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Q8N695 (SC5A8_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 86. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Sodium-coupled monocarboxylate transporter 1
Alternative name(s):
Apical iodide transporter
Electrogenic sodium monocarboxylate cotransporter
Sodium iodide-related cotransporter
Solute carrier family 5 member 8
Gene names
Name:SLC5A8
Synonyms:AIT, SMCT, SMCT1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length610 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Acts as an electrogenic sodium (Na+) and chloride (Cl-)-dependent sodium-coupled solute transporter, including transport of monocarboxylates (short-chain fatty acids including L-lactate, D-lactate, pyruvate, acetate, propionate, valerate and butyrate), lactate, mocarboxylate drugs (nicotinate, benzoate, salicylate and 5-aminosalicylate) and ketone bodies (beta-D-hydroxybutyrate, acetoacetate and alpha-ketoisocaproate), with a Na+:substrate stoichiometry of between 4:1 and 2:1. Catalyzes passive carrier mediated diffusion of iodide. Mediates iodide transport from the thyrocyte into the colloid lumen through the apical membrane. May be responsible for the absorption of D-lactate and monocarboxylate drugs from the intestinal tract. Acts as a tumor suppressor, suppressing colony formation in colon cancer, prostate cancer and glioma cell lines. May play a critical role in the entry of L-lactate and ketone bodies into neurons by a process driven by an electrochemical Na+ gradient and hence contribute to the maintenance of the energy status and function of neurons. Ref.1 Ref.2 Ref.3 Ref.4 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15

Subcellular location

Apical cell membrane; Multi-pass membrane protein. Note: Expressed at the apical membrane of normal tall thyrocytes and of colonic epithelial cells. Ref.1 Ref.8 Ref.15

Tissue specificity

Expressed in normal thyroid, localized at the apical pole of thyroid cells facing the colloid lumen, but expression profoundly decreased in thyroid carcinomas. Expressed in normal colon but absent in colon aberrant crypt foci and colon cancers. Present in normal kidney cortex, brain, prostate, gastric mucosa and breast tissue but was significantly down-regulated in primary gliomas, gastric cancer, prostate tumors and breast tumors. Ref.1 Ref.2 Ref.3 Ref.4 Ref.8 Ref.9 Ref.10 Ref.11 Ref.14 Ref.15

Induction

Down-regulated in some primary cancers; due to aberrant methylation in primary colon cancers, astrocytomas and oligodendrogliomas as well as in cancers of the colon, prostate and gastric regions, and glial cell lines. Expression reactivated on treatment with a demethylating drug, 5-azacytidine. Ref.2 Ref.9 Ref.10 Ref.14

Miscellaneous

Increase of iodide influx inhibited by addition of perchlorate (NaClO4), a competitive inhibitor of iodide uptake catalyzed by sodium iodide symporter (NIS). Cotransport of monocarboxylates and nicotinate strongly inhibited by probenecid, nonsteroid anti-inflammatory drugs (ibuprofen, fenoprofen, ketprofen, naproxen) in a Na+-dependent manner or by prolonged exposure to external concentrations of monocarboxylates. Ref.1 Ref.4 Ref.13

Sequence similarities

Belongs to the sodium:solute symporter (SSF) (TC 2.A.21) family. [View classification]

Biophysicochemical properties

Kinetic parameters:

KM=1442 µM for beta-D-hydroxybutyate Ref.12

KM=2327 µM for beta-L-hydroxybutyate Ref.12

KM=1088 µM for D-lactate Ref.12

KM=184 µM for L-lactate Ref.12

KM=387 µM for pyruvate Ref.12

KM=213 µM for acetoacetate Ref.12

KM=209 µM for alpha-ketoisocaproate Ref.12

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 610610Sodium-coupled monocarboxylate transporter 1
PRO_0000334499

Regions

Topological domain1 – 99Extracellular Potential
Transmembrane10 – 3021Helical; Potential
Topological domain31 – 5121Cytoplasmic Potential
Transmembrane52 – 7221Helical; Potential
Topological domain73 – 8311Extracellular Potential
Transmembrane84 – 10421Helical; Potential
Topological domain105 – 13228Cytoplasmic Potential
Transmembrane133 – 15321Helical; Potential
Topological domain154 – 1618Extracellular Potential
Transmembrane162 – 18221Helical; Potential
Topological domain183 – 1897Cytoplasmic Potential
Transmembrane190 – 21021Helical; Potential
Topological domain211 – 23929Extracellular Potential
Transmembrane240 – 26021Helical; Potential
Topological domain261 – 27919Cytoplasmic Potential
Transmembrane280 – 30021Helical; Potential
Topological domain301 – 33636Extracellular Potential
Transmembrane337 – 35923Helical; Potential
Topological domain360 – 38930Cytoplasmic Potential
Transmembrane390 – 41021Helical; Potential
Topological domain411 – 4155Extracellular Potential
Transmembrane416 – 43621Helical; Potential
Topological domain437 – 4393Cytoplasmic Potential
Transmembrane440 – 46021Helical; Potential
Topological domain461 – 51858Extracellular Potential
Transmembrane519 – 53921Helical; Potential
Topological domain540 – 61071Cytoplasmic Potential
Compositional bias569 – 5724Poly-Lys

