A.S., O'Sullivan, W.J., and Gero, A.M. (1990) Purine salvage and metabolism in Babesia bovis. Parasitol. Res. 76, 207213.
  • [145]
    Conrad, P.A. (1986) Uptake of tritiated nucleic acid precursors by Babesia bovis in vitro. Int. J. Parasitol. 16, 263268.
  • [146]
    Gero, A.M. (1989) Induction of nucleoside transport sites into the host cell membrane of Babesia bovis infected erythrocytes. Mol. Biochem. Parasitol. 35, 269276.
  • [147]
    Kerr, E.A., and Gero, A.M. (1991) The toxicity of adenosine analogues against Babesia bovis in vitro. Int. J. Parasitol. 21, 747751.
  • [148]
    Nozaki, T., and Dvorak, J.A. (1993) Molecular biology studies of tubercidin resistance in Trypanosoma cruzi. Parasitol. Res. 79, 451455.
  • [149]
    Avila, J.L., and Avila, A. (1987) Defective transport of pyrazolopyrimidine ribosides in insensitive Trypanosoma cruzi wild strains is a parasite-stage specific and reversible characteristic. Comp Biochem. Physiol B 87, 489495.
  • [150]
    Avila, J.L., and Avila, A. (1981) Trypanosoma cruzi: allopurinol in the treatment of mice with experimental acute Chagas disease. Exp. Parasitol. 51, 204208.
  • [151]
    Gallerano, R.H., Marr, J.J., and Sosa, R.R. (1990) Therapeutic efficacy of allopurinol in patients with chronic Chagas' disease. Am. J. Trop. Med. Hyg. 43, 159166.
  • [152]
    Sanchez, G., Zulantay, I., Venegas, J., Solari, A., Galvez, R., Pena, P., Rodriguez, J., and Apt, W. (1995) Treatment with allopurinol and itraconazole changes lytic activity in patients with chronic, low grade Trypanosoma cruzi infection. Trans. R. Soc. Trop. Med. Hyg. 89, 438439.
  • [153]
    Apt, W., Arribada, A., Zulantay, I., Sanchez, G., Vargas, S.L., and Rodriguez, J. (2003) Itraconazole or allopurinol in the treatment of chronic American trypanosomiasis: the regression and prevention of electrocardiographic abnormalities during 9 years of follow-up. Ann. Trop. Med. Parasitol. 97, 2329.
  • [154]
    Marr, J.J., Berens, R.L., and Nelson, D.J. (1978) Antitrypanosomal effect of allopurinol: conversion in vivo to aminopyrazolopyrimidine nucleotides by Trypanosoma cruzi. Science 201, 10181020.
  • [155]
    Hyde, R.J., Cass, C.E., Young, J.D., and Baldwin, S.A. (2001) The ENT family of eukaryote nucleoside and nucleobase transporters: recent advances in the investigation of structure/function relationships and the identification of novel isoforms. Mol. Membr. Biol. 18, 5363.
  • [156]
    Yao, S.Y., Ng, A.M., Vickers, M.F., Sundaram, M., Cass, C.E., Baldwin, S.A., and Young, J.D. (2002) Functional and molecular characterization of nucleobase transport by recombinant human and rat equilibrative nucleoside transporters 1 and 2. Chimeric constructs reveal a role for the ENT2 helix 5–6 region in nucleobase translocation. J. Biol. Chem. 277, 2493824948.
  • [157]
    Matovu, E., Geiser, F., Schneider, V., Mäser, P., Enyaru, J.C., Kaminsky, R., Gallati, S., and Seebeck, T. (2001) Genetic variants of the TbAT1 adenosine transporter from African trypanosomes in relapse infections following melarsoprol therapy. Mol. Biochem. Parasitol. 117, 7381.
  • [158]
    De Koning, H.P., and Jarvis, S.M. (2001) Uptake of pentamidine in Trypanosoma brucei brucei is mediated by the P2 adenosine transporter and at least one novel, unrelated transporter. Acta Trop. 80, 245250.
