UC San Diego

Organic anion transporters (OATs), organic cation transporters (OCTs) and organic carnitine and zwitterion transporters (OCTNs), which belong to the solute carrier 22 family (SLC22);TC# 2.A.1.19, transport a wide variety of metabolites, environmental toxins and drugs. Evolutionary analysis of these so called "drug" transporters may shed light on the endogenous role of SLC22 transporters which is only beginning to be explored. We took advantage of the sequencing of multiple genomes, and here, present a phylogenetic analysis of 31 known SLC22 members. Our studies indicate that they evolved from a common ancestor over 450 million years ago before the separation of bony fish and land vertebrates. Several putative SLC22 orthologs exist in worms, sea urchins, flies, and ciona while several other OAT, OCT, and OCTN family members first appear in mammals based on phylogenetic tree topologies. There is a particularly large expansion of SLC22 members in mammals, suggesting a physiological and/or toxicological role for these SLC22 transporters in the successful mammalian radiation into new environments. Moreover, phylogenetic analysis indicates that OATs (e.g. SLC22A6 also known as OAT1 or NKT) and OCTs (SLC22A1 or OCT1) represent two major subclades with the OAT subclade being by the largest; nevertheless there are clear OCTN (e.g. OCTN1 or SLC22A4, OCTN2 or SLC22A5), OAT-like (e.g. OAT10 or SLC22A13, SLC22A14 or OCTL2), OCTN-like subclades, as well as a distantly related group which we have named the OAT- related group containing SLC22A17, SLC22A18, SLC22A23, and SLC22A31. The uniqueness of the OAT-related subgroup raises the possibility of distinct functions for this set of transporters. Motif analysis suggests the first extracellular region is highly conserved within subclades but not between subclades and may be particularly important for subclade-specific function