title: Toxoplasma gondii is capable of exogenous folate transport. A likely expansion of the BT1 family of transmembrane proteins.
abstract: Folates are key elements in eukaryotic biosynthetic processes. The protozoan parasite Toxoplasma gondii possesses the enzymes necessary for de novo folate synthesis and has been suggested to lack alternative mechanisms for folate acquisition. In this paper, we present a different view by providing evidence that Toxoplasma is capable of salvaging exogenous folates. By monitoring uptake of radiolabeled folates by parasites in axenic conditions, our studies revealed a common folate transporter that has a high affinity for folic acid. Transport of this compound across the parasite plasma membrane is rapid, biphasic, temperature dependent, bi-directional, concentration dependent and specific. In addition, morphological evidence demonstrates that fluorescent methotrexate, a folate analog, is internalized by Toxoplasma and shows localization reminiscent to the mitochondrion. The presence of putative folate transporter genes in the Toxoplasma genome, which are homologous to the BT1 family of proteins, suggests that Toxoplasma may encode proteins involved in folate transport. Interestingly, genome analysis suggests that the BT1 family of proteins exists not only in Toxoplasma, but in other Apicomplexan parasites as well. Altogether, our results not only have implications for current therapeutic regimens against T. gondii, but they also allude that the folate transport mechanism may represent a novel Apicomplexan target for the development of new drugs.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Massimine
authors.forename: Lanxuan T
authors.initials: LT
authors.lastname: Doan
authors.forename: Chloé A
authors.initials: CA
authors.lastname: Atreya
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Stedman
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
authors.forename: Keith A
authors.initials: KA
authors.lastname: Joiner
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coppens
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D003001:Cloning, Molecular; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology; D008727:Methotrexate / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D015800:Protozoan Proteins / Q000235:genetics / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014122:Toxoplasma / Q000235:genetics / Q000378:metabolism*
chemical_list: D026901:Membrane Transport Proteins; D015800:Protozoan Proteins; C424383:biopterin transporter 1 protein, Leishmania; D005492:Folic Acid; D008727:Methotrexate