  • [159]
    De Koning, H.P. (2001) Uptake of pentamidine in Trypanosoma brucei brucei is mediated by three distinct transporters: implications for cross-resistance with arsenicals. Mol. Pharmacol. 59, 586592.
  • [160]
    Bray, P.G., Barrett, M.P., Ward, S.A., and De Koning, H.P. (2003) Pentamidine uptake and resistance in pathogenic protozoa: past, present and future. Trends Parasitol. 19, 232239.
  • [161]
    Pisoni, R.L., and Thoene, J.G. (1989) Detection and characterization of a nucleoside transport system in human fibroblast lysosomes. J. Biol. Chem. 264, 48504856.
  • [162]
    Jimenez, A., Pubill, D., Pallas, M., Camins, A., Llado, S., Camarasa, J., and Escubedo, E. (2000) Further characterization of an adenosine transport system in the mitochondrial fraction of rat testis. Eur. J. Pharmacol. 398, 3139.
  • [163]
    Ralph, S.A., Van Dooren, G.G., Waller, R.F., Crawford, M.J., Fraunholz, M.J., Foth, B.J., Tonkin, C.J., Roos, D.S., and McFadden, G.I. (2004) Tropical infectious diseases: Metabolic maps and functions of the Plasmodium falciparum apicoplast. Nat. Rev. Microbiol. 2, 203216.
  • [164]
    Hassan, H.F., Mottram, J.C., and Coombs, G.H. (1985) Subcellular localisation of purine-metabolising enzymes in Leishmania mexicana mexicana. Comp Biochem. Physiol B 81, 10371040.
  • [165]
    Hammond, D.J., Aman, R.A., and Wang, C.C. (1985) The role of compartmentation and glycerol kinase in the synthesis of ATP within the glycosome of Trypanosoma brucei. J. Biol. Chem. 260, 1564615654.
  • [166]
    Hammond, D.J., and Gutteridge, W.E. (1982) UMP synthesis in the kinetoplastida. Biochim. Biophys. Acta 718, 110.
  • [167]
    Shih, S., Hwang, H.Y., Carter, D., Stenberg, P., and Ullman, B. (1998) Localization and targeting of the Leishmania donovani hypoxanthine-guanine phosphoribosyltransferase to the glycosome. J. Biol. Chem. 273, 15341541.
  • [168]
    Shih, S., Stenberg, P., and Ullman, B. (1998) Immunolocalization of Trypanosoma brucei hypoxanthine-guanine phosphoribosyltransferase to the glycosome. Mol. Biochem. Parasitol. 92, 367371.
  • [169]
    Vasudevan, G., Ullman, B., and Landfear, S.M. (2001) Point mutations in a nucleoside transporter gene from Leishmania donovani confer drug resistance and alter substrate selectivity. Proc. Natl. Acad. Sci. USA 98, 60926097.
  • [170]
    Arastu-Kapur, S., Ford, E., Ullman, B., and Carter, N.S. (2003) Functional analysis of an inosine-guanosine transporter from Leishmania donovani. The role of conserved residues, aspartate 389 and arginine 393. J. Biol. Chem. 278, 3332733333.
  • [171]
    Piper, R.C., Xu, X., Russell, D.G., Little, B.M., and Landfear, S.M. (1995) Differential targeting of two glucose transporters from Leishmania enriettii is mediated by an NH2-terminal domain. J. Cell Biol. 128, 499508.
  • [172]
    Snapp, E.L., and Landfear, S.M. (1999) Characterization of a targeting motif for a flagellar membrane protein in Leishmania enriettii. J. Biol. Chem. 274, 2954329548.
  • [173]
    Nasser, M.I., and Landfear, S.M. (2004) Sequences required for the flagellar targeting of an integral membrane protein. Mol. Biochem. Parasitol. 135, 89100.
  • [174]
    Borst, P., and Elferink, R.O. (2002) Mammalian ABC transporters in health and disease. Annu. Rev. Biochem. 71, 537592.
