{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T02:00:32Z","timestamp":1789610432968,"version":"build-2803163510"},"reference-count":66,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2015,3,21]],"date-time":"2015-03-21T00:00:00Z","timestamp":1426896000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["84733"],"award-info":[{"award-number":["84733"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Microbiology"],"published-print":{"date-parts":[[2015,5]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>The <jats:styled-content style=\"fixed-case\"><jats:italic>T<\/jats:italic><\/jats:styled-content><jats:italic>rypanosoma brucei<\/jats:italic> aminopurine transporter <jats:styled-content style=\"fixed-case\">P<\/jats:styled-content>2\/<jats:styled-content style=\"fixed-case\">TbAT<\/jats:styled-content>1 has long been implicated in the transport of, and resistance to, the diamidine and melaminophenyl arsenical classes of drugs that form the backbone of the pharmacopoeia against African trypanosomiasis. Genetic alterations including deletions and single nucleotide polymorphisms (<jats:styled-content style=\"fixed-case\">SNPs<\/jats:styled-content>) have been observed in numerous strains and clinical isolates. Here, we systematically investigate each reported mutation and assess their effects on transporter function after expression in a <jats:italic>tbat1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> <jats:styled-content style=\"fixed-case\"><jats:italic>T<\/jats:italic><\/jats:styled-content><jats:italic>.\u2009brucei<\/jats:italic> line. Out of a set of six reported <jats:styled-content style=\"fixed-case\">SNPs<\/jats:styled-content> from a reported \u2018resistance allele\u2019, none significantly impaired sensitivity to pentamidine, diminazene or melarsoprol, relative to the <jats:styled-content style=\"fixed-case\"><jats:italic>TbAT<\/jats:italic><\/jats:styled-content><jats:italic>1<\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> allele, although several combinations, and the deletion of the codon for residue <jats:styled-content style=\"fixed-case\">F<\/jats:styled-content>316, resulted in highly significant impairment. These combinations of <jats:styled-content style=\"fixed-case\">SNPs<\/jats:styled-content>, and \u0394<jats:styled-content style=\"fixed-case\">F<\/jats:styled-content>316, also strongly impaired the uptake of [<jats:sup>3<\/jats:sup><jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>]\u2010adenosine and [<jats:sup>3<\/jats:sup><jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>]\u2010diminazene, identical to the <jats:italic>tbat1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> control. The <jats:styled-content style=\"fixed-case\">TbAT<\/jats:styled-content>1 protein model predicted that residues <jats:styled-content style=\"fixed-case\">F<\/jats:styled-content>19, <jats:styled-content style=\"fixed-case\">D<\/jats:styled-content>140 and <jats:styled-content style=\"fixed-case\">F<\/jats:styled-content>316 interact with the substrate of the transporter. Mutation of <jats:styled-content style=\"fixed-case\">D<\/jats:styled-content>140 to alanine resulted in an inactive transporter, whereas the mutation <jats:styled-content style=\"fixed-case\">F<\/jats:styled-content>19A produced a transporter with a slightly increased affinity for [<jats:sup>3<\/jats:sup><jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>]\u2010diminazene but reduced the uptake rate. The results presented here validate earlier hypotheses of drug binding motifs for <jats:styled-content style=\"fixed-case\">TbAT<\/jats:styled-content>1.<\/jats:p>","DOI":"10.1111\/mmi.12979","type":"journal-article","created":{"date-parts":[[2015,2,24]],"date-time":"2015-02-24T10:23:32Z","timestamp":1424773412000},"page":"887-900","source":"Crossref","is-referenced-by-count":54,"title":["Functional analysis of drug resistance\u2010associated mutations in the <scp><i>T<\/i><\/scp><i>rypanosoma brucei<\/i> adenosine transporter 1 (<scp>TbAT<\/scp>1) and the proposal of a structural model for the protein"],"prefix":"10.1111","volume":"96","author":[{"given":"Jane C.","family":"Munday","sequence":"first","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow  Glasgow G12 8TA UK"},{"name":"Wellcome Trust Centre for Molecular Parasitology University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel N. A.","family":"Tagoe","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow  Glasgow G12 8TA UK"},{"name":"Department of Laboratory Technology University of Cape Coast  Cape Coast Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthonius A.","family":"Eze","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow  Glasgow G12 8TA UK"},{"name":"Department of Medical Biochemistry College of Medicine University of Nigeria  Enugu Campus Enugu Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica A. M.","family":"Krezdorn","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow  Glasgow G12 8TA UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla E.","family":"Rojas L\u00f3pez","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow  Glasgow G12 8TA UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulsalam A. M.","family":"Alkhaldi","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow  Glasgow G12 8TA UK"},{"name":"Department of Biology College of Science Aljouf University  Sakaka Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"McDonald","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow  Glasgow G12 8TA UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Still","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow  Glasgow G12 8TA UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid J.","family":"Alzahrani","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow  Glasgow G12 8TA UK"},{"name":"Faculty of Medical Sciences Taif University  Taif Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Settimo","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow  Glasgow G12 8TA UK"},{"name":"Department of Chemistry and Chemical Biology 417 Egan Research Center Northeastern University  360 Huntington Avenue Boston MA 02115 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry P.","family":"De Koning","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow  Glasgow G12 8TA 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