Systems Biology Analysis Reveals Eight SLC22 Transporter Subgroups, Including OATs, OCTs, and OCTNs

• Published in: International journal of molecular sciences Vol. 21; no. 5; p. 1791
• Main Authors: Engelhart, Darcy C, Granados, Jeffry C, Shi, Da, Saier Jr, Jr, Milton H, Baker, Michael E, Abagyan, Ruben, Nigam, Sanjay K
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05.03.2020; MDPI
• Subjects: Animals; Biological Transport; Carnitine; chronic kidney disease; Crosstalk; Cyclic nucleotides; Digestive system; drug transporters; endogenous metabolism; functional subgroups; Gene Expression Regulation; Gene Regulatory Networks; gut microbiome; Hormones; Humans; Metabolites; Microbiota; Multigene Family; Mutation; Neurotransmitters; Nucleotides; Oats; Odorants; Organic Anion Transporters - classification; Organic Anion Transporters - genetics; Organic Anion Transporters - metabolism; Organic Cation Transport Proteins - classification; Organic Cation Transport Proteins - genetics; Organic Cation Transport Proteins - metabolism; Remote sensing; remote sensing and signaling; Sex hormones; Signal Transduction; slc22; Subgroups; Substrate Specificity; Substrates; Systems Biology - methods; Toxins; transporters; Uric acid; drug transporters; chronic kidney disease; gut microbiome; transporters; endogenous metabolism; remote sensing and signaling; functional subgroups; SLC22
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21051791

The SLC22 family of OATs, OCTs, and OCTNs is emerging as a central hub of endogenous physiology. Despite often being referred to as "drug" transporters, they facilitate the movement of metabolites and key signaling molecules. An in-depth reanalysis supports a reassignment of these proteins into eight functional subgroups, with four new subgroups arising from the previously defined OAT subclade: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and Slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, and SLC22A25). We propose merging the OCTN (SLC22A4, SLC22A5, and Slc22a21) and OCT-related (SLC22A15 and SLC22A16) subclades into the OCTN/OCTN-related subgroup. Using data from GWAS, in vivo models, and in vitro assays, we developed an SLC22 transporter-metabolite network and similar subgroup networks, which suggest how multiple SLC22 transporters with mono-, oligo-, and multi-specific substrate specificity interact to regulate metabolites. Subgroup associations include: OATS1 with signaling molecules, uremic toxins, and odorants, OATS2 with cyclic nucleotides, OATS3 with uric acid, OATS4 with conjugated sex hormones, particularly etiocholanolone glucuronide, OCT with neurotransmitters, and OCTN/OCTN-related with ergothioneine and carnitine derivatives. Our data suggest that the SLC22 family can work among itself, as well as with other ADME genes, to optimize levels of numerous metabolites and signaling molecules, involved in organ crosstalk and inter-organismal communication, as proposed by the remote sensing and signaling theory.