Q4U2R8 · S22A6_HUMAN
- ProteinSolute carrier family 22 member 6
- GeneSLC22A6
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids563 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Secondary active transporter that functions as a Na+-independent organic anion (OA)/dicarboxylate antiporter where the uptake of one molecule of OA into the cell is coupled with an efflux of one molecule of intracellular dicarboxylate such as 2-oxoglutarate or glutarate (PubMed:11669456, PubMed:11907186, PubMed:14675047, PubMed:22108572, PubMed:23832370, PubMed:28534121, PubMed:9950961).
Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine (PubMed:9887087).
Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121).
Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion (PubMed:11907186).
Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP (PubMed:26377792).
Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain (PubMed:22108572, PubMed:23832370).
May transport glutamate (PubMed:26377792).
Also involved in the disposition of uremic toxins and potentially toxic xenobiotics by the renal organic anion secretory pathway, helping reduce their undesired toxicological effects on the body (PubMed:11669456, PubMed:14675047).
Uremic toxins include the indoxyl sulfate (IS), hippurate/N-benzoylglycine (HA), indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate (CMPF) and urate (PubMed:14675047, PubMed:26377792).
Xenobiotics include the mycotoxin ochratoxin (OTA) (PubMed:11669456).
May also contribute to the transport of organic compounds in testes across the blood-testis-barrier (PubMed:35307651).
Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine (PubMed:9887087).
Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121).
Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion (PubMed:11907186).
Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP (PubMed:26377792).
Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain (PubMed:22108572, PubMed:23832370).
May transport glutamate (PubMed:26377792).
Also involved in the disposition of uremic toxins and potentially toxic xenobiotics by the renal organic anion secretory pathway, helping reduce their undesired toxicological effects on the body (PubMed:11669456, PubMed:14675047).
Uremic toxins include the indoxyl sulfate (IS), hippurate/N-benzoylglycine (HA), indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate (CMPF) and urate (PubMed:14675047, PubMed:26377792).
Xenobiotics include the mycotoxin ochratoxin (OTA) (PubMed:11669456).
May also contribute to the transport of organic compounds in testes across the blood-testis-barrier (PubMed:35307651).
Miscellaneous
Involved in the renal transport of a variety of drugs with well-known nephrotoxic potential, therefore may play a role in the etiology of the drug-associated nephrotoxicity (PubMed:10462545, PubMed:12538807).
Uptakes the diagnostic agent PAH/para-aminohippurate and clinically used drugs (PubMed:10462545, PubMed:12538807, PubMed:15644426, PubMed:15914676, PubMed:17038320, PubMed:17502342, PubMed:23832370, PubMed:26377792, PubMed:9762842, PubMed:9887087).
Mediates the pH- and chloride-dependent bidirectional transport of PAH/para-aminohippurate in exchange for 2-oxoglutarate or glutarate as counteranions (PubMed:15644426, PubMed:26377792, PubMed:9950961).
Can also mediate PAH/cGMP exchange (PubMed:26377792).
Uptakes the diagnostic agent PAH/para-aminohippurate and clinically used drugs (PubMed:10462545, PubMed:12538807, PubMed:15644426, PubMed:15914676, PubMed:17038320, PubMed:17502342, PubMed:23832370, PubMed:26377792, PubMed:9762842, PubMed:9887087).
Mediates the pH- and chloride-dependent bidirectional transport of PAH/para-aminohippurate in exchange for 2-oxoglutarate or glutarate as counteranions (PubMed:15644426, PubMed:26377792, PubMed:9950961).
Can also mediate PAH/cGMP exchange (PubMed:26377792).