  • [175]
    Begley, D.J. (2004) ABC transporters and the blood-brain barrier. Curr. Pharm. Des 10, 12951312.
  • [176]
    Reid, G., Wielinga, P., Zelcer, N., De Haas, M., Van Deemter, L., Wijnholds, J., Balzarini, J., and Borst, P. (2003) Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol. Pharmacol. 63, 10941103.
  • [177]
    Domin, B.A., Mahony, W.B., and Zimmerman, T.P. (1991) Desciclovir permeation of the human erythrocyte membrane by nonfacilitated diffusion. Biochem. Pharmacol. 42, 147152.
  • [178]
    Mahony, W.B., Domin, B.A., Daluge, S.M., and Zimmerman, T.P. (2004) Membrane permeation characteristics of abacavir in human erythrocytes and human T-lymphoblastoid CD4+ CEM cells: comparison with (-)-carbovir. Biochem. Pharmacol. 68, 17971805.
  • [179]
    Wanner, M.J., Rodenko, B., Koch, M., and Koomen, G.J. (2004) New (1-deaza)purine derivatives via efficient C-2 nitration of the (1-deaza)purine ring. Nucleosides Nucleotides Nucleic Acids 23, 13131320.
  • [180]
    Mäser, P., Lüscher, A., and Kaminsky, R. (2003) Drug transport and drug resistance in African trypanosomes. Drug Resist. Updat. 6, 281290.
  • [181]
    Carter, N.S., Barrett, M.P., and De Koning, H.P. (1999) A drug resistance determinant in Trypanosoma brucei. Trends Microbiol. 7, 469471.
  • [182]
    Biagini, G.A., Pasini, E.M., Hughes, R., De Koning, H.P., Vial, H.J., O'Neill, P.M., Ward, S.A., and Bray, P.G. (2004) Characterization of the choline carrier of Plasmodium falciparum: a route for the selective delivery of novel antimalarial drugs. Blood 104, 33723377.
  • [183]
    Baum, K.F., and Berens, R.L. (1994) Successful treatment of cutaneous leishmaniasis with allopurinol after failure of treatment with ketoconazole. Clin. Infect. Dis. 18, 813815.
  • [184]
    Abrishami, M., Dowlati, Y., Farahi, A., and Soheilian, M. (2002) Successful treatment of ocular leishmaniasis. Eur. J. Dermatol. 12, 8889.
  • [185]
    Martinez, S., and Marr, J.J. (1992) Allopurinol in the treatment of American cutaneous leishmaniasis. N. Engl. J. Med. 326, 741744.
  • [186]
    Baneth, G., and Shaw, S.E. (2002) Chemotherapy of canine leishmaniosis. Vet. Parasitol. 106, 315324.
  • [187]
    Kamau, S.W., Hurtado, M., Muller-Doblies, U.U., Grimm, F., and Nunez, R. (2000) Flow cytometric assessment of allopurinol susceptibility in Leishmania infantum promastigote. Cytometry 40, 353360.
  • [188]
    Natto, M.J., Wallace, L.J.M., Candlish, D., Al Salabi, M.I., Coutts, S.E., and De Koning, H.P. (2005) Trypanosoma brucei: expression of multiple purine transporters prevents the development of allopurinol resistance. Exp. Parasitol. 109, 8086.
  • [189]
    Katakura, K., Fujise, H., Takeda, K., Kaneko, O., Torii, M., Suzuki, M., Chang, K.P., and Hashiguchi, Y. (2004) Overexpression of LaMDR2, a novel multidrug resistance ATP-binding cassette transporter, causes 5-fluorouracil resistance in Leishmania amazonensis. FEBS Lett. 561, 207212.
  • [190]
    Wallace, L.J., Candlish, D., Hagos, A., Seley, K.L., and De Koning, H.P. (2004) Selective transport of a new class of purine antimetabolites by the protozoan parasite Trypanosoma brucei. Nucleosides Nucleotides Nucleic Acids 23, 14411444.
