Proton-coupled folate transporter

Last updated
SLC46A1
Identifiers
Aliases SLC46A1 , G21, HCP1, PCFT, solute carrier family 46 member 1
External IDs OMIM: 611672; MGI: 1098733; HomoloGene: 41693; GeneCards: SLC46A1; OMA:SLC46A1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

113235

52466

Ensembl

ENSG00000076351

ENSMUSG00000020829

UniProt

Q96NT5

Q6PEM8

RefSeq (mRNA)

NM_001242366
NM_080669

NM_026740

RefSeq (protein)

NP_001229295
NP_542400

NP_081016

Location (UCSC) Chr 17: 28.39 – 28.41 Mb Chr 11: 78.36 – 78.36 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The proton-coupled folate transporter is a protein that in humans is encoded by the SLC46A1 gene. [5] [6] [7] The major physiological roles of PCFTs are in mediating the intestinal absorption of folate (Vitamin B9), and its delivery to the central nervous system.

Contents

Structure

PCFT is located on chromosome 17q11.2 and consists of five exons encoding a protein with 459 amino acids and a MW of ~50kDa. PCFT is highly conserved, sharing 87% identity to the mouse and rat PCFT and retaining more than 50% amino acid identity to the frog (XP415815) and zebrafish (AAH77859) proteins. [8] Structurally, there are twelve transmembrane helices with the N- and C- termini directed to the cytoplasm and a large internal loop that divides the molecule in half. [9] [10] There are two glycosylation sites (N58, N68) and a disulfide bond connecting residues C66, in the 1st and C298 in the 4th, external loop. Neither glycosylation nor the disulfide bond are essential for function. [9] [11] Residues have been identified that play a role in proton-coupling, proton binding, folate binding and oscillation of the carrier between its conformational states. [12] PCFT forms oligomers and some of the linking residues have been identified. [13] [14]

Regulation

PCFT-mediated transport into cells is optimal at pH 5.5. The low-pH activity and the structural specificity of PCFT (high affinity for folic acid, and low affinity for PT523 - a non-polyglutamable analog of aminopterin) distinguishes this transporter functionally from the other major folate transporter, the reduced folate carrier [15] (optimal activity at pH 7.4, very low affinity for folic acid and very high affinity for PT523), another member (SLC19A1) of the superfamily of solute transporters. [8] [15] [16] Influx mediated by PCFT is electrogenic and can be assessed by current, cellular acidification, and radiotracer uptake. [8] [16] [17] [18] Influx has a Km range of 0.5 to 3 μM for most folates and antifolates at pH 5.5. The influx Km rises and the influx Vmax falls as the pH is increased, least so for the antifolate, pemetrexed. [19] The transporter is specific for the monoglutamyl forms of folates. [16] A variety of organic anions inhibit PCFT-mediated transport at extremely high ratio of inhibitor to folate, the most potent are sulfobromophthalein, p-aminobenzylglutamate, and sulfathalazine. [18] [20] This may have pharmacological relevance in terms of the inhibitory effect of these agents on the intestinal absorption of folates. The PCFT minimal promoter has been defined [21] [22] and contains an NRF1 response element. [23] There is also evidence for a role of vitamin D in the regulation of PCFT with a VDR response element upstream of the minimal promoter. [24] PCFT mRNA was reported to be increased in folate-deficient mice. [16]

Tissue distribution

PCFT is expressed in the proximal jejunum with a lower level of expression elsewhere in the intestine. [8] [16] [25] Expression is localized to the apical membrane of intestinal [16] [18] [25] and polarized MDCK dog kidney cells. [26] PCFT is also expressed at the basolateral membrane of the choroid plexus. In view of the low levels of folate in the cerebrospinal fluid (CSF) in PCFT-null humans, [27] PCFT must play a role in transport of folates across the choroid plexus into the CSF; however, the underlying mechanism for this has not been established. [28] PCFT is expressed at the sinusoidal (basolateral) membrane of the hepatocyte, the apical brush-border membrane of the proximal tubule of the kidney, the basolateral membrane of the retinal pigment epithelium and the placenta. [9] [29] [30] There is a prominent low-pH folate transport activity in the cells and/or membrane vesicles derived from these tissues which, in some cases, has been shown to be indicative of a proton-coupled folate transport process. [31] [32] [33] [34] [35] However, it is unclear as to the extent that PCFT contributes to folate transport across these epithelia.

