Q96NT5 (PCFT_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Proton-coupled folate transporter

Alternative name(s):
G21
Heme carrier protein 1
PCFT/HCP1
Solute carrier family 46 member 1

Gene names

Name:	SLC46A1
Synonyms:	HCP1, PCFT

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	459 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Ref.6 Ref.7 Ref.8 Ref.10
Subcellular location	Apical cell membrane; Multi-pass membrane protein. Cytoplasm By similarity. Note: Localizes to the apical membrane of intestinal cells in iron-deficient cells, while it resides in the cytoplasm in iron-replete cells By similarity. Ref.5 Ref.6 Ref.7 Ref.8 Ref.10
Tissue specificity	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. Ref.6 Ref.9
Involvement in disease	Defects in SLC46A1 are the cause of hereditary folate malabsorption (HFM) [MIM:229050]. HFM is a rare 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. Ref.6 Ref.8 Ref.15
Sequence similarities	Belongs to the major facilitator superfamily. SLC46A family.
Biophysicochemical properties	Kinetic parameters: KM=1.3 µM for folic acid (at pH 5.5) Ref.6 Ref.10 KM=1.5 µM for folic acid (at pH 6.0) KM=2.7 µM for folic acid (at pH 6.5) KM=6.0 µM for folic acid (at pH 7.0) KM=56.2 µM for folic acid (at pH 7.5) pH dependence: Optimum pH is 4.0-5.5. Activity decreases above pH 5.5 and reaches negligible levels at neutral pH and above.

Ontologies

Keywords
Biological process	Transport
Cellular component	Cell membrane Cytoplasm Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Transmembrane Transmembrane helix
Ligand	Folate-binding
PTM	Acetylation Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	cellular iron ion homeostasis Traceable author statement. Source: Reactome folic acid metabolic process Traceable author statement. Source: Reactome
Cellular component	apical plasma membrane Inferred from direct assay Ref.10. Source: UniProtKB cytoplasm Inferred from sequence or structural similarity. Source: UniProtKB integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	folic acid binding Inferred from electronic annotation. Source: UniProtKB-KW folic acid transporter activity Inferred from direct assay Ref.6Ref.10. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q96NT5-1)

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.

Isoform 2 (identifier: Q96NT5-2)

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).