  • [191]
    El Kouni, M.H. (2003) Potential chemotherapeutic targets in the purine metabolism of parasites. Pharmacol. Ther. 99, 283309.
  • [192]
    LaFon, S.W., Nelson, D.J., Berens, R.L., and Marr, J.J. (1985) Inosine analogs. Their metabolism in mouse L cells and in Leishmania donovani. J. Biol. Chem. 260, 96609665.
  • [193]
    Bacchi, C.J., Berens, R.L., Nathan, H.C., Klein, R.S., Elegbe, I.A., Rao, K.V., McCann, P.P., and Marr, J.J. (1987) Synergism between 9-deazainosine and DL-alpha-difluoromethylornithine in treatment of experimental African trypanosomiasis. Antimicrob. Agents Chemother. 31, 14061413.
  • [194]
    Marr, J.J., and Berens, R.L. (1983) Pyrazolopyrimidine metabolism in the pathogenic trypanosomatidae. Mol. Biochem. Parasitol. 7, 339356.
  • [195]
    Battacharya, B.K., Otter, B.A., Berens, R.L., and Klein, R.S. (1990) Studies on the synthesis of furo[3,2-d]pyrimidine C-nucleotides: new inosine analogues with antiprotozoan activity. Nucleosides Nucleotides 9, 10211043.
  • [196]
    Lim, M.I., and Klein, R.S. (1981) Synthesis of 9-deazaadenosine: a new cytotoxic C-nucleoside isostere of adenosine. Tetrahedron Lett. 22, 2528.
  • [197]
    Opperdoes, F.R. (1987) Compartmentation of carbohydrate metabolism in trypanosomes. Annu. Rev. Microbiol. 41, 127151.
  • [198]
    Bressi, J.C., Choe, J., Hough, M.T., Buckner, F.S., Van Voorhis, W.C., Verlinde, C.L., Hol, W.G., and Gelb, M.H. (2000) Adenosine analogues as inhibitors of Trypanosoma brucei phosphoglycerate kinase: elucidation of a novel binding mode for a 2-amino-N(6)-substituted adenosine. J. Med. Chem. 43, 41354150.
  • [199]
    Jarvis, S.M., Thorn, J.A., and Glue, P. (1998) Ribavirin uptake by human erythrocytes and the involvement of nitrobenzylthioinosine-sensitive (es)-nucleoside transporters. Br. J. Pharmacol. 123, 15871592.
  • [200]
    Ogbunude, P.O., and Ikediobi, C.O. (1982) Effect of nitrobenzylthioinosinate on the toxicity of tubercidin and ethidium against Trypanosoma gambiense. Acta Trop. 39, 219224.
  • [201]
    Gati, W.P., Stoyke, A.F., Gero, A.M., and Paterson, A.R. (1987) Nucleoside permeation in mouse erythrocytes infected with Plasmodium yoelii. Biochem. Biophys. Res. Commun. 145, 11341141.
  • [202]
    Gero, A.M., Scott, H.V., O'Sullivan, W.J., and Christopherson, R.I. (1989) Antimalarial action of nitrobenzylthioinosine in combination with purine nucleoside antimetabolites. Mol. Biochem. Parasitol. 34, 8797.
  • [203]
    Baer, H.P., El-Soofi, A., and Selim, A. (1988) Treatment of Schistosoma mansoni- and Schistosoma haematobium-infected mice with a combination of tubercidin and nucleoside transport inhibitor. Med. Sci. Res. 16, 919.
  • [204]
    El Kouni, M.H., Diop, D., and Cha, S. (1983) Combination therapy of schistosomiasis by tubercidin and nitrobenzylthioinosine 5′-monophosphate. Proc. Natl. Acad. Sci. USA 80, 66676670.
  • [205]
    El Kouni, M.H., Knopf, P.M., and Cha, S.M. (1985) Combination therapy of Schistosoma japonicum by tubercidin and nitrobenzylthioinosine 5′-monophosphate. Biochem. Pharmacol. 34, 39213923.
