title: Evolutionary Analysis and Classification of OATs, OCTs, OCTNs, and Other SLC22 Transporters: Structure-Function Implications and Analysis of Sequence Motifs.
abstract: The SLC22 family includes organic anion transporters (OATs), organic cation transporters (OCTs) and organic carnitine and zwitterion transporters (OCTNs). These are often referred to as drug transporters even though they interact with many endogenous metabolites and signaling molecules (Nigam, S.K., Nature Reviews Drug Discovery, 14:29-44, 2015). Phylogenetic analysis of SLC22 supports the view that these transporters may have evolved over 450 million years ago. Many OAT members were found to appear after a major expansion of the SLC22 family in mammals, suggesting a physiological and/or toxicological role during the mammalian radiation. Putative SLC22 orthologs exist in worms, sea urchins, flies, and ciona. At least six groups of SLC22 exist. OATs and OCTs form two Major clades of SLC22, within which (apart from Oat and Oct subclades), there are also clear Oat-like, Octn, and Oct-related subclades, as well as a distantly related group we term "Oat-related" (which may have different functions). Based on available data, it is arguable whether SLC22A18, which is related to bacterial drug-proton antiporters, should be assigned to SLC22. Disease-causing mutations, single nucleotide polymorphisms (SNPs) and other functionally analyzed mutations in OAT1, OAT3, URAT1, OCT1, OCT2, OCTN1, and OCTN2 map to the first extracellular domain, the large central intracellular domain, and transmembrane domains 9 and 10. These regions are highly conserved within subclades, but not between subclades, and may be necessary for SLC22 transporter function and functional diversification. Our results not only link function to evolutionarily conserved motifs but indicate the need for a revised sub-classification of SLC22.
authors.affiliation: Departments of Pediatrics, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Departments of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Kabir B
authors.initials: KB
authors.lastname: Nigam
authors.affiliation: Departments of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Rishabh C
authors.initials: RC
authors.lastname: Date
authors.affiliation: Departments of Pediatrics, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Bush
authors.affiliation: Departments of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Stevan A
authors.initials: SA
authors.lastname: Springer
authors.affiliation: Departments of Molecular Biology, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Milton H
authors.initials: MH
authors.lastname: Saier
authors.affiliation: Departments of Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Departments of Pediatrics, University of California at San Diego, La Jolla, California, United States of America.|Departments of Medicine, University of California at San Diego, La Jolla, California, United States of America.|Departments of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, United States of America.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Nigam
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D005075:Biological Evolution; D001692:Biological Transport / Q000235:genetics*; D002331:Carnitine / Q000378:metabolism; D006801:Humans; D051379:Mice; D005810:Multigene Family; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017434:Protein Structure, Tertiary
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D002331:Carnitine