Biology of the Major Facilitative Folate Transporters SLC19A1 and SLC46A1

Hou, Zhanjun; Matherly, Larry H.

doi:10.1016/b978-0-12-800223-0.00004-9

Cited by 120 publications

(92 citation statements)

References 126 publications

(245 reference statements)

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“…The results of the present study showed that high expression of the two folate transport genes SLC19A1/RFC-1 and SLC46A1/PCFT in tumor tissue correlated with decreased risk of recurrent disease, measured as DFS. Both SLC19A1/RFC-1 and SLC46A1/PCFT belong to the superfamily of solute carriers, but are functionally distinct (26). The SLC19A1/RFC-1 gene encodes the reduced folate carrier which functions optimally at physiological pH, transferring reduced folates, including The expression levels for the two curves have been set one standard deviation above and one standard deviation below the mean, where one standard deviation corresponds to a fold change in log expression levels of 1.57.…”

Section: Ggh) and Folate Metabolism (Aldh1l1 Aldh1l2 Amt Atic Ftcmentioning

confidence: 99%

Expression of Folate Pathway Genes in Stage III Colorectal Cancer Correlates with Recurrence Status Following Adjuvant Bolus 5-FU-Based Chemotherapy

Odin

Sondén

Gustavsson

et al. 2015

Mol Med

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Colorectal cancer is commonly treated with 5-fluorouracil and 5-formyltetrahydrofolate (leucovorin). Metabolic action of leucovorin requires several enzymatic steps that are dependent on expression of corresponding coding genes. To identify folate pathway genes with possible impact on leucovorin metabolism, a retrospective study was performed on 193 patients with stage III colorectal cancer. Relative expression of 22 genes putatively involved in leucovorin transport, polyglutamation and metabolism was determined in tumor and mucosa samples using quantitative real-time polymerase chain reaction. After surgery, patients received adjuvant 5-fluorouracil-based bolus chemotherapy with leucovorin during six months, and were followed for 3 to 5 years. Cox regression analysis showed that high tumoral expression of the genes SLC46A1/PCFT (proton-coupled folate transporter) and SLC19A1/RFC-1 (reduced folate carrier 1) correlated significantly (p < 0.001 and p < 0.01, respectively) with a decreased risk of recurrent disease, measured as disease-free survival (DFS). These two genes are involved in the transport of folates into the cells and each functions optimally at a different pH. 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. Such patients might need a more intensified therapeutic approach than those with high gene expression. Future prospective studies will determine if the expression of any of these genes can be used to predict response to leucovorin.

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Section: Ggh) and Folate Metabolism (Aldh1l1 Aldh1l2 Amt Atic Ftcmentioning

confidence: 99%

Expression of Folate Pathway Genes in Stage III Colorectal Cancer Correlates with Recurrence Status Following Adjuvant Bolus 5-FU-Based Chemotherapy

Odin

Sondén

Gustavsson

et al. 2015

Mol Med

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“…Unlike RFC, PCFT operates optimally in acidic microclimates (pH 5-5.5) as those in the upper small intestine and tumor tissues [30,31]. RFC and PCFT are 400-600 amino acid transmembrane proteins consisting of 12 transmembrane domains [30,31]. The weak substrate affinity (μM Kd values) and high transport capacity of Note that equivalent sequence numbering for FRβ is incremented +16 relative to FRα.…”

Section: Interaction Between Frs and Antifolatesmentioning

confidence: 98%

“…b) The proton-coupled folate transporter (PCFT) mediates intestinal absorption of dietary folates and has equal affinities for reduced and oxidized folates [30,31]. Unlike RFC, PCFT operates optimally in acidic microclimates (pH 5-5.5) as those in the upper small intestine and tumor tissues [30,31].…”

Section: Interaction Between Frs and Antifolatesmentioning

confidence: 99%

“…a) The reduced folate carrier (RFC), ubiquitously expressed, is the major folate transporter of reduced folates in mammalian cells; it has no affinity for folic acid (oxidized folate) [30,31]. b) The proton-coupled folate transporter (PCFT) mediates intestinal absorption of dietary folates and has equal affinities for reduced and oxidized folates [30,31].…”

Section: Interaction Between Frs and Antifolatesmentioning

confidence: 99%

“…They are as potent inhibitors of these enzymes capable of ceasing nucleotide biosynthesis and causing cell death [30][31][32][33].…”

Section: Interaction Between Frs and Antifolatesmentioning

confidence: 99%

See 2 more Smart Citations

The complex interplay between ligand binding and conformational structure of the folate binding protein (folate receptor): Biological perspectives

Holm

Bruun²,

Hansen

2015

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Molecular Genetics of Hereditary Folate Malabsorption

Watkins

2016

Encyclopedia of Life Sciences

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Hereditary folate malabsorption is a genetic disorder that results in the specific inability to absorb ingested folate in the intestine and to transport serum folate across the blood–brain barrier into the cerebrospinal fluid. Absorption of other vitamins and nutrients is unimpaired. Affected individuals come to medical attention during the first year of life with low serum and cerebrospinal folate levels, megaloblastic anaemia and immunologic and neurologic findings. The disorder is inherited as an autosomal recessive trait and is caused by mutations in the SLC46A1 gene, which encodes the proton‐coupled folate transporter (PCFT). Mutations at SLC46A1 have been identified in over 30 patients with hereditary folate malabsorption. Several of these result in failure to translocate PCFT at the cell membrane; one was shown to encode a protein that was targeted to the cell membrane but did not support folate uptake. Key Concepts Hereditary folate malabsorption is a rare autosomal recessive genetic disorder. The disorder results in decreased intestinal folate absorption and decreased serum folate levels. It also results in decreased cerebrospinal fluid folate levels owing to decreased folate transport across the blood–brain barrier. Patients have megaloblastic anaemia, immunological deficits and, in some cases, neurological problems. Hereditary folate malabsorption is caused by mutations in the SLC46A1 gene, which encodes the proton‐coupled folate transporter (PCFT). Treatment with parenteral folinic acid corrects both haematological and neurological problems in hereditary folate malabsorption. Study of patients with hereditary folate malabsorption demonstrated that PCFT was the physiological folate transporter in the small intestine. PCFT and folate receptor α are required for folate transport across the blood–brain barrier.

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Biology of the Major Facilitative Folate Transporters SLC19A1 and SLC46A1

Cited by 120 publications

References 126 publications

Expression of Folate Pathway Genes in Stage III Colorectal Cancer Correlates with Recurrence Status Following Adjuvant Bolus 5-FU-Based Chemotherapy

Expression of Folate Pathway Genes in Stage III Colorectal Cancer Correlates with Recurrence Status Following Adjuvant Bolus 5-FU-Based Chemotherapy

The complex interplay between ligand binding and conformational structure of the folate binding protein (folate receptor): Biological perspectives

Molecular Genetics of Hereditary Folate Malabsorption

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