Summary
Leishmania parasites rely heavily upon membrane transport proteins to deliver essential nutrients from their hosts to the interior of the parasite. Some of these transporters also serve as routes for uptake of drugs used for treatment of leishmaniasis or experimental drugs with potential for development of novel anti-leishmanial therapies. Hence, mutations within the coding regions of such permeases or alterations in the expression of the carrier proteins can confer drug resistance upon the parasites. This chapter reviews the current level of knowledge regarding several classes of membrane transporters known to play roles in uptake or sensitivity to drugs. The increasing knowledge of the “permeome,” provided by complete genome sequences of several Leishmania species, has advanced considerably our knowledge of how nutrients and drugs or other cytotoxic compounds enter these pathogenic protozoa.
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Al-Salabi MI, de Koning HP (2005) Purine nucleobase transport in amastigotes of Leishmania mexicana: involvement in allopurinol uptake. Antimicrob Agents Chemother 49:3682–3689
Al-Salabi MI, Wallace LJ, De Koning HP (2003) A Leishmania major nucleobase transporter responsible for allopurinol uptake is a functional homolog of the Trypanosoma brucei H2 transporter. Mol Pharmacol 63:814–820
Antoine JC, et al (1990) Parasitophorous vacuoles of Leishmania amazonensis-infected macrophages maintain an acidic pH. Infect Immun 58:779–787
Arastu-Kapur S, et al (2003) Functional analysis of an inosine-guanosine transporter from Leishmania donovani: the role of conserved residues, aspartate 389 and arginine 393. J Biol Chem 278:33327–33333
Arastu-Kapur S, et al (2005) Second-site suppression of a nonfunctional mutation within the Leishmania donovani inosine-guanosine transporter. J Biol Chem 280:2213–2219
Aronow B, et al (1987) Two high affinity nucleoside transporters in Leishmania donovani. Mol Biochem Parasitol 22:29–37
Beverley SM, Ellenberger TE, Cordingley JS (1986) Primary structure of the gene encoding the bifunctional dihydrofolate reductase-thymidylate synthase of Leishmania major. Proc Natl Acad Sci USA 83:2584–2588
Brochu C, et al (2003) Antimony uptake systems in the protozoan parasite Leishmania and accumulation differences in antimony-resistant parasites. Antimicrob Agents Chemother 47:3073–3079
Callahan HL, Beverley SM (1992) A member of the aldoketo reductase family confers methotrexate resistance in Leishmania. J Biol Chem 267:24165–24168
Callahan HL, et al (1997) An axenic amastigote system for drug screening. Antimicrob Agents Chemother 41:818–822
Carrió J, et al (2000) Leishmania infantum: stage-specific activity of pentavalent antimony related with the assay conditions. Exp Parasitol 95:209–214
Carson DA, Chang KP (1981) Phosphorylation and anti-leishmanial activity of formycin B. Bioch Biophys Res Commun 100:1377–1383
Carter NS, et al (2000) Cloning of a novel inosine-guanosine transporter gene from Leishmania donovani by functional rescue of a transport-deficient mutant. J Biol Chem 275:20935–20941
Carter NS, et al (2008) Purine and pyrimidine metabolism in Leishmania. Adv Exp Med Biol 625:141–154
Coderre JA, et al (1983) Overproduction of a bifunctional thymidylate synthetase-dihydrofolate reductase and DNA amplification in methotrexate-resistant Leishmania tropica. Proc Natl Acad Sci USA 80:2132–2136
Croft SL, Sundar S, Fairlamb AH (2006) Drug resistance in leishmaniasis. Clin Microbiol Rev 19(1):111–126
Cunningham ML, Beverley SM (2001) Pteridine salvage throughout the Leishmania infectious cycle: implications for antifolate chemotherapy. Mol Biochem Parasitol 113:199–213
Das R, Baker D (2008) Macromolecular modeling with rosetta. Annu Rev Biochem 77:363–382
Decuypere S, et al (2005) Gene expression analysis of the mechanism of natural SbV resistance in Leishmania donovani isolates from Nepal. Antimicrob Agents Chemother 49:4616–4621
