ABC transporter; Saccharomyces cerevisiae; Trypanosoma brucei; Drug target; Lipid precursor; Xenopus laevis oocyte; Amino acid permease; Ion channel
Mathieu C, Macedo JP, Hürlimann D, Wirdnam C, Haindrich AC, Suter Grotemeyer M, Gonzalez-Salgado A, Schmidt RS, Inbar E, Mäser P, Bütikofer P, Zilberstein D, Rentsch D (2017), Arginine and lysine transporters are essential for Trypanosoma brucei, in PLoS One
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Russo-Abrahão T, Koeller CM, Steinmann ME, Silva-Rito S, Marins-Lucena T, Alves-Bezerra M, Lima-Giarola NL, de-Paula IF, Gonzalez-Salgado A, Sigel E, Bütikofer P, Heise N, Gondim KC (2017), H+-dependent inorganic phosphate uptake in Trypanosoma brucei is influenced by myo-inositol transporter, in Meyer-Fernandes, JR
, J Bioenerg Biomembr(49), 183.
Gottier P, Gonzalez-Salgado A, Menon AK, Liu YC, Acosta-Serrano A, Bütikofer P (2017), RFT1 Protein Affects Glycosylphosphatidylinositol (GPI) Anchor Glycosylation, in J Biol Chem
, 292, 1103.
Steinmann ME, Schmidt RS, Bütikofer P, Mäser P, Sigel E (2017), TbIRK is a signature sequence free potassium channel from Trypanosoma brucei locating to acidocalcisomes, in Scientific Reports
, 7(1), 656.
Goldman-Pinkovich A, Balno C, Strasser R, Zeituni-Molad M, Bendelak K, Rentsch D, Ephros M, Jardim A, Wiese M, Myler PJ, Zilberstein D (2016), An Arginine Deprivation Response Pathway Is Induced in Leishmania during Macrophage Invasion, in PLoS Pathogens
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de Macêdo J (2015), An Atypical Mitochondrial Carrier That Mediates Drug Action in Trypanosoma brucei, in PLoS Pathogens
, 11, e1004875.
Serricchio M, Schmid AW, Steinmann ME, Sigel E, Rauch M, Julkowska D, Bonnefoy S, Fort C, Bastin P, Bütikofer P (2015), Flagellar membranes are rich in raft-forming phospholipids, in Biol Open
, 14, 1143.
Schlisselberg D, Mazarib E, Inbar E, Rentsch D, Myler PJ, Zilberstein D (2015), Size does matter: 18 amino acids at the N-terminal tip of an amino acid transporter in Leishmania determine substrate specificity, in Scientific Reports
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Shameer S (2015), TrypanoCyc: a community-led biochemical pathways database for Trypanosoma brucei, in Nucleic Acids Res
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González-Salgado A (2015), Trypanosoma brucei Bloodstream Forms Depend upon Uptake of myo-Inositol for Golgi Complex Phosphatidylinositol Synthesis and Normal Cell Growth, in Eukaryot Cell
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Mathieu Christoph, Salgado Amaia González, Wirdnam Corina, Meier Stefan, Grotemeyer Marianne Suter, Inbar Ehud, Mäser Pascal, Zilberstein Dan, Sigel Erwin, Bütikofer Peter, Rentsch Doris (2014), Trypanosoma brucei eflornithine transporter AAT6 is a low-affinity low-selective transporter for neutral amino acids., in The Biochemical journal
, 463(1), 9-18.
Inbar E, Schlisselberg D, Suter Grotemeyer M, Rentsch D, Zilberstein D (2013), A versatile proline/alanine transporter in the unicellular pathogen Leishmania donovani regulates amino acid homoeostasis and osmotic stress responses, in Biochem
, 449, 555.
Macêdo Juan P, Schmidt Remo S, Mäser Pascal, Rentsch Doris, Vial Henri J, Sigel Erwin, Bütikofer Peter (2013), Characterization of choline uptake in Trypanosoma brucei procyclic and bloodstream forms., in Molecular and biochemical parasitology
, 190(1), 16-22.
Greganova Eva, Steinmann Michael, Mäser Pascal, Fankhauser Niklaus (2013), In silico ionomics segregates parasitic from free-living eukaryotes., in Genome biology and evolution
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Steinmann M, A heteromeric potassium channel involved in the modulation of the plasma membrane potential is essential for the survival of African trypanosomes, in FASEB J
Transporters are increasingly being recognized as key players in cell physiology and determinants of drug susceptibility. This is particularly the case for parasites, which - by definition - rely on import of nutrients from their hosts. In our ongoing Sinergia project on functional genomics of nutrient transporters in Trypanosoma brucei, we are investigating four selected groups of nutrient transporters which we believe to be of particular pharmacological interest in the sleeping sickness parasite: ion channels, amino acid transporters, ABC transporters, and transporters of lipid precursors. Substrate specificities and transport kinetics are being determined by expression in Saccharomyces cerevisiae and Xenopus laevis oocytes while the physiological role is studied by reverse genetics in T. brucei. This combination has proven very fruitful. By investigating transporters in an interdisciplinary way, we are validating them as drug targets or drug delivery systems. In the present research proposal we will further extend and deepen these analyses. Incorporating phylogenomic comparisons with fully sequenced trypanosomatid genomes and new developments in the field of T. brucei molecular genetics will allow us to understand the transporters in the context of their phylogeny, physiology and pharmacology.Essentiality of T. brucei nutrient transporters will be predicted in silico based on conserved orthology groups amongst trypanosomatids and imprints of negative selection in the coding regions. Essentiality prediction in vivo will be performed by a combination of genome-wide RNAi screens and high throughput sequencing. Thus nutrient transporters will be prioritized according to their predicted pharmacological and physiological importance. Heterologous expression in S. cerevisiae and X. laevis oocytes functionally characterizes the transporters and serves as a screening platform for inhibitors and toxic substrates of transporters that have been validated as essential in T. brucei bloodstream forms. The subcellular localization of transporters will be determined in trypanosomes, and lipidomics and metabolomics will be applied to study transport physiology and to de-orphanize transporters of unknown substrates. Finally, drug tests against bloodstream-form T. brucei in culture or in a mouse model will validate the identified inhibitors or toxic substrates and identify further leads. Integrated data management will be done on the KNIME (Konstanz Information Miner) platform.The proposed research will result in an increased understanding of the evolution of T. brucei transporters, their physiology in terms of nutrient acquisition and metabolism, and their pharmacological potential for chemotherapeutic strategies that exploit transporters as drug delivery systems or targets. New starting points for drug development against trypanosomatid parasites and potentially novel kinds of nutrient transporters will be discovered.