Amino acid modifications

Glycosylation4851N-linked (GlcNAc...) Potential

Natural variations

Natural variant1931V → I. Ref.2 Ref.3
Corresponds to variant rs1709189 [ dbSNP | Ensembl ].
VAR_057336
Natural variant2511F → V. Ref.3
Corresponds to variant rs11834933 [ dbSNP | Ensembl ].
VAR_057337

Experimental info

Sequence conflict4901M → I in AAL88746. Ref.1
Sequence conflict4901M → I in AAP46193. Ref.2
Sequence conflict4901M → I in AAP46194. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Q8N695 [UniParc].

Last modified May 18, 2010. Version 2.
Checksum: 47FF410B895DB692

FASTA61066,578
        10         20         30         40         50         60 
MDTPRGIGTF VVWDYVVFAG MLVISAAIGI YYAFAGGGQQ TSKDFLMGGR RMTAVPVALS 

        70         80         90        100        110        120 
LTASFMSAVT VLGTPSEVYR FGAIFSIFAF TYFFVVVISA EVFLPVFYKL GITSTYEYLE 

       130        140        150        160        170        180 
LRFNKCVRLC GTVLFIVQTI LYTGIVIYAP ALALNQVTGF DLWGAVVATG VVCTFYCTLG 

       190        200        210        220        230        240 
GLKAVIWTDV FQVGIMVAGF ASVIIQAVVM QGGISTILND AYDGGRLNFW NFNPNPLQRH 

       250        260        270        280        290        300 
TFWTIIIGGT FTWTSIYGVN QSQVQRYISC KSRFQAKLSL YINLVGLWAI LTCSVFCGLA 

       310        320        330        340        350        360 
LYSRYHDCDP WTAKKVSAPD QLMPYLVLDI LQDYPGLPGL FVACAYSGTL STVSSSINAL 

       370        380        390        400        410        420 
AAVTVEDLIK PYFRSLSERS LSWISQGMSV VYGALCIGMA ALASLMGALL QAALSVFGMV 

       430        440        450        460        470        480 
GGPLMGLFAL GILVPFANSI GALVGLMAGF AISLWVGIGA QIYPPLPERT LPLHLDIQGC 

       490        500        510        520        530        540 
NSTYNETNLM TTTEMPFTTS VFQIYNVQRT PLMDNWYSLS YLYFSTVGTL VTLLVGILVS 

       550        560        570        580        590        600 
LSTGGRKQNL DPRYILTKED FLSNFDIFKK KKHVLSYKSH PVEDGGTDNP AFNHIELNSD 

