Organic Anion Transporting Polypeptides of the OATP/SLCO Superfamily: Identification of New Members in Nonmammalian Species, Comparative Modeling and a Potential Transport Mode

Abstract

Organic anion-transporting polypeptides (human, OATPs; other animals, Oatps; gene symbol, SLCO/Slco) form a transport protein superfamily that mediates the translocation of amphipathic substrates across the plasma membrane of animal cells. So far, OATPs/Oatps have been identified in human, rat and mouse tissues. In this study, we used bioinformatic tools to detect new members of the OATP/SLCO superfamily in nonmammalian species and to build models for the three-dimensional structure of OATPs/Oatps. New OATP/SLCO superfamily members, some of which form distinct novel families, were identified in chicken, zebrafish, frog, fruit fly and worm species. The lack of OATP/SLCO superfamily members in plants, yeast and bacteria suggests the emergence of an ancient Oatp protein in an early ancestor of the animal kingdom. Structural models were generated for the representative members OATP1B3 and OATP2B1 based on the known structures of the major facilitator superfamily of transport proteins. A model was also built for the large extracellular region between transmembrane helices 9 and 10, following the identification of a novel homology with the Kazal-type serine protease inhibitors. Along with the electrostatic potential and the conservation of key amino acid residues, we propose a common transport mechanism for all OATPs/Oatps, whereby substrates are translocated through a central, positively charged pore in a rocker-switch type of mechanism. Several amino acid residues were identified that may play crucial roles in the proposed transport mechanism.

Molecular and biological characterization of the Amblyomma americanum organic anion transporter polypeptide

“…Given that these cysteine residues are 100% conserved in the AamOatp, it is a good indicator that this protein is likely to be functional. In humans, mice and rats, at least 39 Oatp/OATP proteins were described by (Meier-Abt et al, 2005. Given that the A. americanum genome has not been sequenced, the full repertoire of Oatp proteins in this tick will remain unknown.…”

Excretion of biliary compounds during intrauterine life

“…Many xenobiotics are substrates of OATP isoforms [124] , which are expressed in the human placenta [63,66] . These transporters have partially different and overlapping substrate preferences for a wide range of exogenous organic solutes, including gadodexate, ouabain, iloprost, Gd-B 20790, methotrexate, rifampicin, the endothelin receptor antagonist BQ-123, the thrombin inhibitor CRC-220, the opioid receptor agonists D-penicillamine-(2,5)-enkephalin (DPDPE) and deltorphin Ⅱ, the angiotensin-converting enzyme inhibitors enalapril and temocaprilat, the HMG-CoA reductase inhibitor pravastatin, and the antihistamine fexofenadine, in addition to several cytostatic derivatives obtained by coupling bile acid moieties to chlorambucil or cisplatin [125][126][127] . Some OATP isoforms have also been shown to transport bulky organic cations [124,128] .…”

The Kidney Vero-E6 Cell Line: A Suitable Model to Study the Toxicity of Microcystins

“…They are responsible for the sodiumindependent uptake of large amphipathic endogenous and exogenous organic anions into cells and across the blood-brain barrier [9,10]. The knowledge on the mechanism(s) of OATPmediated transport is still scarce [9] however, the available information suggests that, in a general way, OATPs act as organic anion exchangers [11], functioning in a rocker-switch type of mechanism and translocating the substrate through a central positively charged pore [9]. Some OATPs are expressed ubiquitously, whereas others are expressed in a tissue-specific way [10].…”