Catalytic activity
- (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin(out) + a dicarboxylate(in) = (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin(in) + a dicarboxylate(out)
- a dicarboxylate(in) + L-erythro-7,8-dihydrobiopterin(out) = a dicarboxylate(out) + L-erythro-7,8-dihydrobiopterin(in)
- a dicarboxylate(in) + L-sepiapterin(out) = a dicarboxylate(out) + L-sepiapterin(in)
- a dicarboxylate(in) + prostaglandin F2alpha(out) = a dicarboxylate(out) + prostaglandin F2alpha(in)
- a dicarboxylate(in) + prostaglandin E2(out) = a dicarboxylate(out) + prostaglandin E2(in)
- 3',5'-cyclic AMP(out) + a dicarboxylate(in) = 3',5'-cyclic AMP(in) + a dicarboxylate(out)
- 3',5'-cyclic GMP(out) + a dicarboxylate(in) = 3',5'-cyclic GMP(in) + a dicarboxylate(out)
- a dicarboxylate(in) + urate(out) = a dicarboxylate(out) + urate(in)
- glutarate(in) + kynurenate(out) = glutarate(out) + kynurenate(in)
- (indol-3-yl)acetate(out) + a dicarboxylate(in) = (indol-3-yl)acetate(in) + a dicarboxylate(out)
- a dicarboxylate(in) + indoxyl sulfate(out) = a dicarboxylate(out) + indoxyl sulfate(in)
- a dicarboxylate(in) + N-benzoylglycine(out) = a dicarboxylate(out) + N-benzoylglycine(in)
- 3-carboxy-4-methyl-5-propyl-2-furanpropanoate(out) + a dicarboxylate(in) = 3-carboxy-4-methyl-5-propyl-2-furanpropanoate(in) + a dicarboxylate(out)
Kinetics
KM | SUBSTRATE | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|---|
970 nM | prostaglandin E2 | |||||
575 nM | prostaglandin F2-alpha | |||||
23.5 μM | hippurate/N-benzoylglycine | |||||
14 μM | indole acetate | |||||
20.5 μM | indoxyl sulfate | |||||
141 μM | 3-carboxy-4- methyl-5-propyl-2-furanpropionate | |||||
4.83 μM | xanthurenate | |||||
5.06 μM | kynurenate | |||||
0.42 μM | ochratoxin A |
Vmax | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|
430 pmol/min/mg | for hippurate/N-benzoylglycine uptake | ||||
110 pmol/min/mg | for indole acetate uptake | ||||
216 pmol/min/mg | for indoxyl sulfate uptake | ||||
801 pmol/min/mg | for 3-carboxy-4- methyl-5-propyl-2-furanpropionate uptake |
Features
Showing features for site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 230 | Important for interaction with cidofovir | ||||
Sequence: Y | ||||||
Site | 438 | Important for interaction with cidofovir and PAH | ||||
Sequence: F |
GO annotations
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameSolute carrier family 22 member 6
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ4U2R8
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Basolateral cell membrane ; Multi-pass membrane protein
Basal cell membrane ; Multi-pass membrane protein
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-9 | Cytoplasmic | ||||
Sequence: MAFNDLLQQ | ||||||
Transmembrane | 10-30 | Helical | ||||
Sequence: VGGVGRFQQIQVTLVVLPLLL | ||||||
Topological domain | 31-135 | Extracellular | ||||
Sequence: MASHNTLQNFTAAIPTHHCRPPADANLSKNGGLEVWLPRDRQGQPESCLRFTSPQWGLPFLNGTEANGTGATEPCTDGWIYDNSTFPSTIVTEWDLVCSHRALRQ | ||||||
Transmembrane | 136-156 | Helical | ||||
Sequence: LAQSLYMVGVLLGAMVFGYLA | ||||||
Topological domain | 157-164 | Cytoplasmic | ||||
Sequence: DRLGRRKV | ||||||
Transmembrane | 165-187 | Helical | ||||
Sequence: LILNYLQTAVSGTCAAFAPNFPI | ||||||
Topological domain | 188-190 | Extracellular | ||||
Sequence: YCA | ||||||
Transmembrane | 191-213 | Helical | ||||
Sequence: FRLLSGMALAGISLNCMTLNVEW | ||||||
Topological domain | 214-224 | Cytoplasmic | ||||
Sequence: MPIHTRACVGT | ||||||
Transmembrane | 225-245 | Helical | ||||
Sequence: LIGYVYSLGQFLLAGVAYAVP | ||||||
Topological domain | 246-248 | Extracellular | ||||
Sequence: HWR | ||||||
Transmembrane | 249-269 | Helical | ||||
Sequence: HLQLLVSAPFFAFFIYSWFFI | ||||||
Topological domain | 270-337 | Cytoplasmic | ||||
Sequence: ESARWHSSSGRLDLTLRALQRVARINGKREEGAKLSMEVLRASLQKELTMGKGQASAMELLRCPTLRH | ||||||