Loss-of-function

The physiological role of PCFT is known based upon the phenotype of subjects with loss-of-function mutations of this gene – the rare autosomal hereditary disorder, hereditary folate malabsorption (HFM). [8] [27] [36] These subjects have two major abnormalities: (i) severe systemic folate deficiency and (ii) a defect in the transport of folates from blood across the choroid plexus into the CSF with very low CSF folate levels even when the blood folate level is corrected or supranormal. [37] Severe anemia, usually macrocytic, always accompanies the folate deficiency. Sometimes there is pancytopenia and/or hypogammaglobulinemia and/or T-cell dysfunction which can result in infections such as Pneumocystis jirovecii pneumonia. There can be GI signs including diarrhea and mucositis. The CNS folate deficiency is associated with a variety of neurological findings including developmental delays and seizures. The phenotype of the PCFT-null mouse has been reported and mirrors many of the findings in humans. [38] PCFT was initially reported to be a low-affinity heme transporter. [25] However, a role for PCFT in heme and iron homeostasis is excluded by the observation that humans or mice with loss-of-function PCFT mutations are not iron or heme deficient and the anemia, and all other systemic consequences of the loss of this transporter, are completely corrected with high-dose oral, or low-dose, parenteral folate. [27] [36]

As a drug target

Because of the Warburg effect, and a compromised blood supply, human epithelial cancers grow within an acidic milieu, as lactate is produced during anaerobic glycolysis. Because PCFT activity is optimal at low pH, and its expression and a prominent low-pH transport activity are present in human cancers, [39] [40] there is interest in exploiting these properties by the development of antifolates that have a high affinity for this transporter and a very low affinity for the reduced folate carrier which delivers antifolates to normal tissues and thereby mediates the toxicity of these agents. [41] A novel class of inhibitors of one carbon incorporation into purines is being developed with these properties. [41] Pemetrexed, an antifolate inhibitor primarily of thymidylate synthase, is a good substrate for PCFT even at neutral pH as compared to other antifolates and folates. [19]

Related Research Articles

<span class="mw-page-title-main">Antiporter</span> Class of transmembrane transporter protein

An antiporter is an integral membrane protein involved in secondary active transport. It is a type of cotransporter, which means that uses the movement of one In the case of an antiporter, two or more different molecules or ions are moved across a phospholipid membrane, such as the plasma membrane, in opposite directions, one into the cell and one out of the cell. This is in contrast to symporters, which are another type of cotransporter that moves two or more ions in the same direction.

<span class="mw-page-title-main">Cotransporter</span> Type of membrane transport proteins

Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable coupled or cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.

The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membranes of synaptic vesicles of presynaptic neurons. It transports monoamine neurotransmitters – such as dopamine, serotonin, norepinephrine, epinephrine, and histamine – into the vesicles, which release the neurotransmitters into synapses, as chemical messages to postsynaptic neurons. VMATs utilize a proton gradient generated by V-ATPases in vesicle membranes to power monoamine import.

<span class="mw-page-title-main">Folate deficiency</span> Abnormally low level of folate (vitamin B9) in the body

Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. This may result in a type of anemia in which red blood cells become abnormally large and is a late finding in folate deficiency and folate deficiency anemia is the term given for this medical condition. Signs of folate deficiency are often subtle. Symptoms may include feeling tired, heart palpitations, shortness of breath, feeling faint, open sores on the tongue, loss of appetite, changes in the color of the skin or hair, irritability, and behavioral changes. Temporary reversible infertility may occur. Folate deficiency anemia during pregnancy may give rise to the birth of low weight birth premature infants and infants with neural tube defects.

The solute carrier (SLC) group of membrane transport proteins include over 400 members organized into 66 families. Most members of the SLC group are located in the cell membrane. The SLC gene nomenclature system was originally proposed by the HUGO Gene Nomenclature Committee (HGNC) and is the basis for the official HGNC names of the genes that encode these transporters. A more general transmembrane transporter classification can be found in TCDB database.

Sodium-dependent glucose cotransporters are a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron. They contribute to renal glucose reabsorption. In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along the nephron. If the plasma glucose concentration is too high (hyperglycemia), glucose passes into the urine (glucosuria) because SGLT are saturated with the filtered glucose.

<span class="mw-page-title-main">Natural resistance-associated macrophage protein 2</span>

Natural resistance-associated macrophage protein 2, also known as divalent metal transporter 1 (DMT1) and divalent cation transporter 1 (DCT1), is a protein that in humans is encoded by the SLC11A2 gene. DMT1 represents a large family of orthologous metal ion transporter proteins that are highly conserved from bacteria to humans.