  • [206]
    El Kouni, M.H., Diop, D., O'Shea, P., Carlisle, R., and Sommadossi, J.P. (1989) Prevention of tubercidin host toxicity by nitrobenzylthioinosine 5′-monophosphate for the treatment of schistosomiasis. Antimicrob. Agents Chemother. 33, 824827.
  • [207]
    Kolassa, N., Jakobs, E.S., Buzzell, G.R., and Paterson, A.R. (1982) Manipulation of toxicity and tissue distribution of tubercidin in mice by nitrobenzylthioinosine 5′-monophosphate. Biochem. Pharmacol. 31, 18631874.
  • [208]
    El Kouni, M.H., Guarcello, V., Al Safarjalani, O.N., and Naguib, F.N. (1999) Metabolism and selective toxicity of 6-nitrobenzylthioinosine in Toxoplasma gondii. Antimicrob. Agents Chemother. 43, 24372443.
  • [209]
    Yadav, V., Chu, C.K., Rais, R.H., Al Safarjalani, O.N., Guarcello, V., Naguib, F.N., and El Kouni, M.H. (2004) Synthesis, biological activity and molecular modeling of 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase. J. Med. Chem. 47, 19871996.
  • [210]
    El Kouni, M.H., Messier, N.J., and Cha, S. (1987) Treatment of schistosomiasis by purine nucleoside analogues in combination with nucleoside transport inhibitors. Biochem. Pharmacol. 36, 38153821.
  • [211]
    Coomber, D.W., O'Sullivan, W.J., and Gero, A.M. (1994) Adenosine analogues as antimetabolites against Plasmodium falciparum malaria. Int. J. Parasitol. 24, 357365.
  • [212]
    Gero, A.M., and Hall, S.T. (1997) Plasmodium falciparum: transport of entantiomers of nucleosides into Sendai-treated trophozoites. Exp. Parasitol. 86, 228231.
  • [213]
    Gero, A.M., Perrone, G., Brown, D.M., Hall, S.T., and Chu, C.K. (1999) L-purine nucleosides as selective antimalarials. Nucleosides Nucleotides 18, 885889.
  • [214]
    Brown, D.M., Netting, A.G., Chun, B.K., Choi, Y., Chu, C.K., and Gero, A.M. (1999) L-nucleoside analogues as potential antimalarials that selectively target Plasmodium falciparum adenosine deaminase. Nucleosides Nucleotides 18, 25212532.
  • [215]
    Gero, A.M., Dunn, C.G., Brown, D.M., Pulenthiran, K., Gorovits, E.L., Bakos, T., and Weis, A.L. (2003) New malaria chemotherapy developed by utilization of a unique parasite transport system. Curr. Pharm. Des 9, 867877.
  • [216]
    Matovu, E., Enyaru, J.C., Legros, D., Schmid, C., Seebeck, T., and Kaminsky, R. (2001) Melarsoprol refractory T. b. gambiense from Omugo, north-western Uganda. Trop. Med. Int. Health 6, 407411.
  • [217]
    Perez-Victoria, J.M., Di Pietro, A., Barron, D., Ravelo, A.G., Castanys, S., and Gamarro, F. (2002) Multidrug resistance phenotype mediated by the P-glycoprotein-like transporter in Leishmania: a search for reversal agents. Curr. Drug Targets. 3, 311333.
  • [218]
    Legare, D., Cayer, S., Singh, A.K., Richard, D., Papadopoulou, B., and Ouellette, M. (2001) ABC proteins of Leishmania. J. Bioenerg. Biomembr. 33, 469474.
  • [219]
    Mäser, P., and Kaminsky, R. (1998) Identification of three ABC transporter genes in Trypanosoma brucei spp. Parasitol. Res. 84, 106111.