Transmembrane | 338-358 | Helical | ||||
Sequence: LFLCLSMLWFATSFAYYGLVM | ||||||
Topological domain | 359-368 | Extracellular | ||||
Sequence: DLQGFGVSIY | ||||||
Transmembrane | 369-389 | Helical | ||||
Sequence: LIQVIFGAVDLPAKLVGFLVI | ||||||
Topological domain | 390-395 | Cytoplasmic | ||||
Sequence: NSLGRR | ||||||
Transmembrane | 396-416 | Helical | ||||
Sequence: PAQMAALLLAGICILLNGVIP | ||||||
Topological domain | 417-425 | Extracellular | ||||
Sequence: QDQSIVRTS | ||||||
Transmembrane | 426-446 | Helical | ||||
Sequence: LAVLGKGCLAASFNCIFLYTG | ||||||
Topological domain | 447-455 | Cytoplasmic | ||||
Sequence: ELYPTMIRQ | ||||||
Transmembrane | 456-475 | Helical | ||||
Sequence: TGMGMGSTMARVGSIVSPLV | ||||||
Topological domain | 476-484 | Extracellular | ||||
Sequence: SMTAELYPS | ||||||
Transmembrane | 485-505 | Helical | ||||
Sequence: MPLFIYGAVPVAASAVTVLLP | ||||||
Topological domain | 506-563 | Cytoplasmic | ||||
Sequence: ETLGQPLPDTVQDLESRWAPTQKEAGIYPRKGKQTRQQQEHQKYMVPLQASAQEKNGL |
Keywords
- Cellular component
Disease & Variants
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_039682 | 7 | in dbSNP:rs1415632329 | |||
Sequence: L → P | ||||||
Mutagenesis | 30 | Complete loss of PAH transport activity. | ||||
Sequence: L → A | ||||||
Mutagenesis | 36 | Complete loss of PAH transport activity. | ||||
Sequence: T → A | ||||||
Mutagenesis | 39 | Complete loss of PAH transport activity. | ||||
Sequence: N → Q | ||||||
Natural variant | VAR_039683 | 50 | lower Vmax; increase in substrate affinity and increase in the affinity for the nucleoside phosphonate analogs cidofovir, adefovir and tenofovir; dbSNP:rs11568626 | |||
Sequence: R → H | ||||||
Natural variant | VAR_047878 | 104 | in dbSNP:rs11568627 | |||
Sequence: P → L | ||||||
Mutagenesis | 230 | Loss of membrane protein expression and little uptake of cidofovir. | ||||
Sequence: Y → A | ||||||
Natural variant | VAR_039684 | 293 | increase in substrate affinity; dbSNP:rs45607933 | |||
Sequence: R → W | ||||||
Mutagenesis | 431 | Decrease in the level of membrane protein expression and 70 % loss of PAH uptake. | ||||
Sequence: K → A | ||||||
Mutagenesis | 438 | Decrease in the level of membrane protein expression, 70 % loss of PAH uptake, increased affinity for cidofovir, lower Vmax for PAH, and lower Km and Vmax for cidofovir. | ||||
Sequence: F → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 672 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, glycosylation.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000324166 | 1-563 | Solute carrier family 22 member 6 | |||
Sequence: MAFNDLLQQVGGVGRFQQIQVTLVVLPLLLMASHNTLQNFTAAIPTHHCRPPADANLSKNGGLEVWLPRDRQGQPESCLRFTSPQWGLPFLNGTEANGTGATEPCTDGWIYDNSTFPSTIVTEWDLVCSHRALRQLAQSLYMVGVLLGAMVFGYLADRLGRRKVLILNYLQTAVSGTCAAFAPNFPIYCAFRLLSGMALAGISLNCMTLNVEWMPIHTRACVGTLIGYVYSLGQFLLAGVAYAVPHWRHLQLLVSAPFFAFFIYSWFFIESARWHSSSGRLDLTLRALQRVARINGKREEGAKLSMEVLRASLQKELTMGKGQASAMELLRCPTLRHLFLCLSMLWFATSFAYYGLVMDLQGFGVSIYLIQVIFGAVDLPAKLVGFLVINSLGRRPAQMAALLLAGICILLNGVIPQDQSIVRTSLAVLGKGCLAASFNCIFLYTGELYPTMIRQTGMGMGSTMARVGSIVSPLVSMTAELYPSMPLFIYGAVPVAASAVTVLLPETLGQPLPDTVQDLESRWAPTQKEAGIYPRKGKQTRQQQEHQKYMVPLQASAQEKNGL | ||||||
Glycosylation | 39 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 56 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 92 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 97 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 113 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N |
Post-translational modification
Glycosylated. Glycosylation at Asn-113 may occur at a secondary level. Glycosylation is necessary for proper targeting of the transporter to the plasma membrane.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Strongly expressed in kidney (PubMed:10049739, PubMed:10462545, PubMed:10964714, PubMed:9887087, PubMed:9950961).