Detke S (1997) Identification of a transcription factor like protein at the TOR locus in Leishmania mexicana amazonensis. Mol Biochem Parasitol 90:505–511
Detke S (2007) TOR-induced resistance to toxic adenosine analogs in Leishmania brought about by the internalization and degradation of the adenosine permease. Exp Cell Res 313:1963–1978
Dewes H, Ostergaard HL, Simpson L (1986) Impaired drug uptake in methotrexate resistant Crithidia fasciculata without changes in dihydrofolate reductase activity or gene amplification. Mol Biochem Parasitol 19:149–161
Dey S, et al (1996) An ATP-dependent As(III)-glutathione transport system in membrane vesicles of Leishmania tarentolae. Proc Natl Acad Sci USA 93:2192–2197
Dridi L, Haimeur A, Ouellette M (2010a) Structure-function analysis of the highly conserved charged residues of the membrane protein FT1, the main folic acid transporter of the protozoan parasite Leishmania. Biochem Pharmacol 79:30–38
Dridi L, Ahmed Ouameur A, Ouellette M (2010b) High affinity S-adenosylmethionine plasma membrane transporter of Leishmania is a member of the folate biopterin transporter (FBT) family. J Biol Chem 285:19767–19775
Ellenberger TE, Beverley SM (1987) Biochemistry and regulation of folate and methotrexate transport in Leishmania major. J Biol Chem 262:10053–10058
Eudes A, et al (2010) Identification of transport-critical residues in a folate transporter from the folate-biopterin transporter (FBT) family. J Biol Chem 285:2867–2875
Figarella K, et al (2007) Biochemical characterization of Leishmania major aquaglyceroporin LmAQP1: possible role in volume regulation and osmotaxis. Mol Microbiol 65:1006–1017
Fu D, et al (2000) Structure of a glycerol-conducting channel and the basis for its selectivity. Science 290:481–486
Goldberg B, et al (1997) A unique transporter of S-adenosylmethionine in African trypanosomes. FASEB J 11:256–260
Goodwin LG (1995) Pentostam (sodium stibogluconate): a 50-year personal reminiscence. Trans R Soc Trop Med Hyg 89:339–341
Goodwin LG, Page JE (1943) A study of the excretion of organic antimonials using a polarographic procedure. Biochem J 37:198–209
Gourbal B, et al (2004) Drug uptake and modulation of drug resistance in Leishmania by an aquaglyceroporin. J Biol Chem 279:31010–31017
Griffiths M, et al (1997) Cloning of a human nucleoside transporter implicated in the cellular uptake of adenosine and chemotherapeutic drugs. Nat Med 3:89–93
Grondin K, et al (1997) Co-amplification of the γ-glutamylcysteine synthetase gene gsh1 and of the ABC transporter gene pgpA in arsenite-resistant Leishmania tarentolae. EMBO J 16:3057–3065
Guan L, Kaback HR (2006) Lessons from lactose permease. Annu Rev Biophys Biomol Struct 35:67–91
Hammond DJ, Gutteridge WE (1984) Purine and pyrimidine metabolism in the Trypanosomatidae. Mol Biochem Parasitol 13:243–261
Hansen BD, et al (1982) The specificity of purine base and nucleoside uptake in promastigotes of Leishmania braziliensis panamensis. Parasitology 85:271–282
Iovannisci DM, Ullman B (1983) High efficiency plating method for Leishmania promastigotes in semidefined or completely-defined medium. J Parasitol 69:633–636
Iovannisci DM, et al (1984) Genetic analysis of nucleoside transport in Leishmania donovani. Mol Cell Biol 4:1013–1019
Ivens AC, et al (2005) The genome of the kinetoplastid parasite, Leishmania major. Science 309:436–442
Javitch JA, et al (1995) Mapping the binding-site crevice of the dopamine D2 receptor by the substituted-cysteine accessibility method. Neuron 14:825–831
Kaur K, et al (1988) Methotrexate-resistant Leishmania donovani genetically deficient in the folate-methotrexate transporter. J Biol Chem 263:7020–7028
Kavanaugh MP (1998) Neurotransmitter transport: models in flux. Proc Natl Acad Sci USA 95:12737–12738
Kerby BR, Detke S (1993) Reduced purine accumulation is encoded on an amplified DNA in Leishmania mexicana amazonensis resistant to toxic nucleosides. Mol Biochem Parasitol 60:171–185
King LS, Kozono D, Agre P (2004) From structure to disease: the evolving tale of aquaporin biology. Nat Rev Mol Cell Biol 5:687–698