       610 
QSGKSNGTRL 

« Hide

References

« Hide 'large scale' references
[1]"Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes."
Rodriguez A.-M., Perron B., Lacroix L., Caillou B., Leblanc G., Schlumberger M., Bidart J.-M., Pourcher T.
J. Clin. Endocrinol. Metab. 87:3500-3503(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INHIBITION.
Tissue: Kidney.
[2]"SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers."
Li H., Myeroff L., Smiraglia D., Romero M.F., Pretlow T.P., Kasturi L., Lutterbaugh J., Rerko R.M., Casey G., Issa J.-P., Willis J., Willson J.K., Plass C., Markowitz S.D.
Proc. Natl. Acad. Sci. U.S.A. 100:8412-8417(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANT ILE-193, FUNCTION, INDUCTION, TISSUE SPECIFICITY.
Tissue: Colon.
[3]"Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na(+)-coupled transporter for short-chain fatty acids."
Miyauchi S., Gopal E., Fei Y.-J., Ganapathy V.
J. Biol. Chem. 279:13293-13296(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, STOICHIOMETRY, VARIANTS ILE-193 AND VAL-251.
Tissue: Intestine.
[4]"The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter."
Coady M.J., Chang M.-H., Charron F.M., Plata C., Wallendorff B., Sah J.F., Markowitz S.D., Romero M.F., Lapointe J.-Y.
J. Physiol. (Lond.) 557:719-731(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, STOICHIOMETRY, INHIBITION.
Tissue: Kidney cortex.
[5]"The finished DNA sequence of human chromosome 12."
Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R. expand/collapse author list , Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., Gibbs R.A.
Nature 440:346-351(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[8]"Expression of the apical iodide transporter in human thyroid tissues: a comparison study with other iodide transporters."
Lacroix L., Pourcher T., Magnon C., Bellon N., Talbot M., Intaraphairot T., Caillou B., Schlumberger M., Bidart J.-M.
J. Clin. Endocrinol. Metab. 89:1423-1428(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[9]"Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer."
Ueno M., Toyota M., Akino K., Suzuki H., Kusano M., Satoh A., Mita H., Sasaki Y., Nojima M., Yanagihara K., Hinoda Y., Tokino T., Imai K.
Tumor Biol. 25:134-140(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY, INDUCTION.
[10]"Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8."
Hong C., Maunakea A., Jun P., Bollen A.W., Hodgson J.G., Goldenberg D.D., Weiss W.A., Costello J.F.
Cancer Res. 65:3617-3623(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY, INDUCTION.
[11]"SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases."
Thangaraju M., Gopal E., Martin P.M., Ananth S., Smith S.B., Prasad P.D., Sterneck E., Ganapathy V.
Cancer Res. 66:11560-11564(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY.
[12]"Identity of SMCT1 (SLC5A8) as a neuron-specific Na+-coupled transporter for active uptake of L-lactate and ketone bodies in the brain."
Martin P.M., Gopal E., Ananth S., Zhuang L., Itagaki S., Prasad B.M., Smith S.B., Prasad P.D., Ganapathy V.
J. Neurochem. 98:279-288(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES.
[13]"Interaction of ibuprofen and other structurally related NSAIDs with the sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8)."
Itagaki S., Gopal E., Zhuang L., Fei Y.-J., Miyauchi S., Prasad P.D., Ganapathy V.
Pharm. Res. 23:1209-1216(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INHIBITION.
[14]"Candidate tumor suppressor gene SLC5A8 is frequently down-regulated by promoter hypermethylation in prostate tumor."
Park J.Y., Zheng W., Kim D., Cheng J.Q., Kumar N., Ahmad N., Pow-Sang J.
Cancer Detect. Prev. 31:359-365(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY, INDUCTION.
[15]"Transport of nicotinate and structurally related compounds by human SMCT1 (SLC5A8) and its relevance to drug transport in the mammalian intestinal tract."
Gopal E., Miyauchi S., Martin P.M., Ananth S., Roon P., Smith S.B., Ganapathy V.
Pharm. Res. 24:575-584(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, STOICHIOMETRY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AY081220 mRNA. Translation: AAL88746.1.
AF536216 mRNA. Translation: AAP46193.1.
AF536217 Genomic DNA. Translation: AAP46194.1.
AC079953 Genomic DNA. No translation available.
CH471054 Genomic DNA. Translation: EAW97649.1.
BC110492 mRNA. Translation: AAI10493.1.
CCDSCCDS9080.1.
RefSeqNP_666018.3. NM_145913.3.
UniGeneHs.444536.

3D structure databases

ProteinModelPortalQ8N695.
SMRQ8N695. Positions 57-456.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

STRING9606.ENSP00000299233.

Chemistry

GuidetoPHARMACOLOGY922.

Protein family/group databases

TCDB2.A.21.5.3. the solute:sodium symporter (sss) family.

PTM databases

PhosphoSiteQ8N695.

Polymorphism databases

DMDM296452898.

Proteomic databases

PaxDbQ8N695.
PRIDEQ8N695.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000536262; ENSP00000445340; ENSG00000256870.
ENST00000572861; ENSP00000461697; ENSG00000262217.
GeneID160728.
KEGGhsa:160728.
UCSCuc001thz.4. human.

Organism-specific databases

CTD160728.
GeneCardsGC12M101549.
H-InvDBHIX0036731.
HGNCHGNC:19119. SLC5A8.
MIM608044. gene.
neXtProtNX_Q8N695.
PharmGKBPA134989874.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0591.
HOGENOMHOG000261662.
HOVERGENHBG057280.
InParanoidQ8N695.
KOK14388.
OMAWISQGMS.
OrthoDBEOG70PBX7.
PhylomeDBQ8N695.
TreeFamTF316728.

Enzyme and pathway databases

ReactomeREACT_15518. Transmembrane transport of small molecules.
REACT_19419. Amino acid and oligopeptide SLC transporters.

Gene expression databases

BgeeQ8N695.
CleanExHS_SLC5A8.
GenevestigatorQ8N695.

Family and domain databases

InterProIPR001734. Na/solute_symporter.
IPR019900. Na/solute_symporter_subgr.
[Graphical view]
PANTHERPTHR11819. PTHR11819. 1 hit.
PfamPF00474. SSF. 1 hit.
[Graphical view]
TIGRFAMsTIGR00813. sss. 1 hit.
PROSITEPS50283. NA_SOLUT_SYMP_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiSLC5A8.
GenomeRNAi160728.
NextBio87983.
PROQ8N695.
SOURCESearch...

Entry information

Entry nameSC5A8_HUMAN
AccessionPrimary (citable) accession number: Q8N695
Secondary accession number(s): Q2TB99, Q7Z2H9
Entry history
Integrated into UniProtKB/Swiss-Prot: May 20, 2008
Last sequence update: May 18, 2010
Last modified: July 9, 2014
This is version 86 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 12

Human chromosome 12: entries, gene names and cross-references to MIM