Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Am J Physiol Cell Physiol
2010 Nov 01;2995:C1153-61. doi: 10.1152/ajpcell.00113.2010.
Show Gene links
Show Anatomy links
Properties of the Arg376 residue of the proton-coupled folate transporter (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate malabsorption.
Mahadeo K
,
Diop-Bove N
,
Shin D
,
Unal ES
,
Teo J
,
Zhao R
,
Chang MH
,
Fulterer A
,
Romero MF
,
Goldman ID
.
???displayArticle.abstract???
The proton-coupled folate transporter (PCFT-SLC46A1) is required for intestinal folate absorption and is mutated in the autosomal recessive disorder, hereditary folate malabsorption (HFM). This report characterizes properties and requirements of the R376 residue in PCFT function, including a R376Q mutant associated with HFM. Gln, Cys, and Ala substitutions resulted in markedly impaired transport of 5-formyltetrahydrofolate (5-FTHF) and 5-methyltetrahydrofolate (5-MTHF) due to an increase in K(m) and decrease in V(max) in HeLa R1-11 transfectants lacking endogenous folate transport function. In contrast, although the influx K(m) for pemetrexed was increased, transport was fully preserved at saturating concentrations and enhanced for the like-charged R376K- and R376H-PCFT. Pemetrexed and 5-FTHF influx mediated by R376Q-PCFT was markedly decreased at pH 5.5 compared with wild-type PCFT. However, while pemetrexed transport was substantially preserved at low pH (4.5-5.0), 5-FTHF transport remained very low. Electrophysiological studies in Xenopus oocytes demonstrated that 1) the R376Q mutant, like wild-type PCFT, transports protons in the absence of folate substrate, and in this respect has channel-like properties; and 2) the influx K(m) mediated by R376Q-PCFT is increased for 5-MTHF, 5-FTHF, and pemetrexed. The data suggest that mutation of the R376 residue to Gln impairs proton binding which, in turn, modulates the folate-binding pocket and depresses the rate of conformational alteration of the carrier, a change that appears to be, in part, substrate dependent.
Atabay,
Mutation of the proton-coupled folate transporter gene (PCFT-SLC46A1) in Turkish siblings with hereditary folate malabsorption.
2010, Pubmed
Atabay,
Mutation of the proton-coupled folate transporter gene (PCFT-SLC46A1) in Turkish siblings with hereditary folate malabsorption.
2010,
Pubmed
Borzutzky,
Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter.
2009,
Pubmed
Cario,
Congenital null mutations of the FOLR1 gene: a progressive neurologic disease and its treatment.
2009,
Pubmed
Chang,
Entry to "formula tunnel" revealed by SLC4A4 human mutation and structural model.
2008,
Pubmed
,
Xenbase
Chattopadhyay,
Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications.
2007,
Pubmed
Diop-Bove,
Hypermethylation of the human proton-coupled folate transporter (SLC46A1) minimal transcriptional regulatory region in an antifolate-resistant HeLa cell line.
2009,
Pubmed
Geller,
Hereditary folate malabsorption: family report and review of the literature.
2002,
Pubmed
Gunshin,
Cloning and characterization of a mammalian proton-coupled metal-ion transporter.
1997,
Pubmed
,
Xenbase
Jebnoun,
A family study of congenital malabsorption of folate.
2001,
Pubmed
Kamen,
A review of folate receptor alpha cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro.
2004,
Pubmed
Lanzkowsky,
Isolated defect of folic acid absorption associated with mental retardation and cerebral calcification.
1969,
Pubmed
Lasry,
A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function.
2008,
Pubmed
Mackenzie,
Divalent metal-ion transporter DMT1 mediates both H+ -coupled Fe2+ transport and uncoupled fluxes.
2006,
Pubmed
,
Xenbase
McEwan,
A combined TDDA-PVC pH and reference electrode for use in the upper small intestine.
1990,
Pubmed
Meyer,
A novel PCFT gene mutation (p.Cys66LeufsX99) causing hereditary folate malabsorption.
2010,
Pubmed
Min,
The clinical course and genetic defect in the PCFT gene in a 27-year-old woman with hereditary folate malabsorption.
2008,
Pubmed
Qiu,
Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption.
2006,
Pubmed
,
Xenbase
Qiu,
Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction.
2007,
Pubmed
,
Xenbase
Reynolds,
Anticonvulsants, folic acid, and epilepsy.
1973,
Pubmed
Steinfeld,
Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism.
2009,
Pubmed
Umapathy,
Cloning and functional characterization of the proton-coupled electrogenic folate transporter and analysis of its expression in retinal cell types.
2007,
Pubmed
,
Xenbase
Unal,
N-linked glycosylation and its impact on the electrophoretic mobility and function of the human proton-coupled folate transporter (HsPCFT).
2008,
Pubmed
Unal,
The functional roles of the His247 and His281 residues in folate and proton translocation mediated by the human proton-coupled folate transporter SLC46A1.
2009,
Pubmed
,
Xenbase
Unal,
Role of the glutamate 185 residue in proton translocation mediated by the proton-coupled folate transporter SLC46A1.
2009,
Pubmed
Wang,
Localization of the murine reduced folate carrier as assessed by immunohistochemical analysis.
2001,
Pubmed
Weitman,
Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues.
1992,
Pubmed
Weitman,
Cellular localization of the folate receptor: potential role in drug toxicity and folate homeostasis.
1992,
Pubmed
Zhao,
The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption.
2007,
Pubmed
Zhao,
The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier.
2008,
Pubmed
,
Xenbase
Zhao,
Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues.
2009,
Pubmed
Zhao,
A role for the proton-coupled folate transporter (PCFT-SLC46A1) in folate receptor-mediated endocytosis.
2009,
Pubmed
Zhao,
The mechanism of transport of the multitargeted antifolate (MTA) and its cross-resistance pattern in cells with markedly impaired transport of methotrexate.
2000,
Pubmed
Zhao,
A prominent low-pH methotrexate transport activity in human solid tumors: contribution to the preservation of methotrexate pharmacologic activity in HeLa cells lacking the reduced folate carrier.
2004,
Pubmed
Zhao,
Membrane topological analysis of the proton-coupled folate transporter (PCFT-SLC46A1) by the substituted cysteine accessibility method.
2010,
Pubmed
