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2.A.60 The Organo Anion Transporter (OAT) Family

Proteins of the OAT family (solute carrier family 21 (previously called SLC21A; more recently designated SLCO by the HUGO Gene Nomenclature Committee (B. Hagenbuch, personal communication))) 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, respectively), steroid conjugates, thyroid hormones, anionic oligopeptides, drugs, toxins and other xenobiotics (Hong 2013).  Among the well characterized substrates are numerous drugs including statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antibiotics, antihistaminics, antihypertensives and anticancer drugs (Hagenbuch and Stieger 2013).  There are six mammalian OAT families (Hagenbuch and Stieger 2013).

The various paralogues in a mammal have differing but overlapping substrate specificities and tissue distributions as summarized by Hagenbuch and Meier (2003). 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 (Hagenbuch and Meier, 2003). Therefore, these mammalian proteins are all included within a single subfamily of the TC system (TC #2.A.60.1). The detailed substrates transported and their affinities are presented by Hagenbuch and Meier (2003). 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. 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 D. melanogaster, A. gambiae, and C. elegans. The mammalian OAT family proteins exhibit a high degree of tissue specificity. Mammalian homologues consist of 640-722 amino acyl residues and possess 12 putative α-helical transmembrane spanners. They may catalyze electrogenic anion uniport or more frequently, anion exchange. Conformational changes of the multispecific organic anion transporter 1 (OAT1/SLC22A6) has suggested a molecular mechanism for initial stages of drug and metabolite transport (Tsigelny et al., 2011). The OAT family is a distant family within the MFS (TC #2.A.1). Regulation of expression and function of OATps has been described (Svoboda et al., 2011).

The generalized transport reaction catalyzed by members of the OAT family is:

Anion (in) %u21CC Anion (out)

or

Anion1 (in) Anion2 (out) %u21CC Anion1 (out) Anion2 (in).

This family belongs to the: MFS Superfamily.

References associated with 2.A.60 family:

