| SLC46A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | SLC46A1 , G21, HCP1, PCFT, solute carrier family 46 member 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 611672 MGI: 1098733 HomoloGene: 41693 GeneCards: SLC46A1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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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.
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]
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 3µM 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]
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.
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]
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]
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.
Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. Signs of folate deficiency are often subtle. A low number of red blood cells (anemia) is a late finding in folate deficiency and folate deficiency anemia is the term given for this medical condition. It is characterized by the appearance of large-sized, abnormal red blood cells (megaloblasts), which form when there are inadequate stores of folic acid within the body.
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.
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.
Thiamine transporter 1, also known as thiamine carrier 1 (TC1) or solute carrier family 19 member 2 (SLC19A2) is a protein that in humans is encoded by the SLC19A2 gene. SLC19A2 is a thiamine transporter. Mutations in this gene cause thiamine-responsive megaloblastic anemia syndrome (TRMA), which is an autosomal recessive disorder characterized by diabetes mellitus, megaloblastic anemia and sensorineural deafness.
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. 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.
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.
Folate transporter 1 is a protein which in humans is encoded by the SLC19A1 gene.
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.
The major facilitator superfamily (MFS) is a superfamily of membrane transport proteins that facilitate movement of small solutes across cell membranes in response to chemiosmotic gradients.
Proton-coupled amino acid transporter 1 is a protein that in humans is encoded by the SLC36A1 gene.
Solute carrier family 22 member 8, or organic anion transporter 3 (OAT3), is a protein that in humans is encoded by the SLC22A8 gene.
Monocarboxylate transporter 1 is a ubiquitous protein that in humans is encoded by the SLC16A1 gene. It is a proton coupled monocarboxylate transporter.
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.
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). Unlike other members of the ENT family, it is impermeable to most nucleosides, with the exception of the inhibitory neurotransmitter and ribonucleoside adenosine, which it is permeable to in a highly pH-dependent manner.
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.
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.
