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

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.

Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target

“…Many transporters are potentially involved in Gln transport. 16,54 However, the contribution of ATB 0,1 (SLC6A14), SN1 (SLC38A3), and SN2 (SLC38A5), known to interact with Gln in other cell models, 16,54 did not appear important (supplemental Figure 5). Three other transporters, LAT1, SNAT1, and ASCT2, showed increased expression during MM progression, suggesting that the affirmation of the neoplastic clone may require a growing supply of the amino acid through their operation.…”

“…14, 15 Moreover, a variety of carriers, operate Gln influx, such as the Na 1 -dependent transporters SNAT1-2 and ASCT2, and the Na 1 -independent transporter LAT1. 16 Gln is a substrate of several enzymes, playing an important role in various processes, such as the synthesis of nucleotides, other amino acids, or glucosamine. 17,18 Moreover, through the activity of glutaminases (GLS1 and GLS2), which hydrolyze the amide group obtaining NH 4 1 and Glu, Gln may fuel the intracellular pool of the Krebs cycle intermediate and anaplerotic substrate 2-oxoglutarate (2-OG, a-ketoglutarate).…”

Comparasion between effects of nutritional immunomodulation with glutamine: An integral part of the treatment of critically ill: Trend and perspective (immunonitrition in critically ill patients)

“…Sintetiše se iz glutamata (amida glutaminske kiseline) dejstvom glutamin sintetaze, pre svega u skeletnim mišićima, kao i u plućima, jetri i mozgu. Ova aminokiselina čini do 50% aminokiselina u plazmi i do 60% slobodnih aminokiselina u telu i predstavlja značajan izvor energije pri deobi potentnih ćelija i nekih imunih ćelija u sintezi nukleotida 5,8 . Glutamin u centralnom nervnom sistemu predstavlja supstrat za sintezu neurotransmitera (gama-aminobuterne kiseline -GABA) i nedavno je potvrđena aktivna uloga astrocita u resorpciji viška i recikliranju glutamina iz sinaptičkog prostora.…”

“…Biosinteza glutamina -Gln iz glutamata -Glu (mozak i druga tkiva) iz glutamina (u jetri) i ciklusa ureje (u jetri). Preuzeto i adaptirano iz: 8 dija je praćena dužina mehaničke ventilacije, u 11 dužina hospitalnog lečenja, a u 7 mortalitet u JIL. Uprkos ovim razlikama, autori su zaključili da rezultati metaanalize snažno sugerišu upotrebu glutamin dipeptida, kao suplementa propisanoj parenteralnoj prehrani, koja će obezbediti dovoljno energije i proteina.…”

Nutrition and its Important Role in Maintaining an Adequate Immunity during Chemotherapy

“…Tumours can modify the regulation of the transporters in some amino-acids because of high demand, whilst at the same time improving levels of chemo-resistance [22][23][24][25]27,28]. This is particularly evident in the metabolic path of glutamine, and is related to increased proliferation of tumours and a consequent deterioration in the clinical condition of patients [26].…”