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Protein

Proton-coupled folate transporter

Gene

SLC46A1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Has been shown to act both as an intestinal proton-coupled high-affinity folate transporter and as an intestinal heme transporter which mediates heme uptake from the gut lumen into duodenal epithelial cells. The iron is then released from heme and may be transported into the bloodstream. Dietary heme iron is an important nutritional source of iron. Shows a higher affinity for folate than heme.4 Publications

Kineticsi

  1. KM=1.3 µM for folic acid (at pH 5.5)2 Publications
  2. KM=1.5 µM for folic acid (at pH 6.0)2 Publications
  3. KM=2.7 µM for folic acid (at pH 6.5)2 Publications
  4. KM=6.0 µM for folic acid (at pH 7.0)2 Publications
  5. KM=56.2 µM for folic acid (at pH 7.5)2 Publications

    pH dependencei

    Optimum pH is 4.0-5.5. Activity decreases above pH 5.5 and reaches negligible levels at neutral pH and above.2 Publications

    GO - Molecular functioni

    • folic acid binding Source: UniProtKB-KW
    • folic acid transmembrane transporter activity Source: UniProtKB
    • heme transporter activity Source: Reactome
    • methotrexate transmembrane transporter activity Source: BHF-UCL
    • proton transmembrane transporter activity Source: BHF-UCL

    GO - Biological processi

    • cellular iron ion homeostasis Source: Reactome
    • folate import across plasma membrane Source: BHF-UCL
    • folic acid metabolic process Source: Reactome
    • folic acid transport Source: UniProtKB
    • intestinal folate absorption Source: BHF-UCL
    • methotrexate transport Source: BHF-UCL
    • proton transmembrane transport Source: BHF-UCL

    Keywordsi

    Biological processTransport
    LigandFolate-binding

    Enzyme and pathway databases

    ReactomeiR-HSA-196757 Metabolism of folate and pterines
    R-HSA-917937 Iron uptake and transport
    SIGNORiQ96NT5

    Protein family/group databases

    TCDBi2.A.1.50.1 the major facilitator superfamily (mfs)

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Proton-coupled folate transporter
    Alternative name(s):
    G21
    Heme carrier protein 1
    PCFT/HCP1
    Solute carrier family 46 member 1
    Gene namesi
    Name:SLC46A1
    Synonyms:HCP1, PCFT
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 17

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000076351.12
    HGNCiHGNC:30521 SLC46A1
    MIMi611672 gene
    neXtProtiNX_Q96NT5

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Topology

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Topological domaini1 – 24CytoplasmicSequence analysisAdd BLAST24
    Transmembranei25 – 48HelicalSequence analysisAdd BLAST24
    Topological domaini49 – 84ExtracellularSequence analysisAdd BLAST36
    Transmembranei85 – 107HelicalSequence analysisAdd BLAST23
    Topological domaini108 – 113CytoplasmicSequence analysis6
    Transmembranei114 – 137HelicalSequence analysisAdd BLAST24
    Topological domaini138 – 145ExtracellularSequence analysis8
    Transmembranei146 – 168HelicalSequence analysisAdd BLAST23
    Topological domaini169 – 180CytoplasmicSequence analysisAdd BLAST12
    Transmembranei181 – 203HelicalSequence analysisAdd BLAST23
    Topological domaini204 – 212ExtracellularSequence analysis9
    Transmembranei213 – 236HelicalSequence analysisAdd BLAST24
    Topological domaini237 – 265CytoplasmicSequence analysisAdd BLAST29
    Transmembranei266 – 288HelicalSequence analysisAdd BLAST23
    Topological domaini289 – 309ExtracellularSequence analysisAdd BLAST21
    Transmembranei310 – 328HelicalSequence analysisAdd BLAST19
    Topological domaini329 – 331CytoplasmicSequence analysis3
    Transmembranei332 – 356HelicalSequence analysisAdd BLAST25
    Topological domaini357 – 359ExtracellularSequence analysis3
    Transmembranei360 – 381HelicalSequence analysisAdd BLAST22
    Topological domaini382 – 393CytoplasmicSequence analysisAdd BLAST12
    Transmembranei394 – 412HelicalSequence analysisAdd BLAST19
    Topological domaini413 – 424ExtracellularSequence analysisAdd BLAST12
    Transmembranei425 – 449HelicalSequence analysisAdd BLAST25
    Topological domaini450 – 459CytoplasmicSequence analysis10

