2.A.1.50.1
The apical intestinal and choroid plexus proton-coupled, high affinity folate transporter, the hereditary folate malabsorption (HFM) protein, PCFT/HCP1 (Shin et al. 2010).  Also reported to mediate heme-iron uptake from the gut lumen with duodenal epithelial cells (Shayeghi et al., 2005; Latunde-Dada et al., 2006; Subramanian et al., 2008, Shin et al., 2012b), but it shows a higher affinity for folate than heme) (Qiu et al., 2006). Responsible for folate uptake by choroid plexus epithelial cells (Wollack et al., 2007) and placenta (Yasuda et al., 2008). The rat orthologue (Q5EBA8) catalyzes H⁺-dependent folate uptake in the intestine (Inoue et al., 2008; Zhao and Goldman, 2007; Qiu et al., 2006; Shin et al., 2012). Evidence for a 12 TMS topology with a renetrant loop between TMSs 2 and 3 has been presented (Zhao et al., 2010; Qiu et al., 2006; Zhao et al., 2011; Wilson et al. 2014).  Downregulated in Chronic Kidney Disease (CKD) in heart, liver, and brain, causing malabsorption (Bukhari et al., 2011). An IGXXG motif in TMS5 is important for folate binding and a GXXXG motif is involved in dimerization (Zhao et al., 2012). It is inhibited by bicarbonate, bisulfite, nitrite and other anions (Zhao et al. 2013).  Its role in antifolate cancer chemotherapy has been reviewed (Matherly et al. 2014). TMSs 3 and 6 may provide critical interfaces for formation of hPCFT oligomers, facilitated by the GXXXG motifs in TMS2 and TMS4 (Wilson et al. 2015).  The extracellular gate has been identified (Zhao et al. 2016), and mechanistic aspects have been considered (Date et al. 2016). Residues in the seventh and eighth TMSs play roles in the translocation pathway and folate binding (Aluri et al. 2017). The mutation, N411K-PCFT, is responsible for HFM (Aluri et al. 2018). PCFT is ubiquitously expressed in solid tumors to which it delivers antifolates, particularly pemetrexed, into cancer cells in a concentrative fashion (Zhao et al. 2018). Substitutions have been identified that lock and unlock PCFT into an inward-open conformation (Aluri et al. 2019). The nanodisc lipid composition influences the cell-free expression of PCFT (Do et al. 2021). Iron deficiency promotes hepatocellular carcinoma metastasis, and the loss of SLC46A1 expression leads to iron deficiency in liver tumor tissues (Wang et al. 2022). Cell-free expression of PCFT in the presence of nanodiscs has been reported (Do and Jansen 2022). Biological and therapeutic applications of the proton-coupled folate transporter have been reviewed (Matherly et al. 2022).  FRα and multiple transporters such as PCFT, RFC, OAT4, and OATPs are likely involved in the uptake of methotraxate (MTX), whereas MDR1 and BCRP are implicated in the efflux of MTX from choriocarcinoma cells (Bai et al. 2024).