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) 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 such as estrone-sulfate and dehydroepiandrosterone-sulfate (Rižner et al. 2017), 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).  Fluorescein is a general OAT family substrate (Patik et al. 2015), but Hagenbuch and Gui 2008 have summarized the general features and substrates of the eleven human OATPs, and Jetter and Kullak-Ublick 2019 have summarized the interplay between various transporters of drugs, xenobiotics and bile salts. Differences in the structures, tissue distribution, substrates, and roles in liver diseases of OATs have been reviewed (Li et al. 2019).

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 primarily in mammals, but characterized homologues are present in D. melanogaster (Eraly et al. 2004; Chahine et al. 2012), 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 TMSs. 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. Regulation of expression and function of OATps has been described (Svoboda et al., 2011). In the OATP proteins, TM1/2-TM7 interactions influence the inner pocket accessibility, while TM1/2-TM11 salt bridges control the substrate binding stability (Tonduru et al. 2022).

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

Anion (in) → Anion (out)

or

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