<span class="mw-page-title-main">Sodium/glucose cotransporter 1</span>

Sodium/glucose cotransporter 1 (SGLT1) also known as solute carrier family 5 member 1 is a protein in humans that is encoded by the SLC5A1 gene which encodes the production of the SGLT1 protein to line the absorptive cells in the small intestine and the epithelial cells of the kidney tubules of the nephron for the purpose of glucose uptake into cells. Recently, it has been seen to have functions that can be considered as promising therapeutic target to treat diabetes and obesity. Through the use of the sodium glucose cotransporter 1 protein, cells are able to obtain glucose which is further utilized to make and store energy for the cell.

<span class="mw-page-title-main">GLUT5</span> Protein-coding gene in the species Homo sapiens

GLUT5 is a fructose transporter expressed on the apical border of enterocytes in the small intestine. GLUT5 allows for fructose to be transported from the intestinal lumen into the enterocyte by facilitated diffusion due to fructose's high concentration in the intestinal lumen. GLUT5 is also expressed in skeletal muscle, testis, kidney, fat tissue (adipocytes), and brain.

<span class="mw-page-title-main">Folate transporter 1</span> Mammalian protein found in Homo sapiens

Folate transporter 1 is a protein which in humans is encoded by the SLC19A1 gene.

<span class="mw-page-title-main">Peptide transporter 1</span> Mammalian protein found in Homo sapiens

Peptide transporter 1 also known as solute carrier family 15 member 1 (SLC15A1) is a protein that in humans is encoded by SLC15A1 gene. PepT 1 is a solute carrier for oligopeptides. It functions in renal oligopeptide reabsorption and in the intestines in a proton dependent way, hence acting like a cotransporter.

<span class="mw-page-title-main">Proton-coupled amino acid transporter 1</span> Protein-coding gene in the species Homo sapiens

Proton-coupled amino acid transporter 1 is a protein that in humans is encoded by the SLC36A1 gene.

<span class="mw-page-title-main">Sodium-coupled monocarboxylate transporter 1</span> Protein-coding gene in the species Homo sapiens

Sodium-coupled monocarboxylate transporter 1 (i.e., SMCT1) and sodium-coupled monocarboxylate transporter 2 (i.e., SMCT2) are plasma membrane transport proteins in the solute carrier family. They transport sodium cations in association with the anionic forms (see conjugated base) of certain short-chain fatty acids (i.e., SC-FAs) through the plasma membrane from the outside to the inside of cells. For example, propionic acid (i.e., CH
3CH
2CO
2H) in its anionic "propionate" form (i.e., CH
3CH
2CO−
2) along with sodium cations (i.e., Na+) are co-transported from the extracellular fluid into a SMCT1-epxressing cell's cytoplasm. Monocarboxylate transporters (MCTs) are also transport proteins in the solute carrier family. They co-transport the anionic forms of various compounds into cells in association with proton cations (i.e. H+). Four of the 14 MCTs, i.e. SLC16A1 (i.e., MCT1), SLC16A7 (i.e., MCT22), SLC16A8 (i.e., MCT3), and SLC16A3 (i.e., MCT4), transport some of the same SC-FAs anions that the SMCTs transport into cells. SC-FAs do diffuse into cells independently of transport proteins but at the levels normally occurring in tissues far greater amounts of the SC-FAs are brought into cells that express a SC-FA transporter.

<span class="mw-page-title-main">Monocarboxylate transporter 1</span>

Monocarboxylate transporter 1 is a ubiquitous protein that in humans is encoded by the SLC16A1 gene. It is a proton coupled monocarboxylate transporter.

<span class="mw-page-title-main">Iminoglycinuria</span> Medical condition

Iminoglycinuria is an autosomal recessive disorder of renal tubular transport affecting reabsorption of the amino acid glycine, and the imino acids proline and hydroxyproline. This results in excess urinary excretion of all three acids.

<span class="mw-page-title-main">Plasma membrane monoamine transporter</span> Protein-coding gene in the species Homo sapiens

The plasma membrane monoamine transporter (PMAT) is a low-affinity monoamine transporter protein which in humans is encoded by the SLC29A4 gene. It is known alternatively as the human equilibrative nucleoside transporter-4 (hENT4). It was discovered in 2004 and has been identified as a potential alternate target for treating various conditions.