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Membrane

    Pathology & Biotechi

    Involvement in diseasei

    Hereditary folate malabsorption (HFM)6 Publications
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionRare autosomal recessive disorder characterized by impaired intestinal folate absorption with folate deficiency resulting in anemia, hypoimmunoglobulinemia with recurrent infections, and recurrent or chronic diarrhea. In many patients, neurological abnormalities such as seizures or mental retardation become apparent during early childhood, attributed to impaired transport of folates into the central nervous system. When diagnosed early, the disorder can be treated by administration of folate. If untreated, it can be fatal and, if treatment is delayed, the neurological defects can become permanent.
    See also OMIM:229050
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_058210113R → C in HFM; loss-of-function mutation; targeted to the plasma membrane but has significantly impaired folate transport activity. 1 PublicationCorresponds to variant dbSNP:rs80338770EnsemblClinVar.1
    Natural variantiVAR_032825113R → S in HFM; abolishes folate uptake. 1 PublicationCorresponds to variant dbSNP:rs80338770EnsemblClinVar.1
    Natural variantiVAR_032826147G → R in HFM; reduces folate uptake to 13% of normal levels. 1 PublicationCorresponds to variant dbSNP:rs80338771EnsemblClinVar.1
    Natural variantiVAR_067960156D → Y in HFM; loss of function measured as methotrexate uptake. 1 PublicationCorresponds to variant dbSNP:rs281875210EnsemblClinVar.1
    Natural variantiVAR_032827318S → R in HFM; abolishes folate uptake. 1 PublicationCorresponds to variant dbSNP:rs80338772EnsemblClinVar.1
    Natural variantiVAR_067961335A → D in HFM; loss of function measured as methotrexate uptake. 1 PublicationCorresponds to variant dbSNP:rs281875208EnsemblClinVar.1
    Natural variantiVAR_067962338G → R in HFM; loss of function measured as methotrexate uptake. 1 PublicationCorresponds to variant dbSNP:rs281875209EnsemblClinVar.1
    Natural variantiVAR_067963376R → Q in HFM; abolishes folate uptake. 1 PublicationCorresponds to variant dbSNP:rs281875211EnsemblClinVar.1
    Natural variantiVAR_032828376R → W in HFM; abolishes folate uptake. 1 PublicationCorresponds to variant dbSNP:rs80338773EnsemblClinVar.1
    Natural variantiVAR_032829425P → R in HFM; reduces folate uptake to 3.5% of normal levels. 1 PublicationCorresponds to variant dbSNP:rs80338774EnsemblClinVar.1

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi109D → A, G, E, K, N or S: Loss of methotrexate uptake. 1 Publication1
    Mutagenesisi156D → E: Does not affect methotrexate uptake. 1 Publication1
    Mutagenesisi156D → F, K, N, V or W: Loss of methotrexate uptake. 1 Publication1
    Mutagenesisi156D → G: 2-fold reduction of methotrexate uptake. 1 Publication1
    Mutagenesisi156D → S: 8-fold reduction of methotrexate uptake. 1 Publication1
    Mutagenesisi376R → A, C, E, H, Q or W: Abolishes folate uptake. 1 Publication1

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    DisGeNETi113235
    GeneReviewsiSLC46A1
    MalaCardsiSLC46A1
    MIMi229050 phenotype
    OpenTargetsiENSG00000076351
    Orphaneti90045 Hereditary folate malabsorption
    PharmGKBiPA162403775

    Chemistry databases

    ChEMBLiCHEMBL1795188
    DrugBankiDB08878 Aminopterin
    DB00158 Folic Acid
    DB00563 Methotrexate
    DB00795 Sulfasalazine
    GuidetoPHARMACOLOGYi1213

    Polymorphism and mutation databases

    DMDMi74732636

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00000848511 – 459Proton-coupled folate transporterAdd BLAST459

