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

International Journal of Molecular Sciences
Darcy C. EngelhartSanjay K Nigam

Abstract

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/OCT...Continue Reading

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Citations

Mar 19, 2020·International Journal of Molecular Sciences·Darcy C EngelhartSanjay K Nigam
Mar 3, 2020·Clinical Pharmacology and Therapeutics·Sanjay K NigamJeremiah D Momper
Jul 13, 2020·Journal of Neurochemistry·Barbara JuraszekKatarzyna A Nałęcz
Oct 31, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sook Wah YeeKathleen M Giacomini
Nov 8, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Shin-Ichi AdachiKazumi Yagasaki
Dec 5, 2020·International Journal of Molecular Sciences·Mohammed Ali SeloJohanna J Salomon
Jan 17, 2021·International Journal of Molecular Sciences·Giuliano Ciarimboli
Mar 23, 2021·Expert Opinion on Drug Metabolism & Toxicology·Adriana M TorresSanjay K Nigam
Mar 25, 2021·The Journal of Biological Chemistry·Jeffry C GranadosSanjay K Nigam

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Methods Mentioned

BETA
RNA-seq

Software Mentioned

SSearch36
Clustal
Metabolomics
Cytoscape
BLASTp
ICM
MSA
Omega
UCSC Genome browser
MAFFT

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