King AE, et al (2006) Nucleoside transporters: from scavengers to novel therapeutic targets. Trends Pharmacol Sci 27:416–425
Kündig C, et al (1999) Increased transport of pteridines compensates for mutations in the high affinity folate transporter and contributes to methotrexate resistance in the protozoan parasite Leishmania tarentolae. EMBO J 18:2342–2351
Légaré D, et al (2001) The Leishmania ATP-binding cassette protein PGPA is an intracellular metal-thiol transporter ATPase. J Biol Chem 276:26301–26307
Lemley C, et al (1999) The Leishmania donovani LD1 locus gene ORFG encodes a biopterin transporter (BT1). Mol Biochem Parasitol 104:93–105
Leslie G, Barrett M, Burchmore R (2002) Leishmania mexicana: promastigotes migrate through osmotic gradients. Exp Parasitol 102:117–120
Liu Z, et al (2002) Arsenite transport by mammalian aquaglyceroporins AQP7 and AQP9. Proc Natl Acad Sci USA 99:6053–6058
Maharjan M, et al (2008) Role of aquaglyceroporin (AQP1) gene and drug uptake in antimony-resistant clinical isolates of Leishmania donovani. Am J Trop Med Hyg 79:69–75
Mandal S, et al (2010) Assessing aquaglyceroporin gene status and expression profile in antimony-susceptible and -resistant clinical isolates of Leishmania donovani from India. J Antimicrob Chemother 65:496–507
Marquis N, et al (2005) Modulation in aquaglyceroporin AQP1 gene transcript levels in drug-resistant Leishmania. Mol Microbiol 57:1690–1699
Marr JJ (1991) Purine analogs as chemotherapeutic agents in leishmaniasis and American trypanosomiasis. J Lab Clin Med 118:111–119
Marr JJ, Berens RL, Nelson DJ (1978) Purine metabolism in Leishmania donovani and Leishmania braziliensis. Biochim Biophys Acta 544:360–371
Martinez S, Marr JJ (1992) Allopurinol in the treatment of American cutaneous leishmaniasis. N Engl J Med 326:741–744
Martinez S, et al (1988) The synergistic action of pyrazolopyrimidines and pentavalent antimony against Leishmania donovani and L. braziliensis. Am J Trop Med Hyg 39:250–255
Murata K, et al (2000) Structural determinants of water permeation through aquaporin-1. Nature 407:599–605
Myler PJ, et al (1994) A frequently amplified region in Leishmania contains a gene conserved in prokaryotes and eukaryotes. Gene 148:187–193
Newby ZE, et al (2008) Crystal structure of the aquaglyceroporin PfAQP from the malarial parasite Plasmodium falciparum. Nat Struct Mol Biol 15:619–625
Ortiz D, et al (2007) Molecular genetic analysis of purine nucleobase transport in Leishmania major. Mol Microbiol 64:1228–1243
Ortiz D, et al (2009) An acid-activated nucleobase transporter from Leishmania major. J Biol Chem 284:16164–16169
Ouameur AA, et al (2008) Functional analysis and complex gene rearrangements of the folate/biopterin transporter (FBT) gene family in the protozoan parasite Leishmania. Mol Biochem Parasitol 162:155–164
Papadopoulou B, Roy G, Ouellette M (1993) Frequent amplification of a short chain dehydrogenase gene as part of circular and linear amplicons in methotrexate resistant Leishmania. Nucleic Acids Res 21:4305–4312
Papadopoulou B, et al (1994) Changes in folate and pterin metabolism after disruption of the Leishmania H locus short chain dehydrogenase gene. J Biol Chem 269:7310–7315
Peacock CS, Seeger K et al (2007) Comparative genomic analysis of three Leishmania species that cause diverse human disease. Nat Genet 39:839–847
Phelouzat MA, et al (1995) Sinefungin shares AdoMet-uptake system to enter Leishmania donovani promastigotes. Biochem J 305:133–137
Preston GM, Agre P (1991) Isolation of the cDNA for erythrocyte integral membrane protein of 28 kilodaltons: member of an ancient channel family. Proc Natl Acad Sci USA 88:11110–11114
Ramírez-Solís A, et al (2004) Experimental and theoretical characterization of arsenite in water: insights into the coordination environment of As-O. Inorg Chem 43:2954–2959
Richard D, Kündig C, Ouellette M (2002) A new type of high affinity folic acid transporter in the protozoan parasite Leishmania and deletion of its gene in methotrexate-resistant cells. J Biol Chem 277:29460–29467
