{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC46A1, also known as the proton‐coupled folate transporter (PCFT), is a high‐affinity, pH‐dependent carrier that mediates the uptake of dietary folates in the proximal small intestine and facilitates folate delivery to critical tissues such as the central nervous system and placenta. Its activity at low pH enables efficient folate absorption under normally acidic luminal conditions, and loss‐of‐function mutations in SLC46A1 underlie the autosomal recessive disorder hereditary folate malabsorption. In addition, PCFT functions in concert with folate receptors and other endocytic processes to maintain intracellular folate homeostasis.<br>."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMolecular dissection of PCFT has revealed that its function depends on a network of conserved residues and structural motifs that govern protein stability, proper membrane targeting, substrate binding, and proton coupling. Site‐directed mutagenesis studies have identified critical roles for specific acidic and basic residues (for example, those in the DXXGRR motif, as well as residues such as D109, E185, R113, R376, and P425) in modulating transport kinetics and folate affinity. Furthermore, investigations using substituted cysteine accessibility methods, cryo‐electron microscopy, and analyses of pH‐dependent transport have defined a 12–transmembrane domain architecture with an aqueous substrate translocation pathway and demonstrated that, at least under physiologic conditions, PCFT functions as a monomer. These studies have provided a detailed mechanistic framework for understanding how proton gradients drive folate uptake.<br>."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "17"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinical and translational investigations have further extended our understanding of PCFT by linking specific mutations to hereditary folate malabsorption and by exploring its role as a target for antifolate chemotherapeutics in solid tumors. Novel mutations identified in affected individuals (for example, those affecting residues A335 and G338) compromise transporter function and have been correlated with altered drug transport kinetics. Structural studies, including recent cryo‐EM analyses, have provided a framework for designing PCFT‐selective antifolate agents that exploit its activity at acidic pH within the tumor microenvironment. Moreover, studies of transcriptional regulation (involving factors such as NRF‑1) and analyses of epigenetic modulation have underscored the dynamic control of PCFT expression in different tissues, with implications for treatment response in colorectal cancer and mesothelioma. Collectively, these findings highlight the dual importance of SLC46A1/PCFT in maintaining folate homeostasis and in serving as a therapeutic conduit for targeted antifolate delivery.<br>."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "34"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andong Qiu, Michaela Jansen, Antoinette Sakaris, et al. 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