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2  structures 544  species 0  interactions 7313  sequences 78  architectures

Family: OATP (PF03137)

Summary: Organic Anion Transporter Polypeptide (OATP) family

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Organo anion transporter family Edit Wikipedia article

Organic-anion-transporting polypeptide (OATP) family
Identifiers
SymbolOATP
PfamPF03137
InterProIPR004156
TCDB2.A.60

Members of the Organo Anion Transporter (OAT) Family (organic-anion-transporting polypeptides, OATP) are membrane transport proteins or 'transporters' that mediate 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) and the major facilitator superfamily.[1]

The generalized transport reactions catalyzed by members of the OAT family are:

Anion (in) → Anion (out)

Anion1 (in) + Anion2 (out) → Anion1 (out) + Anion2 (in)

Function

Proteins of the OAT family catalyze the Na+-independent facilitated transport of fairly large amphipathic organic anions (and less frequently neutral or cationic drugs), such as bromosulfobromophthalein, prostaglandins, conjugated and unconjugated bile acids (taurocholate and cholate), steroid conjugates, thyroid hormones, anionic oligopeptides, drugs, toxins and other xenobiotics.[2] One family member, OATP2B1, has been shown to use cytoplasmic glutamate as the exchanging anion.[3] Among the well characterized substrates are numerous drugs including statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antibiotics, antihistaminics, antihypertensives and anticancer drugs.[4] Other substrates include luciferin, thyroid hormones and quinolones.[2][5][6]

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.[7] 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).[8] Some of these have also been reported as inhibitors of certain OATPs: pazopanib and nilotinib against OATP-1B1 and vandetanib against OATP-1B3.[9]

They also transport the dye bromosulphopthalein, availing it as a liver-testing substance.[7]

Homology

The various paralogues in a mammal have differing but overlapping substrate specificities and tissue distributions as summarized by Hagenbuch and Meier.[4] These authors also provide a phylogenetic tree of the mammalian members of the family, showing that they fall into five recognizable subfamilies, four of which exhibit deep branching sub-subfamilies. However, all sequences within a subfamily are >60% identical while those between subfamilies are >40% identical.[4] As also shown by Hagenbuch and Meier, all but one (OatP4a1) of the mammalian homologues cluster together, separately from all other animal (insect and worm) homologues.[4]

OAT family homologues have been found in other animals but not outside of the animal kingdom. These transporters have been characterized in mammals, but homologues are present in Drosophila melanogaster, Anopheles gambiae, and Caenorhabditis elegans. The mammalian OAT family proteins exhibit a high degree of tissue specificity.

Human 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.[8] 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.[10][11] Both OATP activation and inhibition has been observed and an in silico model for structure-based identification of OATP modulation was developed.[12]

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.[8]

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

Evolution

OATPs are present in many animals, including fruit flies, zebrafish, dogs, cows, rats, mice, monkeys and horses. 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,[13] 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" (PDF). Pflügers Archiv. 447 (5): 653–65. doi:10.1007/s00424-003-1168-y. PMID 14579113. S2CID 21837213.
  2. ^ a b Hong W, Wu Z, Fang Z, Huang J, Huang H, Hong M (December 2015). "Amino Acid Residues in the Putative Transmembrane Domain 11 of Human Organic Anion Transporting Polypeptide 1B1 Dictate Transporter Substrate Binding, Stability, and Trafficking". Molecular Pharmaceutics. 12 (12): 4270–6. doi:10.1021/acs.molpharmaceut.5b00466. PMID 26562723.
  3. ^ Lofthouse EM, Brooks S, Cleal JK, Hanson MA, Poore KR, O'Kelly IM, Lewis RM (October 2015). "Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast". The Journal of Physiology. 593 (20): 4549–59. doi:10.1113/JP270743. PMC 4606536. PMID 26277985.
  4. ^ a b c d Hagenbuch B, Stieger B (2013-06-01). "The SLCO (former SLC21) superfamily of transporters". Molecular Aspects of Medicine. 34 (2–3): 396–412. doi:10.1016/j.mam.2012.10.009. PMC 3602805. PMID 23506880.
  5. ^ Sugiyama D, Kusuhara H, Taniguchi H, Ishikawa S, Nozaki Y, Aburatani H, Sugiyama Y (October 2003). "Functional characterization of rat brain-specific organic anion transporter (Oatp14) at the blood-brain barrier: high affinity transporter for thyroxine". The Journal of Biological Chemistry. 278 (44): 43489–95. doi:10.1074/jbc.M306933200. PMID 12923172.
  6. ^ Patrick PS, Lyons SK, Rodrigues TB, Brindle KM (October 2014). "Oatp1 enhances bioluminescence by acting as a plasma membrane transporter for D-luciferin". Molecular Imaging and Biology. 16 (5): 626–34. doi:10.1007/s11307-014-0741-4. PMC 4161938. PMID 24798747.
  7. ^ a b Pages 980-990 in:Walter F. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN 1-4160-2328-3.
  8. ^ 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 Metabolism and Drug Interactions. 29 (3): 179–90. doi:10.1515/dmdi-2013-0062. PMC 4407685. PMID 24643910.
  9. ^ Khurana V, Minocha M, Pal D, Mitra AK (May 2014). "Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors". Drug Metabolism and Drug Interactions. 29 (4): 249–59. doi:10.1515/dmdi-2014-0014. PMC 4407688. PMID 24807167.
  10. ^ Annaert P, Ye ZW, Stieger B, Augustijns P (March 2010). "Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1" (PDF). Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 40 (3): 163–76. doi:10.3109/00498250903509375. PMID 20102298. S2CID 207426839.
  11. ^ De Bruyn T, Fattah S, Stieger B, Augustijns P, Annaert P (November 2011). "Sodium fluorescein is a probe substrate for hepatic drug transport mediated by OATP1B1 and OATP1B3". Journal of Pharmaceutical Sciences. 100 (11): 5018–30. doi:10.1002/jps.22694. PMID 21837650.
  12. ^ De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP (June 2013). "Structure-based identification of OATP1B1/3 inhibitors". Molecular Pharmacology. 83 (6): 1257–67. doi:10.1124/mol.112.084152. PMID 23571415. S2CID 10627787.
  13. ^ Torrie LS, Radford JC, Southall TD, Kean L, Dinsmore AJ, Davies SA, Dow JA (September 2004). "Resolution of the insect ouabain paradox". Proceedings of the National Academy of Sciences of the United States of America. 101 (37): 13689–93. Bibcode:2004PNAS..10113689T. doi:10.1073/pnas.0403087101. PMC 518814. PMID 15347816.