  • [220]
    Klokouzas, A., Shahi, S., Hladky, S.B., Barrand, M.A., and van Veen, H.W. (2003) ABC transporters and drug resistance in parasitic protozoa. Int. J. Antimicrob. Agents 22, 301317.
  • [221]
    Orozco, E., Lopez, C., Gomez, C., Perez, D.G., Marchat, L., Banuelos, C., and Delgadillo, D.M. (2002) Multidrug resistance in the protozoan parasite Entamoeba histolytica. Parasitol. Int. 51, 353359.
  • [222]
    Sauvage, V., Aubert, D., Bonhomme, A., Pinon, J.M., and Millot, J.M. (2004) P-glycoprotein inhibitors modulate accumulation and efflux of xenobiotics in extra and intracellular Toxoplasma gondii. Mol. Biochem. Parasitol. 134, 8995.
  • [223]
    Shahi, S.K., Krauth-Siegel, R.L., and Clayton, C.E. (2002) Overexpression of the putative thiol conjugate transporter TbMRPA causes melarsoprol resistance in Trypanosoma brucei. Mol. Microbiol. 43, 11291138.
  • [224]
    Reed, M.B., Saliba, K.J., Caruana, S.R., Kirk, K., and Cowman, A.F. (2000) Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403, 906909.
  • [225]
    Ward, S.A., and Bray, P.G. (2000) Definitive proof for a role of pfmdr 1 in quinoline resistance in Plasmodium falciparum. Drug Resist. Updat. 3, 8081.
  • [226]
    Callahan, H.L., and Beverley, S.M. (1991) Heavy metal resistance: a new role for P-glycoproteins in Leishmania. J. Biol. Chem. 266, 1842718430.
  • [227]
    Ouellette, M., Legare, D., and Papadopoulou, B. (2001) Multidrug resistance and ABC transporters in parasitic protozoa. J. Mol. Microbiol. Biotechnol. 3, 201206.
  • [228]
    Detke, S. (1997) Identification of a transcription factor like protein at the TOR locus in Leishmania mexicana amazonensis. Mol. Biochem. Parasitol. 90, 505511.
  • [229]
    Kerby, B.R., and Detke, S. (1993) Reduced purine accumulation is encoded on an amplified DNA in Leishmania mexicana amazonensis resistant to toxic nucleosides. Mol. Biochem. Parasitol. 60, 171185.
  • [230]
    Cotrim, P.C., Garrity, L.K., and Beverley, S.M. (1999) Isolation of genes mediating resistance to inhibitors of nucleoside and ergosterol metabolism in Leishmania by overexpression/selection. J. Biol. Chem. 274, 3772337730.
  • [231]
    Iovannisci, D.M., and Ullman, B. (1984) Characterization of a mutant Leishmania donovani deficient in adenosine kinase activity. Mol. Biochem. Parasitol. 12, 139151.
  • [232]
    Sullivan, W.J. Jr., Chiang, C.W., Wilson, C.M., Naguib, F.N., El Kouni, M.H., Donald, R.G., and Roos, D.S. (1999) Insertional tagging of at least two loci associated with resistance to adenine arabinoside in Toxoplasma gondii, and cloning of the adenosine kinase locus. Mol. Biochem. Parasitol. 103, 114.
  • [233]
    Sundaram, M., Yao, S.Y., Ingram, J.C., Berry, Z.A., Abidi, F., Cass, C.E., Baldwin, S.A., and Young, J.D. (2001) Topology of a human equilibrative, nitrobenzylthioinosine (NBMPR)-sensitive nucleoside transporter (hENT1) implicated in the cellular uptake of adenosine and anti-cancer drugs. J. Biol. Chem. 276, 4527045275.
  • [234]
    Sankar, N., Machado, J., Abdulla, P., Hilliker, A.J., and Coe, I.R. (2002) Comparative genomic analysis of equilibrative nucleoside transporters suggests conserved protein structure despite limited sequence identity. Nucleic Acids Res. 30, 43394350.