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei1N-acetylmethionineCombined sources1
    Modified residuei6PhosphoserineCombined sources1
    Glycosylationi58N-linked (GlcNAc...) asparagine2 Publications1
    Glycosylationi68N-linked (GlcNAc...) asparagine1 Publication1
    Modified residuei458PhosphoserineCombined sources1

    Keywords - PTMi

    Acetylation, Glycoprotein, Phosphoprotein

    Proteomic databases

    MaxQBiQ96NT5
    PaxDbiQ96NT5
    PeptideAtlasiQ96NT5
    PRIDEiQ96NT5
    ProteomicsDBi77556
    77557 [Q96NT5-2]

    PTM databases

    iPTMnetiQ96NT5
    PhosphoSitePlusiQ96NT5
    SwissPalmiQ96NT5

    Expressioni

    Tissue specificityi

    Expressed in kidney, liver, placenta, small intestine, spleen, retina and retinal pigment epithelium. Lower levels found in colon and testis. Very low levels in brain, lung, stomach, heart and muscle. In intestine, expressed in duodenum with lower levels in jejunum, ileum, cecum, rectum and segments of the colon.2 Publications

    Gene expression databases

    BgeeiENSG00000076351
    CleanExiHS_SLC46A1
    ExpressionAtlasiQ96NT5 baseline and differential
    GenevisibleiQ96NT5 HS

    Organism-specific databases

    HPAiCAB011614

    Interactioni

    Subunit structurei

    Monomer.1 Publication

    Protein-protein interaction databases

    BioGridi125236, 2 interactors
    IntActiQ96NT5, 2 interactors
    MINTiQ96NT5
    STRINGi9606.ENSP00000395653

    Chemistry databases

    BindingDBiQ96NT5

    Structurei

    3D structure databases

    ProteinModelPortaliQ96NT5
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Sequence similaritiesi

    Keywords - Domaini

    Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiKOG2816 Eukaryota
    ENOG410ZVCA LUCA
    GeneTreeiENSGT00530000063076
    HOGENOMiHOG000054191
    HOVERGENiHBG055334
    InParanoidiQ96NT5
    KOiK14613
    OMAiTGYGLCF
    OrthoDBiEOG091G08MP
    PhylomeDBiQ96NT5
    TreeFamiTF315701

    Family and domain databases

    CDDicd06174 MFS, 1 hit
    InterProiView protein in InterPro
    IPR011701 MFS
    IPR020846 MFS_dom
    IPR036259 MFS_trans_sf
    IPR005829 Sugar_transporter_CS
    PfamiView protein in Pfam
    PF07690 MFS_1, 1 hit
    SUPFAMiSSF103473 SSF103473, 1 hit
    PROSITEiView protein in PROSITE
    PS50850 MFS, 1 hit

    Sequences (2)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: Q96NT5-1) [UniParc]FASTAAdd to basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

            10         20         30         40         50
    MEGSASPPEK PRARPAAAVL CRGPVEPLVF LANFALVLQG PLTTQYLWHR
    60 70 80 90 100
    FSADLGYNGT RQRGGCSNRS ADPTMQEVET LTSHWTLYMN VGGFLVGLFS
    110 120 130 140 150
    STLLGAWSDS VGRRPLLVLA SLGLLLQALV SVFVVQLQLH VGYFVLGRIL
    160 170 180 190 200
    CALLGDFGGL LAASFASVAD VSSSRSRTFR MALLEASIGV AGMLASLLGG
    210 220 230 240 250
    HWLRAQGYAN PFWLALALLI AMTLYAAFCF GETLKEPKST RLFTFRHHRS
    260 270 280 290 300
    IVQLYVAPAP EKSRKHLALY SLAIFVVITV HFGAQDILTL YELSTPLCWD
    310 320 330 340 350
    SKLIGYGSAA QHLPYLTSLL ALKLLQYCLA DAWVAEIGLA FNILGMVVFA
    360 370 380 390 400
    FATITPLMFT GYGLLFLSLV ITPVIRAKLS KLVRETEQGA LFSAVACVNS
    410 420 430 440 450
    LAMLTASGIF NSLYPATLNF MKGFPFLLGA GLLLIPAVLI GMLEKADPHL

    EFQQFPQSP
    Length:459
    Mass (Da):49,771
    Last modified:December 1, 2001 - v1
    Checksum:i119F89E9E4ACA5F4
    GO
    Isoform 2 (identifier: Q96NT5-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         361-388: Missing.

