Glutamine transporters in mammalian cells and their functions in physiology and cancer

Abstract

The SLC (solute carrier)-type transporters (∼400 in number) in mammalian cells consist of 52 distinct gene families, grouped solely based on the amino acid sequence (primary structure) of the transporter proteins and not on their transport function. Among them are the transporters for amino acids. Fourteen of them, capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. Some of the glutamine transporters are obligatory exchangers whereas some function as active transporters in one direction. While most glutamine transporters mediate the influx of the amino acid into cells, some actually mediate the efflux of the amino acid out of the cells. Glutamine transporters play important roles in a variety of tissues, including the liver, brain, kidney, and placenta, as clearly evident from the biological and biochemical phenotypes resulting from the deletion of specific glutamine transporters in mice. Owing to the obligatory role of glutamine in growth and proliferation of tumor cells, there is increasing attention on glutamine transporters in cancer biology as potential drug targets for cancer treatment. Selective blockers of certain glutamine transporters might be effective in preventing the entry of glutamine and other important amino acids into tumor cells, thus essentially starving these cells to death. This could represent the beginning of a new era in the discovery of novel anticancer drugs with a previously unexplored mode of action.

Relationship between [ 14 C]MeAIB uptake and amino acid transporter family gene expression levels or proliferative activity in a pilot study in human carcinoma cells: Comparison with [ 3 H]methionine uptake

“…In contrast, system A, which also transports amino acids into cells, has no counter transport activity. Amino acid transporter function can therefore be evaluated directly using MeAIB (system A substrate), allowing differentiation from system L [42,43]. The correlation between the uptake of radiotracers and the gene expression of amino acid transporter in tumor cells has been evaluated in a number of recent nuclear medicine studies.…”

Non‐alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion

“…Gene expression was investigated within a biological pathway composed of genes responsible for the hepatic nitrogen conversion chosen a priori based on the literature (Figure ). The following genes were included: the five urea cycle enzymes (carbamoyl phosphate synthetase 1 [CPS1; the flux‐generating enzyme of the cycle], ornithine transcarbamylase [OTC], argininosuccinate synthetase 1 [ASS1; the in vitro rate‐limiting cycle enzyme], argininosuccinate lyase [ASL], and arginase 1 [ARG1]); N‐acetylglutamate synthase (NAGS) (N‐acetylglutamate being the main allosteric activator of CPS); glutamate dehydrogenase 1 (GLUD1) and glutaminase 2 (GLS2) (both responsible for the delivery of ammonia nitrogen into the urea cycle); solute carrier family 25 member 22 (SLC25A22; mitochondrial transporter making glutamate nitrogen available for GLUD1); the transcellular amino acid transporters of solute carrier family 38 members 2 and 3 (SLC38A2 and SLC38A3; responsible for the across‐hepatocyte membrane transport of the most important ureagenic amino acid (alanine) and the most abundant amino acid (glutamine) with potential of delivering two nitrogens to CPS1, respectively); the glucagon receptor (target for the main hormonal regulator of the above, viz. amino acid metabolism and nitrogen conversion); and lastly, glutamine synthetase (GS; responsible for scavenging any ammonia nitrogen escaping conversion in the urea cycle) (Figure ).…”

Inhibition of glucose metabolism prevents glycosylation of the glutamine transporter ASCT2 and promotes compensatory LAT1 upregulation in leukemia cells

“…Predicted glycosylation sites (Asn = Asparagine), nature of substrates, flux direction and expression in HL-60 leukemia cells are presented [13, 14, 27, 28]. …”

“…Numerous amino acid transporters have been reported to transport glutamine. Glutamine transporters belong to different protein families nowadays classified according to the SLC nomenclature, the most frequent belonging to the SLC1, 6, 7, and 38 families [13, 14]. Most transporters share specificity for other neutral or cationic amino acids.…”