ArticleAmerican journal of physiology. Cell physiology2012
A P425R mutation of the proton-coupled folate transporter causing hereditary folate malabsorption produces a highly selective alteration in folate binding.
Article in American journal of physiology. Cell physiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 31 citations in OpenAlex.
- Impact of nanodisc lipid composition on cell-free expression of proton-coupled folate transporter.PloS one · 2021Article
- A proton-coupled folate transporter mutation causing hereditary folate malabsorption locks the protein in an inward-open conformation.The Journal of biological chemistry · 2020Article
- Substitutions that lock and unlock the proton-coupled folate transporter (PCFT-SLC46A1) in an inward-open conformation.The Journal of biological chemistry · 2019Article
- Hereditary folate malabsorption due to a mutation in the external gate of the proton-coupled folate transporter SLC46A1.Blood advances · 2018Article
- The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer.Cancer chemotherapy and pharmacology · 2018Review
- The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption.Molecular aspects of medicine · 2017Review
- Article
- Functional and mechanistic roles of the human proton-coupled folate transporter transmembrane domain 6-7 linker.The Biochemical journal · 2016Article
- Role of the tryptophan residues in proton-coupled folate transporter (PCFT-SLC46A1) function.American journal of physiology. Cell physiology · 2016Article
- Identification of an Extracellular Gate for the Proton-coupled Folate Transporter (PCFT-SLC46A1) by Cysteine Cross-linking.The Journal of biological chemistry · 2016Article
- Experimentally optimized threading structures of the proton-coupled folate transporter.FEBS open bio · 2016Article
- Structural determinants of human proton-coupled folate transporter oligomerization: role of GXXXG motifs and identification of oligomeric interfaces at transmembrane domains 3 and 6.The Biochemical journal · 2015Article
- Identification of Tyr residues that enhance folate substrate binding and constrain oscillation of the proton-coupled folate transporter (PCFT-SLC46A1).American journal of physiology. Cell physiology · 2015Article
- The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer.Drug metabolism and disposition: the biological fate of chemicals · 2014Review
- Biology of the major facilitative folate transporters SLC19A1 and SLC46A1.Current topics in membranes · 2014Review
- The intestinal absorption of folates.Annual review of physiology · 2014Review
- The proton-coupled folate transporter: physiological and pharmacological roles.Current opinion in pharmacology · 2013Review
- Role of the fourth transmembrane domain in proton-coupled folate transporter function as assessed by the substituted cysteine accessibility method.American journal of physiology. Cell physiology · 2013Article
- Delineating the extracellular water-accessible surface of the proton-coupled folate transporter.PloS one · 2013Article
- The human proton-coupled folate transporter: Biology and therapeutic applications to cancer.Cancer biology & therapy · 2012Review
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5 authors at 1 institution in 1 country.
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Abstract
Proton-coupled folate transporter (PCFT) mediates folate intestinal absorption and transport across the choroid plexus, processes defective in subjects with hereditary folate malabsorption (HFM). PCFT is also widely expressed in human solid tumors where it contributes to the transport of pemetrexed and other antifolates. This study defines the basis for the functional changes due to a P425R mutation detected in a subject with HFM. Among various substitutions, only positively charged mutants (P425R and P425K) lost function but in a highly selective manner. Transport of reduced folates mediated by P425R-PCFT was virtually abolished; the methotrexate influx K(t) was increased fivefold (from 2 to 10 μM). In contrast, the pemetrexed influx K(t) mediated by P425R-PCFT was decreased 30% compared with wild-type (WT)-PCFT. Methotrexate inhibition of pemetrexed influx was competitive with a K(i) for WT-PCFT comparable to its influx K(t). However, the methotrexate influx K(i) for P425R-PCFT was ∼15-fold higher than the WT-PCFT influx K(t) and threefold higher than the methotrexate influx K(t) for the P425R-PCFT mutant. The confirmed secondary structure and homology modeling place the P425 residue at the junction of the 6th external loop and 12th transmembrane domain, remote from the aqueous translocation pathway, a prediction confirmed by the failure to label P425C-PCFT with N-biotinylaminoethyl methanethiosulfonate-biotin and the absence of inhibition of P425C-PCFT function by water-soluble sulfhydryl reagents. Hence, despite its location, the P425R-PCFT mutation produces a conformational change that fully preserves pemetrexed binding but markedly impairs binding of methotrexate and other folates to the carrier.
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