2.A.71 The Folate-Biopterin Transporter (FBT) Family The FBT family includes functionally characterized members from protozoa, cyanobacteria (Synechocystis) and plants (Arabidopsis thaliana). Functionally characterized members of the family include FT1 (TC# 2.A.71.1.3), the major protozoan folate transporter, BT1 (2.A.71.1.2), the biopterin/folate transporter and AdoMetT1, the major S-adenosylmethionine uptake porter (2.A.71.1.5). There are at least 6 homologues of the FT1 transporter in Leishmania encoded by tandem genes. A related protein in Trypanosoma brucei, ESAGIO, shows weak folate/biopterin transport activity. Proteins of the FBT family are reported to contain 627-631 aas (Leishmania species), 408-431 aas (A. thaliana) and 453-494 aas (cyanobacteria). All probably have 12 TMSs. They may function by H⁺ symport. The FBT family is a distant family within the major facilitator superfamily (MFS; TC #2.A.1). The probable transport reaction catalyzed by characterized FBT family members is: [folate, biopterin or AdoMet] (out) + nH⁺ (out) → [folate, biopterin or AdoMet] (in) + nH⁺ (in)
This family belongs to the Major Facilitator (MFS) Superfamily.
References:
Dridi, L., A. Ahmed Ouameur, and M. Ouellette. (2010). 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.
Eudes, A., E.R. Kunji, A. Noiriel, S.M. Klaus, T.J. Vickers, S.M. Beverley, J.F. Gregory, 3rd, and A.D. Hanson. (2010). Identification of transport-critical residues in a folate transporter from the folate-biopterin transporter (FBT) family. J. Biol. Chem. 285: 2867-2875.
Gottesdiener, K.M. (1994). A new VSG expression site-associated gene (ESAG) in the promoter region of Trypanosoma brucei encodes a protein with ten potential transmembrane domains. Mol. Biochem. Parasitol. 63: 143-151.
Kaur, K., T. Coons, K. Emmett, and B. Ullman. (1988). Methotrexate-resistant Leishmania donovani genetically deficient in the folate-methotrexate transporter. J. Biol. Chem. 263: 7020-7028.
Klaus, S.M., E.R. Kunji, G.G. Bozzo, A. Noiriel, R.D. de la Garza, G.J. Basset, S. Ravanel, F. Rebeille, J.F. Gregory, 3rd, and A.D. Hanson. (2005). Higher plant plastids and cyanobacteria have folate carriers related to those of trypanosomatids. J. Biol. Chem. 280: 38457-38463.
Kundig, C., A. Haimeur, D. Legare, B. Papadopoulou, and M. Ouellette. (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.
Massimine, K.M., L.T. Doan, C.A. Atreya, T.T. Stedman, K.S. Anderson, K.A. Joiner, and I. Coppens. (2005). Toxoplasma gondii is capable of exogenous folate transport. A likely expansion of the BT1 family of transmembrane proteins. Mol Biochem Parasitol 144: 44-54.
Myler, P.J., M.J. Lodes, G. Merlin, T. de Vos, and K.D. Stuart. (1994). An amplified DNA element in Leishmania encodes potential integral membrane and nucleotide-binding proteins. Mol. Biochem. Parasitol. 66: 11-20.
Ouellette, M., J. Drummelsmith, A. El-Fadili, C. Kundig, D. Richard, and G. Roy. (2002). Pterin transport and metabolism in Leishmania and related trypanosomatid parasites. Int. J. Parasitol. 32: 385-398.
Richard, D., C. Kundig, and M. Ouellette. (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.
Examples:
TC#	Name	Organismal Type	Example
2.A.71.1.1	BT1 biopterin/folate (not methotrexate) transporter	Protozoa	BT1 (OrfG) of Leishmania donovani

2.A.71.1.2	Biopterin transporter	Protozoa	BT1 of Leishmania mexicana

2.A.71.1.3	FT1 folate/biopterin transporter. This protein is nearly identical to the functionally characterized protein from L. infantum (2.A.71.1.5) which is a high affinity S-adenosyl methione uptake porter. Therefore the annotation shown above may be incorrect and this protein may also be an S-adenosyl methionine uptake porter (Dridi et al. 2010).	Protozoa	FT1 of Leishmania donovani

2.A.71.1.4	FT1 (ESAG10) folate/biopterin transporter	Protozoa	ESAG10 of Trypanosoma brucei

2.A.71.1.5	High affinity plasma membrane constitutively synthesized S-Adenosylmethionine (AdoMet) uptake transporter, AdoMetT1 of 706 aas. It also takes up the AdoMet analogue, Sinefungin (Dridi et al. 2010). This protein is nearly identical to 2.A.71.1.3 which may also be an AdoMet uptake transporter (by sequence similarity).		AdoMetT1 of Leishmania infantum

2.A.71.1.6	Folate/biopterin/methotrexate transporter, BT1, of 1057 aas and 14 TMSs in the N-terminal half of the protein (residues 1 - 500) with an equally long C-terminal hydrophilic domain. Uptake of folate across the parasite plasma membrane is rapid, biphasic, temperature dependent, bi-directional, concentration dependent and specific (Massimine et al. 2005).		BT1 of Toxoplasma gondii

Examples:
TC#	Name	Organismal Type	Example
2.A.71.2.1	Functionally uncharacterized Orf	Cyanobacteria	Orf of Synechococcus (PCC7942)

2.A.71.2.2	Folate/biopterin uptake carrier, Fbp. Transports 5-formyl tetrahydrofolate monoglutamate but not 5-formyltetrahydrofolate triglutamate. (Also transports methotrexate and aminopterin) (Klaus et al., 2005) (Nine homologues are present in Arabidopsis thaliana.) (Klaus et al., 2005). Mutational analyses suggest that the folate binding site involves the core helices 1, 4, 7 and 10 and is in the center of the membrane (Eudes et al., 2010).	Plants	Fbp of Arabidopsis thaliana (Q9SKZ5)

2.A.71.2.3	Folate/biopterin uptake carrier of 494 aas, Fbp (also transports methotrexate and aminopterin) (Klaus et al., 2005). Essential residues line the central cavity (based on the LacY structure) in TMSs 1, 4, 7 and 10 (Eudes et al. 2010).	Cyanobacteria	*Fbp (Srl0642) of Synechocystic* sp. PCC6803 (BAA10362)**

2.A.71.2.4	Folate transporter 3, FT3 of 537 aas and 14 putative TMSs.		FT3 of Nitrosospira lacus

2.A.71.2.5	Uncharacterized protein of 551 aas and 13 - 14 TMSs.		UP of Phytophthora parasitica

2.A.71.2.6	Folate transporter, BP1, of 442 aas and 12 TMSs.	Plants	BP1 of Arabidopsis thaliana

2.A.71.2.7	Folate/pABA/5-methyltetrahydrofolate transporter, putative, of 505 aas with 12 TMSs in a 6 + 6 TMS arrangement.		Folate transporter of Plasmodium falciparum

Examples:
TC#	Name	Organismal Type	Example