Expressed at lower level in liver, skeletal muscle, brain and placenta (PubMed:10049739, PubMed:10462545, PubMed:9887087, PubMed:9950961).
In kidney, found at the basolateral membrane of the proximal tubule (PubMed:9887087).
In testis, primarily localized to the basal membrane of Sertoli cells and weakly expressed in Leydig cells and vascular endothelial cells (PubMed:35307651).
Expressed at lower level in liver, skeletal muscle, brain and placenta (PubMed:10049739, PubMed:10462545, PubMed:9887087, PubMed:9950961).
In kidney, found at the basolateral membrane of the proximal tubule (PubMed:9887087).
In testis, primarily localized to the basal membrane of Sertoli cells and weakly expressed in Leydig cells and vascular endothelial cells (PubMed:35307651).
Gene expression databases
Organism-specific databases
Interaction
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q4U2R8 | APPBP2 Q92624 | 3 | EBI-749741, EBI-743771 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 525-563 | Disordered | ||||
Sequence: PTQKEAGIYPRKGKQTRQQQEHQKYMVPLQASAQEKNGL |
Domain
Multiple cysteine residues are necessary for proper targeting to the plasma membrane.
Sequence similarities
Belongs to the major facilitator (TC 2.A.1) superfamily. Organic cation transporter (TC 2.A.1.19) family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
This entry describes 4 isoforms produced by Alternative splicing.
Q4U2R8-1
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.
- Name1
- SynonymsOAT1-1
- Length563
- Mass (Da)61,816
- Last updated2005-07-19 v1
- Checksum74AD3EA2678032E4
Q4U2R8-2
- Name2
- SynonymsOAT1-2
- Differences from canonical
- 523-535: Missing
Q4U2R8-3
- Name3
- SynonymsOAT1-3
Q4U2R8-4
- Name4
- SynonymsOAT1-4
- Differences from canonical
- 455-498: Missing
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
F5H0T7 | F5H0T7_HUMAN | SLC22A6 | 261 |
Features
Showing features for sequence conflict, alternative sequence.
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF057039 EMBL· GenBank· DDBJ | AAC70004.1 EMBL· GenBank· DDBJ | mRNA | ||
AB009697 EMBL· GenBank· DDBJ | BAA75072.1 EMBL· GenBank· DDBJ | mRNA | ||
AB009698 EMBL· GenBank· DDBJ | BAA75073.1 EMBL· GenBank· DDBJ | mRNA | ||
AF104038 EMBL· GenBank· DDBJ | AAD10052.1 EMBL· GenBank· DDBJ | mRNA | ||
AF097490 EMBL· GenBank· DDBJ | AAD19356.1 EMBL· GenBank· DDBJ | mRNA | ||
AF124373 EMBL· GenBank· DDBJ | AAD55356.1 EMBL· GenBank· DDBJ | mRNA | ||
AJ249369 EMBL· GenBank· DDBJ | CAB77184.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AJ251529 EMBL· GenBank· DDBJ | CAB94830.1 EMBL· GenBank· DDBJ | mRNA | ||
AJ271205 EMBL· GenBank· DDBJ | CAB97249.1 EMBL· GenBank· DDBJ | mRNA | ||
EU567146 EMBL· GenBank· DDBJ | ACB21049.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AP001858 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471076 EMBL· GenBank· DDBJ | EAW74129.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471076 EMBL· GenBank· DDBJ | EAW74130.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471076 EMBL· GenBank· DDBJ | EAW74131.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471076 EMBL· GenBank· DDBJ | EAW74132.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC033682 EMBL· GenBank· DDBJ | AAH33682.1 EMBL· GenBank· DDBJ | mRNA |