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1  structure 98  species 0  interactions 1462  sequences 17  architectures

Family: OATP (PF03137)

Summary: Organic Anion Transporter Polypeptide (OATP) family

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This is the Wikipedia entry entitled "Organic anion-transporting polypeptide". More...

Organic anion-transporting polypeptide Edit Wikipedia article

Organic Anion Transporter Polypeptide (OATP) family
Identifiers
Symbol OATP
Pfam PF03137
InterPro IPR004156
TCDB 2.A.60

An organic anion-transporting polypeptide (OATP) is a membrane transport protein or 'transporter' that mediates the transport of mainly organic anions across the cell membrane. Therefore OATPs are present in the lipid bilayer of the cell membrane, acting as the cell's gatekeepers. OATPs belong to the Solute Carrier Family (SLC), more specifically the Solute Carrier Organic Anion (SLCO) gene subfamily [1]

Function

Organic anion transporting polypeptides carry bile acids as well as bilirubin and numerous hormones such as thyroid and steroid hormones across the basolateral membrane (facing sinusoids) in hepatocytes, for excretion in bile.[2] As well as expression in the liver, OATPs are expressed in many other tissues on basolateral and apical membranes, transporting anions, as well as neutral and even cationic compounds. They also transport an extremely diverse range of drug compounds, ranging from anti-cancer, antibiotic, lipid lowering to anti-diabetic drugs, as well as toxins and poisons.

Various anti-cancer drugs like pazopanib, vandetanib, nilotinib, canertinib and erlotinib are known to be transported via OATPs (OATP-1B1 and OATP-1B3).[3]

Also, anti-cancer drugs specially the tyrosine kinase inhibitors have been reported as inhibitors of OATP (OATP-1B1 and OATP-1B3. Pazopanib and Nilotinib have shown their inhibitory potential only towards OATP-1B1 but not towards OATP-1B3 whereas Vandetanib has shown its inhibitory activity only towards OATP-1B3 but not towards OATP-1B1.[4]

They also transport the dye bromosulphopthalein, availing it as a liver-testing substance.[2]

Proteins

The table below shows the 11 known human OATPs. Note: Human OATPs are designated with capital letters, animal Oatps are designated with lower class letters. The 'SLCO' stands for their gene name; 'solute carrier organic anion.' Previous nomenclature using letters and numbers (e.g. OATP-A, OATP-8 is no longer correct. The most well characterised human OATPs are OATP1A2, OATP1B1, OATP1B3 and OATP2B1. Very little is known about the function and characteristics of OATP5A1 and OATP6A1.

Abbreviation Protein Name Location
SLCO1A2 Solute carrier organic anion transporter family member 1A2 Ubiquitous
SLCO1B1 Solute carrier organic anion transporter family member 1B1 Liver
SLCO1B3 Solute carrier organic anion transporter family member 1B3 Liver
SLCO1C1 Solute carrier organic anion transporter family member 1C1 Brain, testis
SLCO2A1 Solute carrier organic anion transporter family member 2A1 Ubiquitous
SLCO2B1 Solute carrier organic anion transporter family member 2B1 Ubiquitous
SLCO3A1 Solute carrier organic anion transporter family member 3A1 Testis, brain, heart, lung, spleen
SLCO4A1 Solute carrier organic anion transporter family member 4A1 Heart, placenta, lung, liver
SLCO4C1 Solute carrier organic anion transporter family member 4C1 Kidney
SLCO5A1 Solute carrier organic anion transporter family member 5A1 Breast, fetal brain, prostate
SLCO6A1 Solute carrier organic anion transporter family member 6A1 Testes, spleen, brain, placenta

