The proton-coupled folate transporter: physiological and pharmacological roles

- PCFT is the mechanism of intestinal absorption of folates and antifolates.
- Inactivating mutations of the PCFT gene result in hereditary folate malabsorption.
- PCFT activity is enhanced within the acidic microclimate of solid tumors.
- PCFT is a potential route for the selective delivery of antifolates to tumor cells.
- PCFT plays a role in folate transport across the choroid plexus.

Recent studies have identified the proton-coupled folate transporter (PCFT) as the mechanism by which folates are absorbed across the apical brush-border membrane of the small intestine and across the basolateral membrane of the choroid plexus into the cerebrospinal fluid. Both processes are defective when there are loss-of-function mutations in this gene as occurs in the autosomal recessive disorder hereditary folate malabsorption. Because this transporter functions optimally at low pH, antifolates are being developed that are highly specific for PCFT in order to achieve selective delivery to malignant cells within the acidic environment of solid tumors. PCFT has a spectrum of affinities for folates and antifolates that narrows and increases at low pH. Residues have been identified that play a role in folate and proton binding, proton coupling, and oscillation of the carrier between its conformational states.