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 459	459	Proton-coupled folate transporter		PRO_0000084851
Regions
	Transmembrane	87 – 107	21	Helical; Potential
	Transmembrane	115 – 135	21	Helical; Potential
	Transmembrane	149 – 169	21	Helical; Potential
	Transmembrane	183 – 203	21	Helical; Potential
	Transmembrane	211 – 231	21	Helical; Potential
	Transmembrane	267 – 287	21	Helical; Potential
	Transmembrane	303 – 325	23	Helical; Potential
	Transmembrane	337 – 357	21	Helical; Potential
	Transmembrane	359 – 379	21	Helical; Potential
	Transmembrane	390 – 410	21	Helical; Potential
	Transmembrane	423 – 443	21	Helical; Potential
Amino acid modifications
	Modified residue	1	1	N-acetylmethionine Ref.11
	Modified residue	6	1	Phosphoserine Ref.11 Ref.12
	Modified residue	458	1	Phosphoserine Ref.12 Ref.13
	Glycosylation	58	1	N-linked (GlcNAc...) Ref.14
Natural variations
	Alternative sequence	361 – 388	28	Missing in isoform 2.		VSP_016053
	Natural variant	113	1	R → C in HFM; loss-of-function mutation; targeted to the plasma membrane but has significantly impaired folate transport activity. Ref.15		VAR_058210
	Natural variant	113	1	R → S in HFM; abolishes folate uptake. Ref.8		VAR_032825
	Natural variant	147	1	G → R in HFM; reduces folate uptake to 13% of normal levels. Ref.8		VAR_032826
	Natural variant	295	1	T → A. Corresponds to variant rs34552966 [ dbSNP | Ensembl ].		VAR_050302
	Natural variant	318	1	S → R in HFM; abolishes folate uptake. Ref.8		VAR_032827
	Natural variant	376	1	R → W in HFM; abolishes folate uptake. Ref.8		VAR_032828
	Natural variant	425	1	P → R in HFM; reduces folate uptake to 3.5% of normal levels. Ref.8		VAR_032829
Experimental info
	Sequence conflict	394	1	A → G in BAB84987. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 1, 2001. Version 1. Checksum: 119F89E9E4ACA5F4	FASTA	459	49,771
	10 20 30 40 50 60 MEGSASPPEK PRARPAAAVL CRGPVEPLVF LANFALVLQG PLTTQYLWHR FSADLGYNGT 70 80 90 100 110 120 RQRGGCSNRS ADPTMQEVET LTSHWTLYMN VGGFLVGLFS STLLGAWSDS VGRRPLLVLA 130 140 150 160 170 180 SLGLLLQALV SVFVVQLQLH VGYFVLGRIL CALLGDFGGL LAASFASVAD VSSSRSRTFR 190 200 210 220 230 240 MALLEASIGV AGMLASLLGG HWLRAQGYAN PFWLALALLI AMTLYAAFCF GETLKEPKST 250 260 270 280 290 300 RLFTFRHHRS IVQLYVAPAP EKSRKHLALY SLAIFVVITV HFGAQDILTL YELSTPLCWD 310 320 330 340 350 360 SKLIGYGSAA QHLPYLTSLL ALKLLQYCLA DAWVAEIGLA FNILGMVVFA FATITPLMFT 370 380 390 400 410 420 GYGLLFLSLV ITPVIRAKLS KLVRETEQGA LFSAVACVNS LAMLTASGIF NSLYPATLNF 430 440 450 MKGFPFLLGA GLLLIPAVLI GMLEKADPHL EFQQFPQSP
	Isoform 2 [UniParc]. Checksum: EE81E0C20CF70C00	FASTA	431	46,644
	10 20 30 40 50 60 MEGSASPPEK PRARPAAAVL CRGPVEPLVF LANFALVLQG PLTTQYLWHR FSADLGYNGT 70 80 90 100 110 120 RQRGGCSNRS ADPTMQEVET LTSHWTLYMN VGGFLVGLFS STLLGAWSDS VGRRPLLVLA 130 140 150 160 170 180 SLGLLLQALV SVFVVQLQLH VGYFVLGRIL CALLGDFGGL LAASFASVAD VSSSRSRTFR 190 200 210 220 230 240 MALLEASIGV AGMLASLLGG HWLRAQGYAN PFWLALALLI AMTLYAAFCF GETLKEPKST 250 260 270 280 290 300 RLFTFRHHRS IVQLYVAPAP EKSRKHLALY SLAIFVVITV HFGAQDILTL YELSTPLCWD 310 320 330 340 350 360 SKLIGYGSAA QHLPYLTSLL ALKLLQYCLA DAWVAEIGLA FNILGMVVFA FATITPLMFT 370 380 390 400 410 420 GALFSAVACV NSLAMLTASG IFNSLYPATL NFMKGFPFLL GAGLLLIPAV LIGMLEKADP 430 HLEFQQFPQS P