Richard D, et al (2004) Growth phase regulation of the main folate transporter of Leishmania infantum and its role in methotrexate resistance. J Biol Chem 279:54494–55450
Saier MH Jr, et al (1999) The major facilitator superfamily. J Mol Microbiol Biotechnol 1:257–279
Sanchez MA, et al (2004) Functional expression and characterisation of a purine nucleobase transporter gene from Leishmania major. Mol Membr Biol 21:11–18
Sanders OI, et al (1997) Antimonite is accumulated by the glycerol facilitator GlpF in Escherichia coli. J Bacteriol 179:3365–3367
Segovia M, Ortiz G (1997) LD1 amplifications in Leishmania. Parasitol Today 13:342–348
Sereno D, et al (1998) Axenically grown amastigotes of Leishmania infantum used as an in vitro model to investigate the pentavalent antimony mode of action. Antimicrob Agents Chemother 42:3097–3102
Shaked-Mishan P, et al (2001) Novel Intracellular SbV reducing activity correlates with antimony susceptibility in Leishmania donovani. J Biol Chem 276:3971–3976
Stein A, et al (2003) Equilibrative nucleoside transporter family members from Leishmania donovani are electrogenic proton symporters. J Biol Chem 278:35127–35134
Stroud RM, et al (2003) Selectivity and conductance among the glycerol and water conducting aquaporin family of channels. FEBS Lett 555:79–84
Sui H, et al (2001) Structural basis of water-specific transport through the AQP1 water channel. Nature 414:872–878
Ubeda JM, et al (2008) Modulation of gene expression in drug resistant Leishmania is associated with gene amplification, gene deletion and chromosome aneuploidy. Genome Biol 9:R115
Ullman B (1984) Pyrazolopyrimidine metabolism in parasitic protozoa. Pharmaceut Res 1:194–203
Uzcategui NL, et al (2008) Alteration in glycerol and metalloid permeability by a single mutation in the extracellular C-loop of Leishmania major aquaglyceroporin LmAQP1. Mol Microbiol 70:1477–1486
Valdés R, et al (2004) Transmembrane domain 5 of the LdNT1.1 nucleoside transporter is an amphipathic helix that forms part of the nucleoside translocation pathway. Biochemistry 43:6793–6802
Valdés R, et al (2006) Comprehensive examination of charged intramembrane residues in a nucleoside transporter. J Biol Chem 281:22647–22655
Valdés R, et al (2009) An ab initio structural model of a nucleoside permease predicts functionally important residues. J Biol Chem 284:19067–19076
Van Winkle LJ (1999) Biomembrane transport. Academic Press, San Diego
Vasudevan G, et al (1998) Cloning of Leishmania nucleoside transporter genes by rescue of a transport-deficient mutant. Proc Natl Acad Sci USA 95:9873–9878
Vasudevan G, Ullman B, Landfear SM (2001) Point mutations in a nucleoside transporter gene from Leishmania donovani confer drug resistance and alter substrate selectivity. Proc Natl Acad Sci USA 98:6092–6097
Vinothkumar KR, Henderson R (2010) Structures of membrane proteins. Q Rev Biophys 43:65–158
Wysocki R, et al (2001) The glycerol channel Fps1p mediates the uptake of arsenite and antimonite in Saccharomyces cerevisiae. Mol Microbiol 40:1391–1401
Zhou Y, et al (2004) Leishmania major LmACR2 is a pentavalent antimony reductase that confers sensitivity to the drug pentostam. J Biol Chem 279:37445–37451
Zilberstein D, Philosoph H, Gepstein A (1989) Maintenance of cytoplasmic pH and proton motive force in promastigotes of Leishmania donovani. Mol Biochem Parasitol 36:109–118
Acknowledgment
Preparation of this chapter was supported by grants AI25920 and AI44138 to the author from the National Institutes of Health.
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Landfear, S.M. (2013). Functional Analysis of Leishmania Membrane (Non-ABC) Transporters Involved in Drug Resistance. In: Ponte-Sucre, A., Diaz, E., Padrón-Nieves, M. (eds) Drug Resistance in Leishmania Parasites. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1125-3_13
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