Haem or Heme carrier protein 1 (HCP1) was originally identified as mediating heme-Fe transport although it later emerged that it was the SLC46A1 folate transporter.

<span class="mw-page-title-main">Hereditary folate malabsorption</span> Medical condition

Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder caused by loss-of-function mutations in the proton-coupled folate transporter (PCFT) gene, resulting in systemic folate deficiency and impaired delivery of folate to the brain.

The Reduced Folate Carrier (RFC) Family is a group of transport proteins that is part of the major facilitator superfamily. RFCs take up folate, reduced folate, derivatives of reduced folate and the drug, methotrexate.

Proton-coupled amino acid transporters belong to the SLC26A5 family; they are protein receptors whose main function is the transmembrane movement of amino acids and their derivatives. This family of receptors is most commonly found within the luminal surface of the small intestine as well as in some lysosomes. The solute carrier family (SLC) of genes includes roughly 400 membrane proteins that are characterized by 66 families in total. The SLC36 family of genes maps to chromosome 11. The diversity of these receptors is vast, with the ability to transport both charged and uncharged amino acids along with their derivatives. In research and practice, SLC36A1/2 are both targets for drug-based delivery systems for a wide range of disorders.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000076351 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000020829 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: PCFT proton-coupled folate transporter".
  6. ↑ Shayeghi M, Latunde-Dada GO, Oakhill JS, Laftah AH, Takeuchi K, Halliday N, et al. (September 2005). "Identification of an intestinal heme transporter". Cell. 122 (5): 789–801. doi: 10.1016/j.cell.2005.06.025 . PMID   16143108. S2CID   9130882.
  7. ↑ Sharma S, Dimasi D, Bröer S, Kumar R, Della NG (April 2007). "Heme carrier protein 1 (HCP1) expression and functional analysis in the retina and retinal pigment epithelium". Experimental Cell Research. 313 (6): 1251–1259. doi:10.1016/j.yexcr.2007.01.019. PMID   17335806.
  8. 1 2 3 4 5 Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, et al. (December 2006). "Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption". Cell. 127 (5): 917–928. doi: 10.1016/j.cell.2006.09.041 . PMID   17129779. S2CID   1918658.
  9. 1 2 3 Zhao R, Unal ES, Shin DS, Goldman ID (April 2010). "Membrane topological analysis of the proton-coupled folate transporter (PCFT-SLC46A1) by the substituted cysteine accessibility method". Biochemistry. 49 (13): 2925–2931. doi:10.1021/bi9021439. PMC   2866095 . PMID   20225891.
  10. ↑ Duddempudi PK, Goyal R, Date SS, Jansen M (2013). "Delineating the extracellular water-accessible surface of the proton-coupled folate transporter". PLOS ONE. 8 (10): e78301. Bibcode:2013PLoSO...878301D. doi: 10.1371/journal.pone.0078301 . PMC   3799626 . PMID   24205192.
  11. ↑ Unal ES, Zhao R, Qiu A, Goldman ID (June 2008). "N-linked glycosylation and its impact on the electrophoretic mobility and function of the human proton-coupled folate transporter (HsPCFT)". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1778 (6): 1407–1414. doi:10.1016/j.bbamem.2008.03.009. PMC   2762823 . PMID   18405659.
  12. ↑ Zhao R, Goldman ID (2013). "Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors". Molecular Aspects of Medicine. 34 (2–3): 373–385. doi:10.1016/j.mam.2012.07.006. PMC   3831518 . PMID   23506878.
  13. ↑ Hou Z, Kugel Desmoulin S, Etnyre E, Olive M, Hsiung B, Cherian C, et al. (February 2012). "Identification and functional impact of homo-oligomers of the human proton-coupled folate transporter". The Journal of Biological Chemistry. 287 (7): 4982–4995. doi: 10.1074/jbc.m111.306860 . PMC   3281668 . PMID   22179615.