Abe, T., M. Kakyo, H. Sakagami, T. Tokui, T. Nishio, M. Tanemoto, H. Nomura, S.C. Hebert, S. Matsuno, H. Kondo, and H. Yawo. (1998). Molecular characterization and tissue distribution of a new organic anion transporter subtype (Oatp3) that transports thyroid hormones and taurocholate and comparison with Oatp2. J. Biol. Chem. 273: 22395-22401. 9712861
Abe, T., M. Kakyo, T. Tokui, R. Nakagomi, T. Nishio, D. Nakai, H. Nomura, M. Unno, M. Suzuki, T. Naitoh, S. Matsuno, and H. Yawo. (1999). Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J. Biol. Chem. 274: 17159-17163. 10358072
Arakawa, H., Y. Shirasaka, M. Haga, T. Nakanishi, and I. Tamai. (2012). Active intestinal absorption of fluoroquinolone antibacterial agent ciprofloxacin by organic anion transporting polypeptide, Oatp1a5. Biopharm Drug Dispos 33: 332-341. 22899169
Briz, O., M.R. Romero, P. Martinez-Becerra, R.I. Macias, M.J. Perez, F. Jimenez, F.G. San Martin, and J.J. Marin. (2006). OATP8/1B3-mediated cotransport of bile acids and glutathione: an export pathway for organic anions from hepatocytes? J. Biol. Chem. 281: 30326-30335. 16877380
Cai, S.Y., W. Wang, C.J. Soroka, N. Ballatori, and J.L. Boyer. (2002). An evolutionarily ancient Oatp: insights into conserved functional domains of these proteins. Am. J. Physiol. Gastrointest Liver Physiol 282: G702-710. 11897630
Chan, B.S., J.A. Satriano, M. Pucci, and V.L. Schuster. (1998). Mechanism of prostaglandin E2 transport across the plasma membrane of HeLa cells and Xenopus oocytes expressing the prostaglandin transporter "PGT". J. Biol. Chem. 273: 6689-6697. 9506966
Chi Y. and Schuster VL. (2010). The prostaglandin transporter PGT transports PGH(2). Biochem Biophys Res Commun. 395(2):168-72. 20346915
Cui, Y., J. König, I. Leier, U. Buchholz, and D. Keppler. (2001). Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J. Biol. Chem. 276: 9626-9630. 11134001
DeGorter, M.K., R.H. Ho, B.F. Leake, R.G. Tirona, and R.B. Kim. (2012). Interaction of three regiospecific amino acid residues is required for OATP1B1 gain of OATP1B3 substrate specificity. Mol Pharm 9: 986-995. 22352740
Gui, C. and B. Hagenbuch. (2008). Amino acid residues in transmembrane domain 10 of organic anion transporting polypeptide 1B3 are critical for cholecystokinin octapeptide transport. Biochemistry 47: 9090-9097. 18690707
Hagenbuch, B. (1997). Molecular properties of hepatic uptake systems for bile acids and organic acids. J. Membr. Biol. 160: 1-8. 9351887
Hagenbuch, B. and B. Stieger. (2013). The SLCO (former SLC21) superfamily of transporters. Mol Aspects Med 34: 396-412. 23506880
Hagenbuch, B. and P.J. Meier. (2003). The superfamily of organic anion transporting polypeptides. Biochim. Biophys. Acta 1609: 1-18. 12507753
Hakes, D.J. and R. Berezney. (1991). Molecular cloning of matrin F/G: a DNA binding protein of the nuclear matrix that contains putative zinc finger motifs. Proc. Natl. Acad. Sci. USA 88: 6186-6190. 2068100
Herfindal, L., C. Krakstad, L. Myhren, H. Hagland, R. Kopperud, K. Teigen, F. Schwede, R. Kleppe, and S.O. Døskeland. (2014). Introduction of Aromatic Ring-Containing Substituents in Cyclic Nucleotides Is Associated with Inhibition of Toxin Uptake by the Hepatocyte Transporters OATP 1B1 and 1B3. PLoS One 9: e94926. 24740327
Hong, M. (2013). Critical Domains within the Sequence of Human Organic Anion Transporting Polypeptides. Curr Drug Metab. [Epub: Ahead of Print] 24372098
Huang, J., N. Li, W. Hong, K. Zhan, X. Yu, H. Huang, and M. Hong. (2013). Conserved Tryptophan Residues within Putative Transmembrane Domain 6 Affect Transport Function of Organic Anion Transporting Polypeptide 1B1. Mol Pharmacol. [Epub: Ahead of Print] 23858103
Jacquemin, E., B. Hagenbuch, B. Stieger, A.W. Wolkoff, and P.J. Meier. (1994). Expression cloning of a rat liver Na(+)-independent organic anion transporter. Proc. Natl. Acad. Sci. USA 91: 133-137. 8278353
