ArticleAmerican journal of physiology. Cell physiology2015
Identification of Tyr residues that enhance folate substrate binding and constrain oscillation of the proton-coupled folate transporter (PCFT-SLC46A1).
Article in American journal of physiology. Cell physiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 18 citations in OpenAlex.
- The Role of Organic Cation Transporters in the Pharmacokinetics, Pharmacodynamics and Drug-Drug Interactions of Tyrosine Kinase Inhibitors.International journal of molecular sciences · 2023Review
- Biology and therapeutic applications of the proton-coupled folate transporter.Expert opinion on drug metabolism & toxicology · 2022Article
- The evolving biology of the proton-coupled folate transporter: New insights into regulation, structure, and mechanism.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Review
- 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
- Substituted-cysteine accessibility and cross-linking identify an exofacial cleft in the 7th and 8th helices of the proton-coupled folate transporter (SLC46A1).American journal of physiology. Cell physiology · 2018Article
- 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
- Residues in the eighth transmembrane domain of the proton-coupled folate transporter (SLC46A1) play an important role in defining the aqueous translocation pathway and in folate substrate binding.Biochimica et biophysica acta. Biomembranes · 2017Article
- Impact of posttranslational modifications of engineered cysteines on the substituted cysteine accessibility method: evidence for glutathionylation.American journal of physiology. Cell physiology · 2017Article
- 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
- 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
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The proton-coupled folate transporter (PCFT) mediates intestinal folate absorption and transport of folates across the choroid plexus. This study focuses on the role of Tyr residues in PCFT function. The substituted Cys-accessibility method identified four Tyr residues (Y291, Y362, Y315, and Y414) that are accessible to the extracellular compartment; three of these (Y291, Y362, and Y315) are located within or near the folate binding pocket. When the Tyr residues were replaced with Cys or Ala, these mutants showed similar (up to 6-fold) increases in influx Vmax and Kt/Ki for [(3)H]methotrexate and [(3)H]pemetrexed. When the Tyr residues were replaced with Phe, these changes were moderated or absent. When Y315A PCFT was used as representative of the mutants and [(3)H]pemetrexed as the transport substrate, this substitution did not increase the efflux rate constant. Furthermore, neither influx nor efflux mediated by Y315A PCFT was transstimulated by the presence of substrate in the opposite compartment; however, substantial bidirectional transstimulation of transport was mediated by wild-type PCFT. This resulted in a threefold greater efflux rate constant for cells that express wild-type PCFT than for cells that express Y315 PCFT under exchange conditions. These data suggest that these Tyr residues, possibly through their rigid side chains, secure the carrier in a high-affinity state for its folate substrates. However, this may be achieved at the expense of constraining the carrier's mobility, thereby decreasing the rate at which the protein oscillates between its conformational states. The Vmax generated by these Tyr mutants may be so rapid that further augmentation during transstimulation may not be possible.
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