Article

Bröer S, Palacín M. The role of amino acid transporters in inherited and acquired diseases

Research School of Biology, Australian National University, Canberra, ACT 0200, Australia.
Biochemical Journal (Impact Factor: 4.78). 06/2011; 436(2):193-211. DOI: 10.1042/BJ20101912
Source: PubMed

ABSTRACT Amino acids are essential building blocks of all mammalian cells. In addition to their role in protein synthesis, amino acids play an important role as energy fuels, precursors for a variety of metabolites and as signalling molecules. Disorders associated with the malfunction of amino acid transporters reflect the variety of roles that they fulfil in human physiology. Mutations of brain amino acid transporters affect neuronal excitability. Mutations of renal and intestinal amino acid transporters affect whole-body homoeostasis, resulting in malabsorption and renal problems. Amino acid transporters that are integral parts of metabolic pathways reduce the function of these pathways. Finally, amino acid uptake is essential for cell growth, thereby explaining their role in tumour progression. The present review summarizes the involvement of amino acid transporters in these roles as illustrated by diseases resulting from transporter malfunction.

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    • "Among the most interesting transporters in human physiology and pathology there is the Na + -dependent glutamine/neutral amino acid transporter ASCT2 (SLC1A5) previously known in humans as ATB0. This transport system has been identified in human cell systems even though the kinetic properties and substrate specificity are not fully understood [2] [3] [12] while the rodent isoform, besides being studied in cell systems [13] [14] [15] [16], has been also functionally and kinetically characterized in proteoliposomes [9] [17] [18]. Basic functional and kinetic parameters of the kidney rat protein determined in both experimental models correlated well. "
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    ABSTRACT: The human glutamine/neutral amino acid transporter ASCT2 (hASCT2) was over-expressed in P. pastoris and purified by Ni(2+)-chelating and gel filtration chromatography. The purified protein was reconstituted in liposomes by detergent removal with a batch-wise procedure. Time dependent [(3)H]glutamine/glutamine antiport was measured in proteoliposomes which was active only in the presence of external Na(+). Internal Na(+) slightly stimulated the antiport. Optimal activity was found at pH 7.0. A substantial inhibition of the transport was observed by Cys, Thr, Ser, Ala, Asn and Met (≥ 70%) and by mercurials and methanethiosulfonates (≥ 80%). Heterologous antiport of [(3)H]glutamine with other neutral amino acids was also studied. The transporter showed asymmetric specificity for amino acids: Ala, Cys, Val, Met were only inwardly transported, while Gln, Ser, Asn, and Thr were transported bi-directionally. From kinetic analysis of [(3)H]glutamine/glutamine antiport Km values of 0.097 and 1.8 mM were measured on the external and internal sides of proteoliposomes, respectively. The Km for Na(+) on the external side was 32 mM. The homology structural model of the hASCT2 protein was built using as template the GltPh of P. horikoshii. Cys395 was the only Cys residue externally exposed, thus being the potential target of SH reagents inhibition and, hence, potentially involved in the transport mechanism.
    Biochimica et Biophysica Acta 06/2013; 1828(9). DOI:10.1016/j.bbamem.2013.05.034 · 4.66 Impact Factor
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    • "In the cells of different organs, AAs may then serve as building blocks for the synthesis of structural and functional proteins, may be used for cellular metabolism or function as signalling molecules (Verrey et al. 2009; Wu, 2009). Therefore, AA transfer across plasma membranes via various cooperating AA transporters plays a crucial role for body AA homeostasis , and the defect of transporters leads to several diseases (Verrey et al. 2009; Broer & Palacin, 2011). The best characterized basolateral AA transporters of the small intestine and proximal kidney tubule (re)absorbing epithelia are the abundant Lat2–4F2hc (Slc7a8) and y + Lat1–4F2hc (Slc7a7) that function as obligatory exchangers (antiporters). "
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    ABSTRACT: The uniporter TAT1 (Slc16a10) mediates the facilitated diffusion of aromatic amino acids across basolateral membranes of kidney, small intestine and liver epithelial cells and across the plasma membrane of non-epithelial cells like skeletal myocytes. Its role for body amino acid homeostasis was now investigated using newly generated TAT1 (Slc16a10) defective mice (tat1-/-). These mice grow and reproduce normally, show no gross phenotype and no obvious neurological defect. Histological analysis did not reveal abnormalities and there is no compensatory change in any tested amino acid transporter mRNA. TAT1 null mice display however increased plasma, muscle and kidney aromatic amino acid concentration under both normal and high protein diet, although this concentration remains normal in liver. A major aromatic aminoaciduria and a smaller urinary loss of all substrates additionally transported by L-type amino acid antiporter Lat2-4F2hc (Slc7a8) were revealed under high protein diet. This suggests an epithelial transport defect as also shown by the accumulation of intravenously injected 123I-2-I-L-Phe in kidney and of 3H-L-Phe in ex vivo everted gut sac enterocytes. Taken together, these data indicate that the uniporter TAT1 is required to equilibrate the concentration of aromatic amino acids across specific membranes. For instance, it enables hepatocytes to function as sink that controls the extracellular aromatic amino acid concentration. Additionally, it facilitates the release of aromatic amino acids across the basolateral membrane of small intestine and proximal kidney tubule epithelial cells, thereby allowing the efflux of other neutral amino acids presumably via Lat2-4F2hc.
    The Journal of Physiology 10/2012; 590. DOI:10.1113/jphysiol.2012.239574 · 4.54 Impact Factor
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    ABSTRACT: Solute carriers (SLC) that transport amino acids are key players in health and diseases in humans. Their prokaryotic relatives are often involved in essential physiological processes in microorganisms, e.g. in homeostasis and acidic/osmotic stress response. High-resolution X-ray structures of the sequence-unrelated amino acid transporters unraveled a striking structural similarity between carriers, which were formerly assigned to different families. The highly conserved fold is characterized by two inverted structural repeats of five transmembrane helices each and indicates common mechanistic transport concepts if not an evolutionary link among a large number of amino acid transporters. Therefore, these transporters are classified now into the structural amino acid-polyamine-organocation superfamily (APCS). The APCS includes among others the mammalian SLC6 transporters and the heterodimeric SLC7/SLC3 transporters. However, it has to be noted that the APCS is not limited entirely to amino acid transporters but contains also transporters for, e.g. amino acid derivatives and sugars. For instance, the betaine-choline-carnitine transporter family of bacterial activity-regulated Na(+)- and H(+)-coupled symporters for glycine betaine and choline is also part of this second largest structural superfamily. The APCS fold provides different possibilities to transport the same amino acid. Arginine can be transported by an H(+)-coupled symport or by antiport mechanism in exchange against agmatine for example. The convergence of the mechanistic concept of transport under comparable physiological conditions allows speculating if structurally unexplored amino acid transporters, e.g. the members of the SLC36 and SLC38 family, belong to the APCS, too. In the kidney, which is an organ that depends critically on the regulated amino acid transport, these different SLC transporters have to work together to account for proper function. Here, we will summarize the basic concepts of Na(+)- and H(+)-coupled amino acid symport and amino acid-product antiport in the light of the respective physiological requirements.
    Current Topics in Membranes 01/2012; 70:1-28. DOI:10.1016/B978-0-12-394316-3.00001-6 · 1.77 Impact Factor
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