Pharmacology

The OATPs play a role in the transport of some classes of drugs across the cell membrane, particularly in the liver and kidney. In the liver, OATPs are expressed on the basolateral membrane of hepatocytes, transporting compounds into the hepatocyte for biotransformation. A number of drug-drug interactions have been associated with the OATPs, affecting the pharmacokinetics and pharmacodynamics of drugs. This is most commonly where one drug inhibits the transport of another drug into the hepatocyte, so that it is retained longer in the body (i.e. increased plasma half-life). The OATPs most associated with these interactions are OATP1B1, OATP1B3 and OATP2B1, which are all present on the hepatocyte basolateral (sinusoidal) membrane. OATP1B1 and OATP1B3 are known to play an important role in hepatic drug disposition. These OATPs contribute towards first step of hepatic accumulation and can influence the disposition of drug via hepatic route.[3] The most clinically relevant interactions have been associated with the lipid lowering drugs statins, which led to the removal of cerivastatin from the market in 2002. Single nucleotide polymorphisms (SNPs) are also associated with the OATPs; particularly OATP1B1.

Many modulators of OATP function have been identified based on in vitro research in OATP-transfected cell lines.[5][6] Both OATP activation and inhibition has been observed and an in silico model for structure-based identification of OATP modulation was developed.[7]

Since tyrosine kinase inhibitors (TKIs) are metabolized in the liver, interaction of TKIs with OATP1B1 and OATP1B3 can be considered as important molecular targets for transporter mediated drug-drug interactions.[3]

Along with the organic anion transporters, organic cation transporters and the ATP-binding cassette transporters, the OATPs play an important role in the absorption, distribution, metabolism and exretion (ADME) of many drugs.

Evolution

Oatps are present in many animals, including fruit fly, zebrafish, dog, cow, rat, mouse, monkey and horse. Oatps are not present in bacteria, indicating their evolution from the animal kingdom. However homologs do not correlate well with the human OATPs and therefore it is likely that isoforms arose by gene duplication. Oatps have however been found in insects,[8] suggesting that their evolution was early in the formation of the animal kingdom.

References

  1. ^ Hagenbuch B, Meier PJ (February 2004). "Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties". Pflugers Arch. 447 (5): 653–65. doi:10.1007/s00424-003-1168-y. PMID 14579113. 
  2. ^ a b Pages 980-990 in:Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN 1-4160-2328-3. 
  3. ^ a b c Khurana V, Minocha M, Pal D, Mitra AK (March 2014). "Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors.". Drug Metabol Drug Interact. 0 (0): 1–11. doi:10.1515/dmdi-2013-0062. PMID 24643910. 
  4. ^ Khurana V, Minocha M, Pal D, Mitra AK (May 2014). "Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors.". Drug Metabol Drug Interact. 0 (0): 1–11. doi:10.1515/dmdi-2014-0014. PMID 24807167. 
  5. ^ Annaert P, Ye ZW, Stieger B, Augustijns P. Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1. Xenobiotica. 2010 Mar;40(3):163-76. doi: 10.3109/00498250903509375. PubMed PMID: 20102298.
  6. ^ De Bruyn T, Fattah S, Stieger B, Augustijns P, Annaert P. Sodium fluorescein is a probe substrate for hepatic drug transport mediated by OATP1B1 and OATP1B3. J Pharm Sci. 2011 Nov;100(11):5018-30. doi: 10.1002/jps.22694. Epub 2011 Aug 11. PubMed PMID: 21837650.
  7. ^ De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP. Structure-based identification of OATP1B1/3 inhibitors. Mol Pharmacol. 2013 Jun;83(6):1257-67. doi: 10.1124/mol.112.084152. Epub 2013 Apr 9. PubMed PMID: 23571415.
  8. ^ Torrie LS, Radford JC, Southall TD, Kean L, Dinsmore AJ, Davies SA, Dow JA (2004-09-07). "Resolution of the insect ouabain paradox". PNAS 101 (37): 13689–93. doi:10.1073/pnas.0403087101. 