Kanai, N., R. Lu, J.A. Satriano, Y. Bao, A.W. Wolkoff, and V.L. Schuster. (1995). Identification and characterization of a prostaglandin transporter. Science 268: 866-869. 7754369
Kinne, A., R. Schülein, and G. Krause. (2011). Primary and secondary thyroid hormone transporters. Thyroid Res 4Suppl1: S7. 21835054
Li, N., W. Hong, H. Huang, H. Lu, G. Lin, and M. Hong. (2012). Identification of Amino Acids Essential for Estrone-3-Sulfate Transport within Transmembrane Domain 2 of Organic Anion Transporting Polypeptide 1B1. PLoS One 7: e36647. 22574206
Maeda, T., K. Takahashi, N. Ohtsu, T. Oguma, T. Ohnishi, R. Atsumi, and I. Tamai. (2007). Identification of influx transporter for the quinolone antibacterial agent levofloxacin. Mol. Pharm. 4: 85-94. 17274666
Mikkaichi, T., T. Suzuki, T. Onogawa, M. Tanemoto, H. Mizutamari, M. Okada, T. Chaki, S. Masuda, T. Tokui, N. Eto, M. Abe, F. Satoh, M. Unno, T. Hishinuma, K. Inui, S. Ito, J. Goto, and T. Abe. (2004). Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc. Natl. Acad. Sci. USA 101: 3569-3574. 14993604
Ohkura, N., Y. Shigetani, N. Yoshiba, K. Yoshiba, and T. Okiji. (2014). Prostaglandin transporting protein-mediated prostaglandin E2 transport in lipopolysaccharide-inflamed rat dental pulp. J Endod 40: 1112-1117. 25069917
Patrick, P.S., S.K. Lyons, T.B. Rodrigues, and K.M. Brindle. (2014). Oatp1 Enhances Bioluminescence by Acting as a Plasma Membrane Transporter for D-luciferin. Mol Imaging Biol. [Epub: Ahead of Print] 24798747
Popovic, M., R. Zaja, K. Fent, and T. Smital. (2013). Molecular characterization of zebrafish Oatp1d1 (Slco1d1), a novel organic anion-transporting polypeptide. J. Biol. Chem. 288: 33894-33911. 24126916
Schuster, V.L. (1998). Molecular mechanisms of prostaglandin transport. Annu. Rev. Physiol. 60: 221-242. 9558462
Schuster, V.L. (2002). Prostaglandin transport. Prostaglandins Other Lipid Mediat 68-69: 633-647. 12432949
Sugiyama, D., H. Kusuhara, H. Taniguchi, S. Ishikawa, Y. Nozaki, H. Aburatani, and Y. Sugiyama. (2003). Functional characterization of rat brain-specific organic anion transporter (Oatp14) at the blood-brain barrier. High affinity transporter for thyroxine. J. Biol. Chem. 278: 43489-43495. 12923172
Svoboda, M., J. Riha, K. Wlcek, W. Jaeger, and T. Thalhammer. (2011). Organic anion transporting polypeptides (OATPs): regulation of expression and function. Curr Drug Metab 12: 139-153. 21395542
Sweet, D.H., D.S. Miller, J.B. Pritchard, Y. Fujiwara, D.R. Beier, and S.K. Nigam. (2002). Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice. J. Biol. Chem. 277: 26934-26943. 12011098
Tirona, R.G., B.F. Leake, G. Merino, and R.B. Kim. (2001). Polymorphisms in OATP-C. Identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J. Biol. Chem. 276: 35669-35675. 11477075
Tsigelny, I.F., D. Kovalskyy, V.L. Kouznetsova, O. Balinskyi, Y. Sharikov, V. Bhatnagar, and S.K. Nigam. (2011). Conformational changes of the multispecific transporter organic anion transporter 1 (OAT1/SLC22A6) suggests a molecular mechanism for initial stages of drug and metabolite transport. Cell Biochem Biophys 61: 251-259. 21499753
van Montfoort, J.E., T.E. Schmid, I.-D. Adler, P.J. Meier, and B. Hagenbuch. (2002). Functional characterization of the mouse organic-anion-transporting polypeptide 2. Biochim. Biophys. Acta 1564: 183-188. 12101011
Wang, P., R.B. Kim, J.R. Chowdhury, and A.W. Wolkoff. (2003). The human organic anion transport protein SLC21A6 is not sufficient for bilirubin transport. J. Biol. Chem. 278: 20695-20699. 12670950
Westholm, D.E., J.D. Marold, K.J. Viken, A.H. Duerst, G.W. Anderson, and J.N. Rumbley. (2010). Evidence of evolutionary conservation of function between the thyroxine transporter Oatp1c1 and major facilitator superfamily members. Endocrinology 151: 5941-5951. 20881245
Zhang, H.X., X. Zhao, Z. Yang, C.Y. Peng, R. Long, G.N. Li, J. Li, and Z.K. He. (2010). [OATP 1B1 T521C/A388G is an important polymorphism gene related to neonatal hyperbilirubinemia]. Zhonghua Er Ke Za Zhi 48: 650-655. 21092521