Solute Carrier (SLC) Transporters: An Overview

ALAN TALEVI; CAROLINA L. BELLERA

The ADME Encyclopedia. A Comprehensive Guide on Biopharmacy and Pharmacokinetics

Springer Nature

Lugar: Basignstoke; Año: 2022;

The solute carrier (SLC) superfamily is one of the two main superfamilies of transporters, along with the ATP-binding cassette (ABC) superfamily. However, whereas ABC transporters function as efflux transporters in eukaryotes (primary active transport upon the hydrolysis of ATP), SLC transporters are mainly involved in the uptake of small molecules (including nutrients and xenobiotics) into cells. To a lesser extent, some SLCs function as efflux or bidirectional transporters, and many of the superfamily members remain orphan, as discussed later. Generally speaking, SLC transporters facilitate the permeation of compounds that display unfavorable physicochemical properties for their diffusion across lipoidal membranesThe SLC transporters superfamily comprises more than 400 membrane-bound proteins that facilitate the transport of a wide range of substrates -including endogenous molecules, nutrients, and xenobiotics (among them, drugs)- across biological membranes. The notion of ?superfamily? to refer to all solute carriers could be misleading here, since it generally implies a common ancestor and detectably sequence and structure similarities [1]. Phylogenetic analysis of human SLC transporters revealed that many SLCs can be clustered in groups that are likely to have common ancestor [2, 3]. However, many of the SLC families lack any significant sequence similarity to other SLC families, meaning that they cannot be aligned in pairwise alignments [3]. About 30% of them are still orphans, uncharacterized with regards to substrates and transport mode [4]. Several marketed drugs target members of this group (prominently, neurotransmitter transporters, such as dopamine or serotonin transporters) and genetic studies have established associations between some recently characterized SLC transporters and rare and common diseases, suggesting new therapeutic opportunities [5]. Furthermore, many SLCs mediate drug absorption and/or disposition. They have been regarded, though, as the most neglected group of genes in the human genome [6], suggesting that they are a much-understudied subject. The Gene Nomenclature Committee of the Human Genome Organization classifies SLC transporters into more than 60 families, based on their sequences, structural features and biological functions [7, 8] (their classification is, however, highly dynamic as knowledge increases). SLC transporters function as facilitative transporters (allowing solutes to flow downhill with their electrochemical gradients) or as secondary active transporters (allowing their substrates to flow uphill against their electrochemical gradient by coupling their transport to the movement of a second solute -antiport or symport, depending on the case-) [9, 10]. A few members exhibit channel like properties [10]. A classical definition of SLCs described them as ATP-independent transporters [2, 11]. SLCs from the same family do not always share substrate specificity, ion stoichiometry, or energy coupling mechanism [9].