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Substituted-cysteine accessibility and cross-linking identify an exofacial cleft in the 7th and 8th helices of the proton-coupled folate transporter (SLC46A1) with a role in defining the aqueous translocation pathway.
Low PCFT expression is associated with treatment response in mesothelioma.
our results demonstrate the substantial therapeutic potential of novel 6-substituted pyrrolo[2,3-d]pyrimidine antifolates with dual targeting of PCFT and FRalpha toward Epithelial ovarian cancer that express a range of FRalpha, along with PCFT, as well as cisplatin resistance
We found that purified detergent solubilized PCFT was able to bind folic acid, thus indicating a functionally active protein. To assess the oligomeric state negative stain electron microscopy was performed which showed a particle with the size of a PCFT dimer.
The 8th transmembrane helix of PCFT plays an important role in defining the aqueous channel and the folate binding pocket.
The hydrophobicity of the PCFT W299 residue is important for function suggesting that during the transport cycle this residue interacts with the lipid membrane thereby impacting on the oscillation of the carrier and, indirectly, on the folate binding pocket.
we observed nominally significant (but not definitive) associations between SLC46A1 SNPs and NTDs and oral clefts, and this finding warrants follow-up in other populations.
A homology model of PCFT, based upon the Escherichia coliglycerol 3-phosphate transporter structure, predicted that PCFT transmembrane domains (TMDs) 1, 2, 7, and 11 form an extracellular gate in the inward-open conformation.
We conclude that SLC46A1/PCFT and SLC19A1/RFC-1 are associated with DFS of patients with colorectal cancer and hypothesize that poor response to 5-fluorouracil plus leucovorin therapy in some patients may be linked to low expression of these genes.
Report sustained inhibition of PCFT by myricetin.
this is the first study to simultaneously evaluate both DNA methylation and protein expression of all three folate transporter genes, FOLR1, PCFT, and RFC1, in colorectal cancer.
results imply that TMDs 3 and 6 provide critical interfaces for formation of hPCFT oligomers, which might be facilitated by the GXXXG motifs in TMD2 and TMD4.
the RFC1 G80A polymorphism does not seem to be a good marker of MTX-related toxicity in pediatric ALL.
The current study addresses the role of Tyr residues in SLC46A1 function; and identifies four residues that enhance the affinity of the carrier for its substrates and decrease the rate at which the carrier oscillates between its conformational states.
SLC46A1 genotype may help to identify patients with increased risk of methotrexate-related toxicity.
Data indicate that 28/33 cysteine-less proton-coupled folate transporter (PCFT) mutant HeLa cells were active for [(3)H]methotrexate uptake.
The molecular bases for methotrexate resistance associated with loss of SLC19A1 transport and for hereditary folate malabsorption, attributable to mutant SLC46A1, were determned (review).
SLC46A1 SNP had a statistically significant association with HDL plasma levels.
At weakly acidic pH (6.5), bisulfite and nitrite exhibited much stronger inhibition of PCFT-mediated transport.
Two loss-of-function mutations in the fourth transmembrane domain of proton-coupled folate transporter (PCFT) play a role in hereditary folate malabsorption in subjects with this disorder.
Functional regulation of P-glycoprotein at the blood-brain barrier in proton-coupled folate transporter (PCFT) mutant mice.
expressed in placenta at highest level during early development
Hemochromatosis is associated not only with excessive accumulation of free iron in the retina and retinal pigment epithelium but also with excessive accumulation of heme.
In vivo folate uptake experiments demonstrated a systemic folate deficiency caused by disruption of PCFT-mediated intestinal folate uptake, thus confirming in vivo a critical role of the PCFT protein in intestinal folate transport and erythropoiesis.
heme carrier protein 1(HCP 1)is the long-sought intestinal heme transporter and was iron regulated and localized to the brush-border membrane of duodenal enterocytes in iron deficiency. Its mRNA was expressed in duodenum and regulated by hypoxia
Slc46a1/PCFT plays critical role in intestinal folate absorption.
Intestinal folate uptake process undergoes differentiation-dependent regulation and that this regulation is mediated via changes in the level of expression of both the RFC and PCFT.
This gene encodes a transmembrane proton-coupled folate transporter protein that facilitates the movement of folate and antifolate substrates across cell membranes, optimally in acidic pH environments. This protein is also expressed in the brain and choroid plexus where it transports folates into the central nervous system. This protein further functions as a heme transporter in duodenal enterocytes, and potentially in other tissues like liver and kidney. Its localization to the apical membrane or cytoplasm of intestinal cells is modulated by dietary iron levels. Mutations in this gene are associated with autosomal recessive hereditary folate malabsorption (HFM) disease. HFM is characterized by folate deficiency due to reduced intestinal folate absorption and subsequent anemia, hypoimmunoglobulinemia, and recurrent infections. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.
solute carrier family 46, member 1
, solute carrier family 46 (folate transporter), member 1
, proton-coupled folate transporter-like
, heme carrier protein 1
, proton-coupled folate transporter
, retinal pigment epithelilum transporter
, retinal pigment epithelium transporter
, solute carrier family 46 member 1