  14. ↑ Wilson MR, Kugel S, Huang J, Wilson LJ, Wloszczynski PA, Ye J, et al. (July 2015). "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. 469 (1): 33–44. doi:10.1042/bj20150169. PMC   4713120 . PMID   25877470.
  15. 1 2 Hou Z, Matherly LH (2014). "Biology of the major facilitative folate transporters SLC19A1 and SLC46A1". Current Topics in Membranes. 73: 175–204. doi:10.1016/B978-0-12-800223-0.00004-9. ISBN   9780128002230. PMC   4185403 . PMID   24745983.
  16. 1 2 3 4 5 6 Qiu A, Min SH, Jansen M, Malhotra U, Tsai E, Cabelof DC, et al. (November 2007). "Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction". American Journal of Physiology. Cell Physiology. 293 (5): C1669–C1678. doi:10.1152/ajpcell.00202.2007. PMID   17898134. S2CID   7250544.
  17. ↑ Umapathy NS, Gnana-Prakasam JP, Martin PM, Mysona B, Dun Y, Smith SB, et al. (November 2007). "Cloning and functional characterization of the proton-coupled electrogenic folate transporter and analysis of its expression in retinal cell types". Investigative Ophthalmology & Visual Science. 48 (11): 5299–5305. doi:10.1167/iovs.07-0288. PMC   3850295 . PMID   17962486.
  18. 1 2 3 Nakai Y, Inoue K, Abe N, Hatakeyama M, Ohta KY, Otagiri M, et al. (August 2007). "Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter". The Journal of Pharmacology and Experimental Therapeutics. 322 (2): 469–476. doi:10.1124/jpet.107.122606. PMID   17475902. S2CID   23277839.
  19. 1 2 Zhao R, Qiu A, Tsai E, Jansen M, Akabas MH, Goldman ID (September 2008). "The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier". Molecular Pharmacology. 74 (3): 854–862. doi:10.1124/mol.108.045443. PMC   2716086 . PMID   18524888.
  20. ↑ Urquhart BL, Gregor JC, Chande N, Knauer MJ, Tirona RG, Kim RB (February 2010). "The human proton-coupled folate transporter (hPCFT): modulation of intestinal expression and function by drugs". American Journal of Physiology. Gastrointestinal and Liver Physiology. 298 (2): G248–G254. doi:10.1152/ajpgi.00224.2009. PMID   19762432. S2CID   12974427.
  21. ↑ Stark M, Gonen N, Assaraf YG (October 2009). "Functional elements in the minimal promoter of the human proton-coupled folate transporter". Biochemical and Biophysical Research Communications. 388 (1): 79–85. doi:10.1016/j.bbrc.2009.07.116. PMID   19643086.
  22. ↑ Diop-Bove NK, Wu J, Zhao R, Locker J, Goldman ID (August 2009). "Hypermethylation of the human proton-coupled folate transporter (SLC46A1) minimal transcriptional regulatory region in an antifolate-resistant HeLa cell line". Molecular Cancer Therapeutics. 8 (8): 2424–2431. doi:10.1158/1535-7163.mct-08-0938. PMC   2735101 . PMID   19671745.
  23. ↑ Gonen N, Assaraf YG (October 2010). "The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1". The Journal of Biological Chemistry. 285 (44): 33602–33613. doi: 10.1074/jbc.m110.135640 . PMC   2962458 . PMID   20724482.
  24. ↑ Eloranta JJ, Zaïr ZM, Hiller C, Häusler S, Stieger B, Kullak-Ublick GA (November 2009). "Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter". Molecular Pharmacology. 76 (5): 1062–1071. doi:10.1124/mol.109.055392. PMID   19666701. S2CID   11155598.
  25. 1 2 3 Shayeghi M, Latunde-Dada GO, Oakhill JS, Laftah AH, Takeuchi K, Halliday N, et al. (September 2005). "Identification of an intestinal heme transporter". Cell. 122 (5): 789–801. doi: 10.1016/j.cell.2005.06.025 . PMID   16143108. S2CID   9130882.
  26. ↑ Subramanian VS, Marchant JS, Said HM (January 2008). "Apical membrane targeting and trafficking of the human proton-coupled transporter in polarized epithelia". American Journal of Physiology. Cell Physiology. 294 (1): C233–C240. doi:10.1152/ajpcell.00468.2007. PMID   18003745. S2CID   7730829.
  27. 1 2 3 Geller J, Kronn D, Jayabose S, Sandoval C (January 2002). "Hereditary folate malabsorption: family report and review of the literature". Medicine. 81 (1): 51–68. doi: 10.1097/00005792-200201000-00004 . PMID   11807405. S2CID   27156694.
