Q8N695 (SC5A8_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	610 AA.
Sequence status	Complete.
Protein existence	Evidence 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

Ontologies

Keywords
Biological process	Apoptosis Ion transport Sodium transport Symport Transport
Cellular component	Cell membrane Membrane
Coding sequence diversity	Polymorphism
Disease	Tumor suppressor
Domain	Transmembrane Transmembrane helix
Ligand	Sodium
PTM	Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW ion transport Traceable author statement. Source: Reactome sodium ion transport Inferred from electronic annotation. Source: UniProtKB-KW transmembrane transport Traceable author statement. Source: Reactome
Cellular_component	apical plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW plasma membrane Traceable author statement. Source: Reactome
Molecular_function	symporter activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 610	610	Sodium-coupled monocarboxylate transporter 1		PRO_0000334499
Regions
	Topological domain	1 – 9	9	Extracellular Potential
	Transmembrane	10 – 30	21	Helical; Potential
	Topological domain	31 – 51	21	Cytoplasmic Potential
	Transmembrane	52 – 72	21	Helical; Potential
	Topological domain	73 – 83	11	Extracellular Potential
	Transmembrane	84 – 104	21	Helical; Potential
	Topological domain	105 – 132	28	Cytoplasmic Potential
	Transmembrane	133 – 153	21	Helical; Potential
	Topological domain	154 – 161	8	Extracellular Potential
	Transmembrane	162 – 182	21	Helical; Potential
	Topological domain	183 – 189	7	Cytoplasmic Potential
	Transmembrane	190 – 210	21	Helical; Potential
	Topological domain	211 – 239	29	Extracellular Potential
	Transmembrane	240 – 260	21	Helical; Potential
	Topological domain	261 – 279	19	Cytoplasmic Potential
	Transmembrane	280 – 300	21	Helical; Potential
	Topological domain	301 – 336	36	Extracellular Potential
	Transmembrane	337 – 359	23	Helical; Potential
	Topological domain	360 – 389	30	Cytoplasmic Potential
	Transmembrane	390 – 410	21	Helical; Potential
	Topological domain	411 – 415	5	Extracellular Potential
	Transmembrane	416 – 436	21	Helical; Potential
	Topological domain	437 – 439	3	Cytoplasmic Potential
	Transmembrane	440 – 460	21	Helical; Potential
	Topological domain	461 – 518	58	Extracellular Potential
	Transmembrane	519 – 539	21	Helical; Potential
	Topological domain	540 – 610	71	Cytoplasmic Potential
	Compositional bias	569 – 572	4	Poly-Lys
Amino acid modifications
	Glycosylation	485	1	N-linked (GlcNAc...) Potential
Natural variations
	Natural variant	193	1	V → I. Ref.2 Ref.3 Corresponds to variant rs1709189 [ dbSNP | Ensembl ].		VAR_057336
	Natural variant	251	1	F → V. Ref.3 Corresponds to variant rs11834933 [ dbSNP | Ensembl ].		VAR_057337
Experimental info
	Sequence conflict	490	1	M → I in AAL88746. Ref.1
	Sequence conflict	490	1	M → I in AAP46193. Ref.2
	Sequence conflict	490	1	M → I in AAP46194. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q8N695 [UniParc]. Last modified May 18, 2010. Version 2. Checksum: 47FF410B895DB692	FASTA	610	66,578
	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

References

	« Hide 'large scale' referencesShow '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. , 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. , 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.
IPI	IPI00166969.
RefSeq	NP_666018.3. NM_145913.3.
UniGene	Hs.444536.
3D structure databases
ProteinModelPortal	Q8N695.
SMR	Q8N695. Positions 57-456.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000299233.
Protein family/group databases
TCDB	2.A.21.5.3. solute:sodium symporter (SSS) family.
PTM databases
PhosphoSite	Q8N695.
Polymorphism databases
DMDM	296452898.
Proteomic databases
PaxDb	Q8N695.
PRIDE	Q8N695.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000536262; ENSP00000445340; ENSG00000256870. ENST00000572861; ENSP00000461697; ENSG00000262217.
GeneID	160728.
KEGG	hsa:160728.
UCSC	uc001thz.4. human.
Organism-specific databases
CTD	160728.
GeneCards	GC12M101549.
H-InvDB	HIX0036731.
HGNC	HGNC:19119. SLC5A8.
MIM	608044. gene.
neXtProt	NX_Q8N695.
PharmGKB	PA134989874.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0591.
HOGENOM	HOG000261662.
HOVERGEN	HBG057280.
InParanoid	Q8N695.
KO	K14388.
OMA	WISQGMS.
OrthoDB	EOG44TP7T.
PhylomeDB	Q8N695.
Enzyme and pathway databases
Reactome	REACT_15518. Transmembrane transport of small molecules. REACT_19419. Amino acid and oligopeptide SLC transporters.
Gene expression databases
Bgee	Q8N695.
CleanEx	HS_SLC5A8.
Genevestigator	Q8N695.
Family and domain databases
InterPro	IPR001734. Na/solute_symporter. IPR019900. Na/solute_symporter_subgr. [Graphical view]
PANTHER	PTHR11819. PTHR11819. 1 hit.
Pfam	PF00474. SSF. 1 hit. [Graphical view]
TIGRFAMs	TIGR00813. sss. 1 hit.
PROSITE	PS00456. NA_SOLUT_SYMP_1. False negative. PS00457. NA_SOLUT_SYMP_2. False negative. PS50283. NA_SOLUT_SYMP_3. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	160728.
NextBio	87983.
SOURCE	Search...

Entry information

Entry name

SC5A8_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 76 of the entry and version 2 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.