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 269-459 (ISOFORM 2). Tissue: Glial tumor and Spleen.
[2]	NIEHS SNPs program Submitted (APR-2006) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Eye.
[4]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed: 17974005] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 199-459 (ISOFORM 1). Tissue: Spinal cord.
[5]	"Identification of an intestinal heme transporter." Shayeghi M., Latunde-Dada G.O., Oakhill J.S., Laftah A.H., Takeuchi K., Halliday N., Khan Y., Warley A., McCann F.E., Hider R.C., Frazer D.M., Anderson G.J., Vulpe C.D., Simpson R.J., McKie A.T. Cell 122:789-801(2005) [PubMed: 16143108] [Abstract] Cited for: SUBCELLULAR LOCATION.
[6]	"Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption." Qiu A., Jansen M., Sakaris A., Min S.H., Chattopadhyay S., Tsai E., Sandoval C., Zhao R., Akabas M.H., Goldman I.D. Cell 127:917-928(2006) [PubMed: 17129779] [Abstract] Cited for: FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INVOLVEMENT IN HFM.
[7]	"Haem carrier protein 1 (HCP1): expression and functional studies in cultured cells." Latunde-Dada G.O., Takeuchi K., Simpson R.J., McKie A.T. FEBS Lett. 580:6865-6870(2006) [PubMed: 17156779] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[8]	"The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption." Zhao R., Min S.H., Qiu A., Sakaris A., Goldberg G.L., Sandoval C., Malatack J.J., Rosenblatt D.S., Goldman I.D. Blood 110:1147-1152(2007) [PubMed: 17446347] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, VARIANTS HFM SER-113; ARG-147; ARG-318; TRP-376 AND ARG-425.
[9]	"Heme carrier protein 1 (HCP1) expression and functional analysis in the retina and retinal pigment epithelium." Sharma S., Dimasi D., Broeer S., Kumar R., Della N.G. Exp. Cell Res. 313:1251-1259(2007) [PubMed: 17335806] [Abstract] Cited for: TISSUE SPECIFICITY.
[10]	"Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter." Nakai Y., Inoue K., Abe N., Hatakeyama M., Ohta K.-Y., Otagiri M., Hayashi Y., Yuasa H. J. Pharmacol. Exp. Ther. 322:469-476(2007) [PubMed: 17475902] [Abstract] Cited for: FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR LOCATION.
[11]	"Evaluation of the low-specificity protease elastase for large-scale phosphoproteome analysis." Wang B., Malik R., Nigg E.A., Korner R. Anal. Chem. 80:9526-9533(2008) [PubMed: 19007248] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-6, ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[12]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-6 AND SER-458, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[13]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-458, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[14]	"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry." Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H. J. Proteome Res. 8:651-661(2009) [PubMed: 19159218] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-58, MASS SPECTROMETRY. Tissue: Liver.
[15]	"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." Lasry I., Berman B., Straussberg R., Sofer Y., Bessler H., Sharkia M., Glaser F., Jansen G., Drori S., Assaraf Y.G. Blood 112:2055-2061(2008) [PubMed: 18559978] [Abstract] Cited for: VARIANT HFM CYS-113, CHARACTERIZATION OF VARIANT HFM CYS-113.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	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.
IPI	IPI00043883. IPI00550230.
RefSeq	NP_001229295.1. NM_001242366.1. NP_542400.2. NM_080669.4.
UniGene	Hs.446689.
3D structure databases
ProteinModelPortal	Q96NT5.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q96NT5. 1 interaction.
STRING	Q96NT5.
Protein family/group databases
TCDB	2.A.1.50.1. major facilitator superfamily (MFS).
PTM databases
PhosphoSite	Q96NT5.
Polymorphism databases
DMDM	74732636.
Proteomic databases
PRIDE	Q96NT5.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000440501; ENSP00000395653; ENSG00000076351.
GeneID	113235.
KEGG	hsa:113235.
Organism-specific databases
CTD	113235.
GeneCards	GC17M026721.
H-InvDB	HIX0013646.
HGNC	HGNC:30521. SLC46A1.
HPA	CAB011614.
MIM	229050. phenotype. 611672. gene.
neXtProt	NX_Q96NT5.
Orphanet	90045. Hereditary folate malabsorption.
PharmGKB	PA162403775.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG19006.
GeneTree	ENSGT00530000063076.
HOGENOM	HBG712992.
HOVERGEN	HBG055334.
InParanoid	Q96NT5.
OMA	HLEFQQF.
OrthoDB	EOG4W6NWF.
PhylomeDB	Q96NT5.
Enzyme and pathway databases
Reactome	REACT_111217. Metabolism. REACT_15518. Transmembrane transport of small molecules.
Gene expression databases
ArrayExpress	Q96NT5.
Bgee	Q96NT5.
CleanEx	HS_SLC46A1.
Genevestigator	Q96NT5.
GermOnline	ENSG00000076351. Homo sapiens.
Family and domain databases
InterPro	IPR011701. MFS. IPR020846. MFS_dom. IPR016196. MFS_dom_general_subst_transpt. IPR005829. Sugar_transporter_CS. [Graphical view]
KO	K14613.
Pfam	PF07690. MFS_1. 1 hit. [Graphical view]
SUPFAM	SSF103473. MFS_gen_substrate_transporter. 1 hit.
PROSITE	PS50850. MFS. 1 hit. [Graphical view]
ProtoNet	Search...
Other
DrugBank	DB00158. Folic Acid.
NextBio	78800.
SOURCE	Search...

Entry information

Entry name

PCFT_HUMAN

Accession

Primary (citable) accession number: Q96NT5
Secondary accession number(s): Q1HE20 , Q86T92, Q8TEG3, Q96FL0

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 8, 2005
Last sequence update:	December 1, 2001
Last modified:	January 25, 2012
This is version 84 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.