Structural basis for recognition and transport of folic acid in mammalian cells

Structural studies on mammalian vitamin transport lag behind other metabolites. Folates, also known as B9 vitamins, are essential cofactors in one-carbon transfer reactions in biology. Three different systems control folate uptake in the human body; folate receptors function to capture and internalise extracellular folates via endocytosis, whereas two major facilitator superfamily transporters, the reduced folate carrier (RFC; SLC19A1) and proton-coupled folate transporter (PCFT; SLC46A1) control the transport of folates across cellular membranes. Targeting specific folate transporters is being pursued as a route to developing new antifolates with improved pharmacology. Recent structures of the proton-coupled folate transporter, PCFT, revealed key insights into antifolate recognition and the mechanism of proton-coupled transport. Combined with previously determined structures of folate receptors and new predictions for the structure of the RFC, we are now able to develop a structure-based understanding of folate and antifolate recognition to accelerate efforts in antifolate drug development.