[5][6][7] The major physiological roles of PCFTs are in mediating the intestinal absorption of folate (Vitamin B9), and its delivery to the central nervous system.

[8] Structurally, there are twelve transmembrane helices with the N- and C- termini directed to the cytoplasm and a large internal loop that divides the molecule in half.

[16] A variety of organic anions inhibit PCFT-mediated transport at extremely high ratio of inhibitor to folate, the most potent are sulfobromophthalein, p-aminobenzylglutamate, and sulfathalazine.

[23] There is also evidence for a role of vitamin D in the regulation of PCFT with a VDR response element upstream of the minimal promoter.

The CNS folate deficiency is associated with a variety of neurological findings including developmental delays and seizures.

[25] However, a role for PCFT in heme and iron homeostasis is excluded by the observation that humans or mice with loss-of-function PCFT mutations are not iron or heme deficient and the anemia, and all other systemic consequences of the loss of this transporter, are completely corrected with high-dose oral, or low-dose, parenteral folate.

[27][36] Because of the Warburg effect, and a compromised blood supply, human epithelial cancers grow within an acidic milieu, as lactate is produced during anaerobic glycolysis.

Because PCFT activity is optimal at low pH, and its expression and a prominent low-pH transport activity are present in human cancers,[39][40] there is interest in exploiting these properties by the development of antifolates that have a high affinity for this transporter and a very low affinity for the reduced folate carrier which delivers antifolates to normal tissues and thereby mediates the toxicity of these agents.