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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


Internal database links

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. All characterized OATPs are predicted to have 12 transmembrane domains and are sodium-independent transport systems [ PUBMED:23506880 ].

Gene Ontology

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

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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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 26 members:

Acatn ATG22 BT1 CLN3 DUF5690 Folate_carrier FPN1 LacY_symp MFS_1 MFS_1_like MFS_2 MFS_3 MFS_4 MFS_5 MFS_Mycoplasma Nodulin-like Nuc_H_symport Nucleoside_tran OATP PTR2 PUCC Sugar_tr TLC TRI12 UNC-93 UVB_sens_prot

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.

  Seed
(207)
Full
(7313)
Representative proteomes UniProt
(13065)
RP15
(1589)
RP35
(2903)
RP55
(5615)
RP75
(7421)
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  Seed
(207)
Full
(7313)
Representative proteomes UniProt
(13065)
RP15
(1589)
RP35
(2903)
RP55
(5615)
RP75
(7421)
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  Seed
(207)
Full
(7313)
Representative proteomes UniProt
(13065)
RP15
(1589)
RP35
(2903)
RP55
(5615)
RP75
(7421)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download  
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

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
Sequence Ontology: SO:0100021
Author: Mifsud W , Bateman A
Number in seed: 207
Number in full: 7313
Average length of the domain: 433.90 aa
Average identity of full alignment: 27 %
Average coverage of the sequence by the domain: 79.81 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null --hand HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.8 25.8
Trusted cut-off 25.8 25.8
Noise cut-off 25.7 25.7
Model length: 545
Family (HMM) version: 23
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence

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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 2 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 sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A0G2JWY3 View 3D Structure Click here
A0A0G2K9W9 View 3D Structure Click here
A0A0N4SU37 View 3D Structure Click here
A0A0N4SUD8 View 3D Structure Click here
A0A0R0FWP3 View 3D Structure Click here
A0A0R4IBD9 View 3D Structure Click here
A0A0R4ICL4 View 3D Structure Click here
A0A0R4IW35 View 3D Structure Click here
A0A2R8QE24 View 3D Structure Click here
A0A2R8QHY9 View 3D Structure Click here
A0A2R8RXR5 View 3D Structure Click here
B3DJD4 View 3D Structure Click here
D3ZZM7 View 3D Structure Click here
E7F2I7 View 3D Structure Click here
E7FFX7 View 3D Structure Click here
E9PVD9 View 3D Structure Click here
F1Q5M5 View 3D Structure Click here
F1Q9B1 View 3D Structure Click here
G3V0H7 View 3D Structure Click here
L7N264 View 3D Structure Click here
M0QWR8 View 3D Structure Click here
M0RAI5 View 3D Structure Click here
O35913 View 3D Structure Click here
O62421 View 3D Structure Click here
O88397 View 3D Structure Click here
O94956 View 3D Structure Click here
P46720 View 3D Structure Click here
P46721 View 3D Structure Click here
P70502 View 3D Structure Click here
Q00910 View 3D Structure Click here
Q1LV73 View 3D Structure Click here
Q20538 View 3D Structure Click here
Q4CQB9 View 3D Structure Click here
Q5RFF0 View 3D Structure Click here
Q6ZQN7 View 3D Structure Click here
Q86UG4 View 3D Structure Click here
Q8BGD4 View 3D Structure Click here
Q8BXB6 View 3D Structure Click here
Q8C0X7 View 3D Structure Click here
Q8HYW2 View 3D Structure Click here