Analysis and update of the human solute carrier (SLC) gene superfamily

Abstract

The solute-carrier gene (SLC) superfamily encodes membrane-bound transporters. The SLC superfamily comprises 55 gene families having at least 362 putatively functional protein-coding genes. The gene products include passive transporters, symporters and antiporters, located in all cellular and organelle membranes, except, perhaps, the nuclear membrane. Transport substrates include amino acids and oligopeptides, glucose and other sugars, inorganic cations and anions (H(+), HCO(3)(-), Cl(-), Na(+), K(+), Ca(2+), Mg(2+), PO(4)(3-), HPO(4)(2-), H(2)PO(4)(-), SO(4)(2-), C(2)O(4)(2-), OH(-), CO(3)(2-)), bile salts, carboxylate and other organic anions, acetyl coenzyme A, essential metals, biogenic amines, neurotransmitters, vitamins, fatty acids and lipids, nucleosides, ammonium, choline, thyroid hormone and urea. Contrary to gene nomenclature commonly assigned on the basis of evolutionary divergence (http://www.genenames.org/), the SLC gene superfamily has been named based largely on transporter function by proteins having multiple transmembrane domains. Whereas all the transporters exist for endogenous substrates, it is likely that drugs, non-essential metals and many other environmental toxicants are able to 'hitch-hike' on one or another of these transporters, thereby enabling these moieties to enter (or leave) the cell. Understanding and characterising the functions of these transporters is relevant to medicine, genetics, developmental biology, pharmacology and cancer chemotherapy.

Figure 1

Dendrogram of a representative member of each of the 55 human SLC gene families, developed using Clustal W software, to test for evolutionary readiness. To avoid clutter, we have selected only the first member of each family, although most families have two or more members. We also added two unrelated 'outlier' genes (SOD1 and CYP1A1) and two additional members of the SLC39 family (SLC39A2 and SLC39A3) as 'internal controls'. This nearest neighbour-joining (NNJ) method uses only global alignments of the entire protein sequences. In this case, although the NNJ method appears to gives various branches of different lengths, reflecting the presumed time since evolutionary divergence of the various branches of the gene tree, this tree is largely an artefact because the superfamily has mainly been pulled together by nomenclature experts who based this superfamily on function, rather than evolutionary divergence (see text).