  28. ↑ Grapp M, Wrede A, Schweizer M, Hüwel S, Galla HJ, Snaidero N, et al. (2013). "Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma". Nature Communications. 4: 2123. Bibcode:2013NatCo...4.2123G. doi: 10.1038/ncomms3123 . hdl: 11858/00-001M-0000-0014-164F-1 . PMID   23828504.
  29. ↑ Bozard BR, Ganapathy PS, Duplantier J, Mysona B, Ha Y, Roon P, et al. (June 2010). "Molecular and biochemical characterization of folate transport proteins in retinal Müller cells". Investigative Ophthalmology & Visual Science. 51 (6): 3226–3235. doi:10.1167/iovs.09-4833. PMC   2891475 . PMID   20053979.
  30. ↑ Williams PJ, Mistry HD, Morgan L (April 2012). "Folate transporter expression decreases in the human placenta throughout pregnancy and in pre-eclampsia". Pregnancy Hypertension. 2 (2): 123–131. doi:10.1016/j.preghy.2011.12.001. PMID   26105097.
  31. ↑ Horne DW, Reed KA, Hoefs J, Said HM (July 1993). "5-Methyltetrahydrofolate transport in basolateral membrane vesicles from human liver". The American Journal of Clinical Nutrition. 58 (1): 80–84. doi: 10.1093/ajcn/58.1.80 . PMID   8317394.
  32. ↑ Chancy CD, Kekuda R, Huang W, Prasad PD, Kuhnel JM, Sirotnak FM, et al. (July 2000). "Expression and differential polarization of the reduced-folate transporter-1 and the folate receptor alpha in mammalian retinal pigment epithelium". The Journal of Biological Chemistry. 275 (27): 20676–20684. doi: 10.1074/jbc.m002328200 . PMID   10787414.
  33. ↑ Zhao R, Diop-Bove N, Visentin M, Goldman ID (August 2011). "Mechanisms of membrane transport of folates into cells and across epithelia". Annual Review of Nutrition. 31: 177–201. doi:10.1146/annurev-nutr-072610-145133. PMC   3885234 . PMID   21568705.
  34. ↑ Keating E, Lemos C, Azevedo I, Martel F (February 2006). "Comparison of folic acid uptake characteristics by human placental choriocarcinoma cells at acidic and physiological pH". Canadian Journal of Physiology and Pharmacology. 84 (2): 247–255. doi:10.1139/y05-129. PMID   16900951.
  35. ↑ Bhandari SD, Joshi SK, McMartin KE (January 1988). "Folate binding and transport by rat kidney brush-border membrane vesicles". Biochimica et Biophysica Acta (BBA) - Biomembranes. 937 (2): 211–218. doi:10.1016/0005-2736(88)90243-x. PMID   2892531.
  36. 1 2 Goldman ID (1993). Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A (eds.). "Hereditary Folate Malabsorption". GeneReviews. Seattle (WA): University of Washington, Seattle. PMID   20301716.
  37. ↑ Torres A, Newton SA, Crompton B, Borzutzky A, Neufeld EJ, Notarangelo L, Berry GT (26 May 2015). "CSF 5-Methyltetrahydrofolate Serial Monitoring to Guide Treatment of Congenital Folate Malabsorption Due to Proton-Coupled Folate Transporter (PCFT) Deficiency". JIMD Reports. 24: 91–96. doi:10.1007/8904_2015_445. ISBN   978-3-662-48226-1. PMC   4582027 . PMID   26006721.
  38. ↑ Salojin KV, Cabrera RM, Sun W, Chang WC, Lin C, Duncan L, et al. (May 2011). "A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency". Blood. 117 (18): 4895–4904. doi:10.1182/blood-2010-04-279653. PMID   21346251.
  39. ↑ Kugel Desmoulin S, Wang L, Hales E, Polin L, White K, Kushner J, et al. (December 2011). "Therapeutic targeting of a novel 6-substituted pyrrolo [2,3-d]pyrimidine thienoyl antifolate to human solid tumors based on selective uptake by the proton-coupled folate transporter". Molecular Pharmacology. 80 (6): 1096–1107. doi:10.1124/mol.111.073833. PMC   3228537 . PMID   21940787.
  40. ↑ Zhao R, Gao F, Hanscom M, Goldman ID (January 2004). "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". Clinical Cancer Research. 10 (2): 718–727. doi: 10.1158/1078-0432.ccr-1066-03 . PMID   14760095.
  41. 1 2 Desmoulin SK, Hou Z, Gangjee A, Matherly LH (December 2012). "The human proton-coupled folate transporter: Biology and therapeutic applications to cancer". Cancer Biology & Therapy. 13 (14): 1355–1373. doi:10.4161/cbt.22020. PMC   3542225 . PMID   22954694.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.