    Note: Inactive isoform which results in impaired folate absorption, giving rise to hereditary folate malabsorption (HFM).
    Show »
    Length:431
    Mass (Da):46,644
    Checksum:iEE81E0C20CF70C00
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti394A → G in BAB84987 (PubMed:14702039).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_058210113R → C in HFM; loss-of-function mutation; targeted to the plasma membrane but has significantly impaired folate transport activity. 1 PublicationCorresponds to variant dbSNP:rs80338770EnsemblClinVar.1
    Natural variantiVAR_032825113R → S in HFM; abolishes folate uptake. 1 PublicationCorresponds to variant dbSNP:rs80338770EnsemblClinVar.1
    Natural variantiVAR_032826147G → R in HFM; reduces folate uptake to 13% of normal levels. 1 PublicationCorresponds to variant dbSNP:rs80338771EnsemblClinVar.1
    Natural variantiVAR_067960156D → Y in HFM; loss of function measured as methotrexate uptake. 1 PublicationCorresponds to variant dbSNP:rs281875210EnsemblClinVar.1
    Natural variantiVAR_050302295T → A. Corresponds to variant dbSNP:rs34552966Ensembl.1
    Natural variantiVAR_032827318S → R in HFM; abolishes folate uptake. 1 PublicationCorresponds to variant dbSNP:rs80338772EnsemblClinVar.1
    Natural variantiVAR_067961335A → D in HFM; loss of function measured as methotrexate uptake. 1 PublicationCorresponds to variant dbSNP:rs281875208EnsemblClinVar.1
    Natural variantiVAR_067962338G → R in HFM; loss of function measured as methotrexate uptake. 1 PublicationCorresponds to variant dbSNP:rs281875209EnsemblClinVar.1
    Natural variantiVAR_067963376R → Q in HFM; abolishes folate uptake. 1 PublicationCorresponds to variant dbSNP:rs281875211EnsemblClinVar.1
    Natural variantiVAR_032828376R → W in HFM; abolishes folate uptake. 1 PublicationCorresponds to variant dbSNP:rs80338773EnsemblClinVar.1
    Natural variantiVAR_032829425P → R in HFM; reduces folate uptake to 3.5% of normal levels. 1 PublicationCorresponds to variant dbSNP:rs80338774EnsemblClinVar.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_016053361 – 388Missing in isoform 2. 2 PublicationsAdd BLAST28

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AK054669 mRNA Translation: BAB70789.1
    AK074161 mRNA Translation: BAB84987.1
    DQ496103 Genomic DNA Translation: ABF47092.1
    BC010691 mRNA Translation: AAH10691.1
    AL832613 mRNA Translation: CAD89945.1
    CCDSiCCDS74019.1 [Q96NT5-2]
    CCDS74020.1 [Q96NT5-1]
    RefSeqiNP_001229295.1, NM_001242366.2 [Q96NT5-2]
    NP_542400.2, NM_080669.5 [Q96NT5-1]
    UniGeneiHs.446689

    Genome annotation databases

    EnsembliENST00000612814; ENSP00000480703; ENSG00000076351 [Q96NT5-1]
    ENST00000618626; ENSP00000483652; ENSG00000076351 [Q96NT5-2]
    GeneIDi113235
    KEGGihsa:113235
    UCSCiuc032ezi.2 human [Q96NT5-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiPCFT_HUMAN
    AccessioniPrimary (citable) accession number: Q96NT5
    Secondary accession number(s): Q1HE20
    , Q86T92, Q8TEG3, Q96FL0
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 8, 2005
    Last sequence update: December 1, 2001
    Last modified: June 20, 2018
    This is version 140 of the entry and version 1 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

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