This chapter focuses on the biology of the major facilitative membrane
folate transporters, the
reduced folate carrier (RFC), and the
proton-coupled folate transporter (PCFT). Folates are essential
vitamins, and
folate deficiency contributes to a variety of heath disorders. RFC is ubiquitously expressed and is the major
folate transporter in mammalian cells and tissues. PCFT mediates intestinal absorption of dietary folates. Clinically relevant
antifolates such as
methotrexate (MTX) are transported by RFC, and the loss of RFC transport is an important mechanism of MTX resistance. PCFT is abundantly expressed in human
tumors and is active under pH conditions associated with the tumor microenvironment.
Pemetrexed (PMX) is an excellent substrate for PCFT as well as for RFC. Novel
tumor-targeted
antifolates related to PMX with selective membrane transport by PCFT over RFC are being developed. The molecular picture of RFC and PCFT continues to evolve relating to membrane topology, N-glycosylation, energetics, and identification of structurally and functionally important domains and
amino acids. The molecular bases for MTX resistance associated with loss of RFC function, and for the rare autosomal recessive condition,
hereditary folate malabsorption (HFM), attributable to mutant PCFT, have been established. From structural homologies to the bacterial transporters GlpT and LacY, homology models were developed for RFC and PCFT, enabling new mechanistic insights and experimentally testable hypotheses. RFC and PCFT exist as homo-oligomers, and evidence suggests that homo-oligomerization of RFC and PCFT monomeric
proteins may be important for intracellular trafficking and/or transport function. Better understanding of the structure and function of RFC and PCFT should facilitate the rational development of new therapeutic strategies for
cancer as well as for HFM.