High affinity S-Adenosylmethionine plasma membrane transporter of Leishmania is a member of the folate biopterin transporter (FBT) family.
S-Adenosylmethionine (AdoMet) is an important methyl group donor that plays a central role in many essential biochemical processes. The parasite Leishmania can both synthesize and transport AdoMet. Leishmania cells resistant to the antifolate methotrexate due to a rearrangement in folate biopterin transporter (FBT) genes were cross-resistant to sinefungin, an AdoMet analogue. FBT gene rearrangements were also observed in Leishmania major cells selected for sinefungin resistance. One of the rearranged FBT genes corresponded to the main AdoMet transporter (AdoMetT1) of Leishmania as determined by gene transfection and gene inactivation experiments. AdoMetT1 was determined to be a high affinity plasma membrane transporter expressed constitutively throughout the growth phases of the parasite. Leishmania cells selected for resistance or naturally insensitive to sinefungin had lower expression of AdoMetT1. A new function in one carbon metabolism, also a pathway of interest for chemotherapeutic interventions, is described for a novel class of membrane proteins found in diverse organisms.
Dridi
Larbi
L
Centre de Recherche en Infectiologie du CHUL, Université Laval, Québec City, Québec G1V 4G2, Canada.
Ahmed Ouameur
Amin
A
Ouellette
Marc
M
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology; D001692:Biological Transport; D001708:Biopterins / Q000378:metabolism; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D005492:Folic Acid / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007891:Leishmania / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008727:Methotrexate / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D009154:Mutation; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012436:S-Adenosylmethionine / Q000378:metabolism*
D000981:Antiprotozoal Agents; D005493:Folic Acid Antagonists; D026901:Membrane Transport Proteins; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D001708:Biopterins; D012436:S-Adenosylmethionine; D005492:Folic Acid; D000241:Adenosine; C006235:sinefungin; D008727:Methotrexate
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