Although a deficiency of folate can occur through dietary insufficiency, impaired transport of folate into cells could have similar deleterious effects. Three cellular mechanisms for folate transport have been identified: folate receptors (FR), reduced folate carrier (RFC), and the newly described proton-coupled folate transporter (PCFT). FRs are anchored to the cell surface plasma membrane by glycosylphosphatidylinositol.
15–18 Upon binding of folate to FR, the receptor-folate complex is internalized by endocytosis. There are four human isoforms of FR (α, β, γ, δ). In mice, the protein is referred to as folate binding protein (Folbp), and it has three isoforms (Folbp 1, 2 3) analogous to the α, β, and δ forms in humans. Depending on the isoform, FRs contain approximately 240 to 260 amino acids and have a molecular mass in the range of approximately 28 to 40 kDa, reflecting the extent of glycosylation. FRα has a much greater affinity for nonreduced folates, such as folic acid, than for reduced folates. RFC is a 57 to 65 kDa integral transmembrane and energy-dependent protein that exhibits a high affinity for N
5-methyltetrahydrofolate (MTF; Moravek Biochemicals, Inc., Brea, CA), the predominant form of folate in blood (see Refs.
19 and
20 for reviews). RFC (also known as reduced folate transporter and as folate transport protein) is a member of the
SLC19 family of solute carriers (
SLC19A1).
20 RFC functions as an anion exchanger operating optimally at pH 7.4; its activity and folate-concentrating ability decrease as pH decreases. PCFT is a newly described folate transport protein that is the product of
SLC46A1.
21 Originally identified as heme carrier protein 1,
22 PCFT mediates H
+-coupled electrogenic transport of folate and its derivatives with similar affinity for the oxidized and reduced forms of folic acid.
21 PCFT is reported to have a molecular weight of 50 to 65 kDa, depending on the extent of glycosylation.
23 PCFT is a typical integral membrane transporter protein and spans the membrane 12 times.
24 Folate transport by PCFT involves the influx of one H
+ per transport cycle. Because the transport process is electrogenic, this stoichiometry suggests that the zwitterionic form of folate is recognized by the transporter as the substrate, and the involvement of one H
+ indicates that folate is accepted as a substrate only in its electroneutral form.
25