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

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          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 2PO 4 -, SO 4 2-, C 2O 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.

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          The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond.

          The monocarboxylate cotransporter (MCT) family now comprises 14 members, of which only the first four (MCT1-MCT4) have been demonstrated experimentally to catalyse the proton-linked transport of metabolically important monocarboxylates such as lactate, pyruvate and ketone bodies. SLC16A10 (T-type amino-acid transporter-1, TAT1) is an aromatic amino acid transporter whilst the other members await characterization. MCTs have 12 transmembrane domains (TMDs) with intracellular N- and C-termini and a large intracellular loop between TMDs 6 and 7. MCT1 and MCT4 require a monotopic ancillary protein, CD147, for expression of functional protein at the plasma membrane. Lactic acid transport across the plasma membrane is fundamental for the metabolism of and pH regulation of all cells, removing lactic acid produced by glycolysis and allowing uptake by those cells utilizing it for gluconeogenesis (liver and kidney) or as a respiratory fuel (heart and red muscle). The properties of the different MCT isoforms and their tissue distribution and regulation reflect these roles.
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            The mitochondrial transporter family (SLC25): physiological and pathological implications.

            The mitochondrial carriers (MCs) shuttle a variety of metabolites across the inner mitochondrial membrane (i.m.m.). In man they are encoded by the SLC25 genes. Some MCs have isoforms encoded by different SLC25 genes, whereas the phosphate carrier has two variants arising from an alternative splicing of SLC25A3. Six MCs have been sequenced after purification, and many more have been identified from their transport and kinetic properties following heterologous over-expression and reconstitution into liposomes. All MCs of known function belong to the same protein family, since their polypeptide chains consist of three tandemly related sequences of about 100 amino acids, and the repeats of the different carriers are homologous. They probably function as homodimers, each monomer being folded in the membrane into six transmembrane segments. The functional information obtained in studies with mitochondria and/or the reconstituted system has helped to gain an insight into the physiological role of the MCs in cell metabolism, as have tissue distribution, the use of knock-out mice (and/or yeast) and over-expression in human cell lines (or yeast) of individual carriers and isoforms. At the same time, the cloning and functional identification of many SLC25 genes has made it possible (i) to identify the genes (and their defects) responsible for some diseases, e.g. Stanley syndrome and Amish microcephaly, and (ii) where the genes were already known, to characterize the function of the gene products and hence understand the molecular basis and the symptoms of the diseases, e.g. hyperornithinaemia, hyperammonaemia and homocitrullinuria (HHH) syndrome and type II citrullinemia. It is likely that further extension and functional characterization of the SLC25 gene family will elucidate other diseases caused by MC deficiency.
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              Active sugar transport in health and disease.

              Secondary active glucose transport occurs by at least four members of the SLC5 gene family. This review considers the structure and function of two premier members, SGLT1 and SGLT2, and their role in intestinal glucose absorption and renal glucose reabsorption. Genetics disorders of SGLTs include Glucose-Galactose Malabsorption, and Familial Renal Glucosuria. SGLT1 plays a central role in Oral Rehydration Therapy used so effectively to treat secretory diarrhoea such as cholera. Increasing attention is being focused on SGLTs as drug targets for the therapy of diabetes.
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                Author and article information

                Journal
                Hum Genomics
                Hum. Genomics
                Human Genomics
                BioMed Central
                1473-9542
                1479-7364
                2009
                1 January 2009
                : 3
                : 2
                : 195-205
                Affiliations
                [1 ]Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA
                [2 ]Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO 80262, USA
                [3 ]Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA
                Article
                1479-7364-3-2-195
                10.1186/1479-7364-3-2-195
                2752037
                19164095
                892fd4c4-d82a-4aae-81be-ae838b43f4f0
                Copyright ©2009 Henry Stewart Publications
                History
                : 2 October 2008
                : 2 October 2008
                Categories
                Genome Update

                Genetics
                solute carrier gene superfamily,uncoupling proteins,evolutionary genomics,mitochondrial proton carriers,transporters,human genome

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