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Review
. 2014 Aug 11:2:61.
doi: 10.3389/fchem.2014.00061. eCollection 2014.

Membrane transporters for the special amino acid glutamine: structure/function relationships and relevance to human health

Lorena Pochini  1 , Mariafrancesca Scalise  1 , Michele Galluccio  1 , Cesare Indiveri  1
Affiliations
Review

Membrane transporters for the special amino acid glutamine: structure/function relationships and relevance to human health

Lorena Pochini et al. Front Chem. .

Abstract

Glutamine together with glucose is essential for body's homeostasis. It is the most abundant amino acid and is involved in many biosynthetic, regulatory and energy production processes. Several membrane transporters which differ in transport modes, ensure glutamine homeostasis by coordinating its absorption, reabsorption and delivery to tissues. These transporters belong to different protein families, are redundant and ubiquitous. Their classification, originally based on functional properties, has recently been associated with the SLC nomenclature. Function of glutamine transporters is studied in cells over-expressing the transporters or, more recently in proteoliposomes harboring the proteins extracted from animal tissues or over-expressed in microorganisms. The role of the glutamine transporters is linked to their transport modes and coupling with Na(+) and H(+). Most transporters share specificity for other neutral or cationic amino acids. Na(+)-dependent co-transporters efficiently accumulate glutamine while antiporters regulate the pools of glutamine and other amino acids. The most acknowledged glutamine transporters belong to the SLC1, 6, 7, and 38 families. The members involved in the homeostasis are the co-transporters B0AT1 and the SNAT members 1, 2, 3, 5, and 7; the antiporters ASCT2, LAT1 and 2. The last two are associated to the ancillary CD98 protein. Some information on regulation of the glutamine transporters exist, which, however, need to be deepened. No information at all is available on structures, besides some homology models obtained using similar bacterial transporters as templates. Some models of rat and human glutamine transporters highlight very similar structures between the orthologs. Moreover the presence of glycosylation and/or phosphorylation sites located at the extracellular or intracellular faces has been predicted. ASCT2 and LAT1 are over-expressed in several cancers, thus representing potential targets for pharmacological intervention.

Keywords: amino acids; cancer; glutamine; homology models; membrane; nutrients; transporters.

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Figures

Figure 1
Figure 1
The glutamine roles in cell pathways. Schematic representation of the cell processes involving glutamine. Proteins, protein synthesis; Aminosugar, aminosugar synthesis; Nucleotides, purine and pyrimidine synthesis; pH homeostasis, mainteinance of acid-base balance; Gluconeogenesis, precursor synthesis; Energy, providing carbon atoms for TCA; Urea, release of NH3 in liver for urea synthesis; Gln/Glu cycle and GABA, neurotransmission regulation; Glutathione, GSH synthesis and redox balance regulation; Insulin secretion, glucose concentration regulation; Gene expression, gene expression regulation.
Figure 2
Figure 2
The glutamine transporter network. Interplay among epithelial polarized cells (apical membrane is depicted as brush-border; basolateral membrane is in contact with blood) and other cells. Glutamine transporters are indicated in the figure with different colors. Arrows indicate glutamine fluxes from (red) or toward (blue) blood or from lumen to epithelial cells (blue); black arrows indicate sodium fluxes; gray arrows indicate other amino acid and proton fluxes. Simplified cytosolic and mitochondrial pathways are depicted: synthesis of glutamine (in brain and other tissues), TCA, glutamine entering in TCA (intestine and kidney tubule), synthesis of glutamate from TCA intermediate (brain and other tissue) or from glutamine (liver), Urea cycle (liver).
Figure 3
Figure 3
Work flow of heterologous over-expression of membrane transporters. Schematic representation of screening of different combination Plasmid/Cell strains (white spots): if the attempts with wild type gene is not successful, codon bias strategy should be applied. Thus, selection of the best plasmid/cell strain combination is performed (red spot) with optimization of conditions for high yield expression. When this result is achieved, purification procedures are applied to perform both structural and functional studies. These strategies allow large scale screening of potential drugs or xenobiotics.
Figure 4
Figure 4
Homology models of ASCT2 human and rat transporters. The homology structural models of rat and human ASCT2 were obtained by the Modeler 9.13 software (Sali and Blundell, 1993) using as template the structure (PDB 1XFH) of the glutamate transporter homolog from P. horikoshii (Glpth). To run the software, sequences were aligned by ClustalX2 software with .pir output format. RMSD for model comparison was calculated by Spdbv 4.1.0. Superposition of the rat and human structural models was performed by VMD 1.9.1. (A) The human protein (transparent) contains a variable loop in bleu, the rat one (purple) contains a variable loop in red. The Cys residues of the CXXC metal binding motif present only in the rat protein are highlighted in yellow. (B) The human protein is in gray; the rat one is in bleu. Putative glycosylation sites of both proteins are highlighted in red. Cysteine residues common to the two orthologous proteins are highlighted in light green. Additional Cys residues present only in rat protein are highlighted in yellow. N- and C- terminals of rat and human proteins are nearly coincident and highlighted by single N and C.
Figure 5
Figure 5
Homology models of B0AT1 human and rat transporters. The homology structural models of rat (gray) and human (blue) B0AT1 were constructed as described in Figure 4 using as template the structure of dopamine transporter from D. melanogaster (PDB 4M48). RMSD for model comparison was calculated by Spdbv 4.1.0. Superposition of the rat and human structural models was performed by VMD 1.9.1. Putative glycosylation sites are highlighted in red; cysteine residues of the metal binding motifs are highlighted in yellow; PKC phosphorylation site is highlighted in green. N- and C- terminals of rat and human proteins are nearly coincident and highlighted by single N and C.
Figure 6
Figure 6
Homology models of LAT2 human and rat transporters. The homology structural models of rat (Chaudhry et al.) and human (purple) LAT2 were constructed as described in Figure 4 using as template the structure of the arginine/agmantine antiporter AdiC from E. coli (PDB 3OB6). Superposition of the rat and human structural models was performed by VMD 1.9.1. C154 of the human protein involved in disulfide bridge with 4F2hc is highlighted in yellow; putative PKC and PKA phosphorylation sites are highlighted in green. N- and C- terminals of rat and human proteins are nearly coincident and highlighted by single N and C.
Figure 7
Figure 7
Homology models of SNAT7 human and rat transporters. The homology structural models of rat (purple) and human (Chaudhry et al.) SNAT7 were constructed as described in Figure 6. Superposition of the rat and human structural models was performed by VMD 1.9.1. Putative PKC and PKA phosphorylation sites are highlighted in green. N- and C- terminals of rat and human proteins are nearly coincident and highlighted by single N and C.
Figure 8
Figure 8
Network of transporters involved in cancer metabolic switch. In cell membrane (red), ASCT2 and LAT1: glutamine plasma membrane transporters; MCT: Monocarboxylate Transporter. In cytosol (upper part of the figure), Gln: glutamine, Glu: glutamate, αKG: α Ketoglutarate, ICIT: isocitrate, IDH1: Isocitrate dehydrognase 1 and simplification of reactions to fatty acid synthesis; (lower part of the figure) Mal: Malate, Lac: lactate and simplification of glycolysis with the end product pyruvate (Pyr). In the Inner Mitochondrial Membrane, putative glutamine transporter (?). In mitochondrial matrix, TCA (Tricarboxylic Acid Cycle) with enzymes, GLS: Glutaminase, GDH: Glutamate dehyfrogenase, ALT: Alanine Amino Transferase. AA: Amino Acid. Dotted arrows indicate metabolic pathways depressed in cancers.
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