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Organic Anion Transporter Polypeptide (OATP) family Provide feedback

This family consists of several eukaryotic Organic-Anion-Transporting Polypeptides (OATPs). Several have been identified mostly in human and rat. Different OATPs vary in tissue distribution and substrate specificity. Since the numbering of different OATPs in particular species was based originally on the order of discovery, similarly numbered OATPs in humans and rats did not necessarily correspond in function, tissue distribution and substrate specificity (in spite of the name, some OATPs also transport organic cations and neutral molecules). Thus, Tamai et al. [1] initiated the current scheme of using digits for rat OATPs and letters for human ones. Prostaglandin transporter (PGT) proteins (e.g. Q92959) are also considered to be OATP family members. In addition, the methotrexate transporter OATK (P70502) is closely related to OATPs. This family also includes several predicted proteins from Caenorhabditis elegans and Drosophila melanogaster. This similarity was not previously noted. Note: Members of this family are described (in the Swiss-Prot database) as belonging to the SLC21 family of transporters.

Literature references

  1. Tamai I, Nezu J, Uchino H, Sai Y, Oku A, Shimane M, Tsuji A; , Biochem Biophys Res Commun 2000;273:251-260.: Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. PUBMED:10873595 EPMC:10873595


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR004156

This family consists of several eukaryotic Organic-Anion-Transporting Polypeptides (OATPs). Several have been identified mostly in human and rat. Different OATPs vary in tissue distribution and substrate specificity. Since the numbering of different OATPs in particular species was based originally on the order of discovery, similarly numbered OATPs in humans and rats did not necessarily correspond in function, tissue distribution and substrate specificity (in spite of the name, some OATPs also transport organic cations and neutral molecules) so a scheme of using digits for rat OATPs and letters for human ones was introduced [PUBMED:10873595]. Prostaglandin transporter (PGT) proteins are also considered to be OATP family members. In addition, the methotrexate transporter OATK is closely related to OATPs. This family also includes several predicted proteins from Caenorhabditis elegans and Drosophila melanogaster. This similarity was not previously noted. Note: Members of this family are described (in the UniProtKB/Swiss-Prot database) as belonging to the SLC21 family of transporters.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

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Pfam Clan

This family is a member of clan MFS (CL0015), which has the following description:

The major facilitator superfamily (MFS) is one of the two largest families of membrane transporters found on Earth [1]. It is present ubiquitously in bacteria, archaea, and eukarya and includes members that can function by solute uniport, solute/cation symport, solute/cation antiport and/or solute/solute antiport with inwardly and/or outwardly directed polarity [1]. All permeases of the MFS possess either 12 or 14 transmembrane helices [1].

The clan contains the following 25 members:

Acatn ATG22 BT1 CLN3 DUF1228 DUF791 Folate_carrier FPN1 FTR1 LacY_symp MFS_1 MFS_1_like MFS_2 MFS_3 MFS_Mycoplasma Nodulin-like Nuc_H_symport Nucleoside_tran OATP PTR2 PUCC Sugar_tr TLC TRI12 UNC-93

Alignments

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

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Full
(1462)
Representative proteomes NCBI
(1674)
Meta
(81)
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(328)
RP35
(378)
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RP75
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  Seed
(16)
Full
(1462)
Representative proteomes NCBI
(1674)
Meta
(81)
RP15
(328)
RP35
(378)
RP55
(620)
RP75
(852)
Alignment:
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  Seed
(16)
Full
(1462)
Representative proteomes NCBI
(1674)
Meta
(81)
RP15
(328)
RP35
(378)
RP55
(620)
RP75
(852)
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

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Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Pfam-B_626 (release 6.5)
Previous IDs: OATP_C;
Type: Family
Author: Mifsud W, Bateman A
Number in seed: 16
Number in full: 1462
Average length of the domain: 439.80 aa
Average identity of full alignment: 25 %
Average coverage of the sequence by the domain: 82.67 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null --hand HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 23.3 23.3
Trusted cut-off 23.3 23.3
Noise cut-off 23.2 23.2
Model length: 539
Family (HMM) version: 15
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Species distribution

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the OATP domain has been found. There are 1 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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