  • [235]
    Acimovic, Y., and Coe, I.R. (2002) Molecular evolution of the equilibrative nucleoside transporter family: identification of novel family members in prokaryotes and eukaryotes. Mol. Biol. Evol. 19, 21992210.
  • [236]
    Sundaram, M., Yao, S.Y., Ng, A.M., Griffiths, M., Cass, C.E., Baldwin, S.A., and Young, J.D. (1998) Chimeric constructs between human and rat equilibrative nucleoside transporters (hENT1 and rENT1) reveal hENT1 structural domains interacting with coronary vasoactive drugs. J. Biol. Chem. 273, 2151921525.
  • [237]
    SenGupta, D.J., Lum, P.Y., Lai, Y., Shubochkina, E., Bakken, A.H., Schneider, G., and Unadkat, J.D. (2002) A single glycine mutation in the equilibrative nucleoside transporter gene, hENT1, alters nucleoside transport activity and sensitivity to nitrobenzylthioinosine. Biochemistry 41, 15121519.
  • [238]
    Yao, S.Y., Sundaram, M., Chomey, E.G., Cass, C.E., Baldwin, S.A., and Young, J.D. (2001) Identification of Cys140 in helix 4 as an exofacial cysteine residue within the substrate-translocation channel of rat equilibrative nitrobenzylthioinosine (NBMPR)-insensitive nucleoside transporter rENT2. Biochem. J. 353, 387393.
  • [239]
    Valdes, R., Vasudevan, G., Conklin, D., and Landfear, S.M. (2004) Transmembrane domain 5 of the LdNT1.1 nucleoside transporter is an amphipathic helix that forms part of the nucleoside translocation pathway. Biochemistry 43, 67936802.
  • [240]
    Javitch, J.A. (1998) Probing structure of neurotransmitter transporters by substituted-cysteine accessibility method. Methods Enzymol. 296, 331346.
  • [241]
    Russ, W.P., and Engelman, D.M. (2000) The GxxxG motif: a framework for transmembrane helix-helix association. J. Mol. Biol. 296, 911919.
  • [242]
    Calladine, C.R., Pratap, V., Chandran, V., Mizuguchi, K., and Luisi, B.F. (2003) Cylindrical channels from concave helices. Science 299, 661662.
  • [243]
    Cheng, Y., and Prusoff, W.H. (1973) Relationship between the inhibition constant (K) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 22, 30993108.
  • [244]
    Deves, R. (1991) Kinetics of transport: characterisation of the interaction of substrates and inhibitors with carrier systems, In: Cell membrane transport (Yudilivich, D.L., Ed.), pp. 318. Plenum Press Inc., New York .
  • [245]
    Zhang, J., Visser, F., Vickers, M.F., Lang, T., Robins, M.J., Nielsen, L.P., Nowak, I., Baldwin, S.A., Young, J.D., and Cass, C.E. (2003) Uridine binding motifs of human concentrative nucleoside transporters 1 and 3 produced in Saccharomyces cerevisiae. Mol. Pharmacol. 64, 15121520.
  • [246]
    Vickers, M.F., Zhang, J., Visser, F., Tackaberry, T., Robins, M.J., Nielsen, L.P., Nowak, I., Baldwin, S.A., Young, J.D., and Cass, C.E. (2004) Uridine recognition motifs of human equilibrative nucleoside transporters 1 and 2 produced in Saccharomyces cerevisiae. Nucleosides Nucleotides Nucleic Acids 23, 361373.
  • [247]
    Morgenstern, B. (1999) DIALIGN 2: improvement of the segment-to-segment approach to multiple sequence alignment. Bioinformatics. 15, 211218.
  • [248]
    Strimmer, K., and von Haeseler, A. (1996) Quartet puzzling: a quartet maximum-likelihood method for reconstructing tree topologies. Mol. Biol. Evol. 13, 964969.
  • [249]
    Felsenstein, J. (1996) Inferring phylogenies from protein sequences by parsimony, distance, and likelihood methods. Methods Enzymol. 266, 418427.