Na+ Interactions with the Neutral Amino Acid Transporter ASCT1

Scopelliti, Amanda J.; Heinzelmann, Germano; Kuyucak, Serdar; Ryan, Renae M.; Vandenberg, Robert J.

doi:10.1074/jbc.m114.565242

Cited by 24 publications

(25 citation statements)

References 41 publications

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“…Although GSH levels in Slc7a11 –/– mice are lower than in wild‐type mice (http://onlinelibrary.wiley.com/doi/10.1002/hep.29117/suppinfo), the fact that measurable GSH levels remain and the presence of normal lipid peroxidation in Slc7a11 –/– mice (http://onlinelibrary.wiley.com/doi/10.1002/hep.29117/suppinfo) suggest that other sources of cysteine might compensate—at least partially—for the loss of Slc7a11. These sources might include alanine, serine, and cysteine transporters . Lastly, Slc7a11 –/– mice have increased expression of the catalase, Gpx4 , and superoxide dismutase 1 genes, which encode GSH‐dependent and GSH‐independent lipid peroxidation scavenging proteins, suggesting that redundant proteins may help maintain redox balance in the absence of Slc7a11.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of ferroptosis in murine models of hemochromatosis

et al. 2017

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Ferroptosis is a recently identified iron‐dependent form of nonapoptotic cell death implicated in brain, kidney, and heart pathology. However, the biological roles of iron and iron metabolism in ferroptosis remain poorly understood. Here, we studied the functional role of iron and iron metabolism in the pathogenesis of ferroptosis. We found that ferric citrate potently induces ferroptosis in murine primary hepatocytes and bone marrow–derived macrophages. Next, we screened for ferroptosis in mice fed a high‐iron diet and in mouse models of hereditary hemochromatosis with iron overload. We found that ferroptosis occurred in mice fed a high‐iron diet and in two knockout mouse lines that develop severe iron overload (Hjv–/– and Smad4Alb/Alb mice) but not in a third line that develops only mild iron overload (Hfe –/– mice). Moreover, we found that iron overload–induced liver damage was rescued by the ferroptosis inhibitor ferrostatin‐1. To identify the genes involved in iron‐induced ferroptosis, we performed microarray analyses of iron‐treated bone marrow–derived macrophages. Interestingly, solute carrier family 7, member 11 (Slc7a11), a known ferroptosis‐related gene, was significantly up‐regulated in iron‐treated cells compared with untreated cells. However, genetically deleting Slc7a11 expression was not sufficient to induce ferroptosis in mice. Next, we studied iron‐treated hepatocytes and bone marrow–derived macrophages isolated from Slc7a11–/– mice fed a high‐iron diet. Conclusion: We found that iron treatment induced ferroptosis in Slc7a11–/– cells, indicating that deleting Slc7a11 facilitates the onset of ferroptosis specifically under high‐iron conditions; these results provide compelling evidence that iron plays a key role in triggering Slc7a11‐mediated ferroptosis and suggest that ferroptosis may be a promising target for treating hemochromatosis‐related tissue damage. (Hepatology 2017;66:449–465).

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Section: Discussionmentioning

confidence: 99%

“…These sources might include alanine, serine, and cysteine transporters. (42) Lastly, Slc7a11 -/mice have increased expression of the catalase, Gpx4, and superoxide dismutase 1 genes, which encode GSHdependent and GSH-independent lipid peroxidation scavenging proteins, suggesting that redundant FIG. 7.…”

Section: Discussionmentioning

confidence: 99%

Characterization of ferroptosis in murine models of hemochromatosis

et al. 2017

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“…The design of the small library of glutamine analogs (Fig 2a) was based on the substrate-specificity of the human glutamine transporter (SLC1A family), that is, a neutral amino acid side chain with hydrogen bonding capabilities [28, 29] . Because the binding mechanism and the exact binding pocket structure of SLC1A is unknown, it is difficult to interpret the differing performances for each analog.…”

Section: Discussionmentioning

confidence: 99%

Supramolecular Probes for Assessing Glutamine Uptake Enable Semi-Quantitative Metabolic Models in Single Cells

Xue

Wei

et al. 2016

J. Am. Chem. Soc.

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We describe a supramolecular surface competition assay for quantifying glutamine uptake from single cells. Cy3-labeled cyclodextrins were immobilized on a glass surface as a supramolecular host/FRET donor, and adamantane-BHQ2 conjugates were employed as the guest/quencher. An adamantane-labeled glutamine analog was selected through screening a library of compounds and validated by cell uptake experiments. When integrated onto a single cell barcode chip (SCBC) with a multiplex panel of 15 other metabolites, associated metabolic enzymes, and phosphoproteins, the resultant data provided input for a steady state model that describes energy potential in single cells, and correlates that potential with receptor tyrosine kinase signaling. We utilize this integrated assay to interrogate a dose-dependent response of model brain cancer cells to EGFR inhibition. We find that low dose (1 μM erlotinib) drugging actually increases cellular energy potential even as glucose uptake and phosphoprotein signaling is repressed. We also identify new interactions between phosphoprotein signaling and cellular energy processes that may help explain the facile resistance exhibited by certain cancer patients to EGFR inhibitors.

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“…For example, the aspartate transporter Glt Ph , from the Achaean organism Pyrococcus horikoshii , 25 shares sequence identity of 24%-35% with the human SLC1 family of glutamate or neutral amino acid transporters. Models of human SLC1 members including the glutamate transporter EAAT3 (SLC1A1) 26 and the neutral amino acid transporters ASCT1 (SLC1A4) 27, 28 and ASCT2 (SLC1A5) 29 based on Glt Ph structures have revealed mechanisms of ion coordination 26, 27 and differential amino acid selectivity 28 in this family; ASCT2 models were also subjected to successful ligand discovery 30 and optimization 29 campaigns.…”

Section: Slc Structurementioning

confidence: 99%

“…Multiple human SLC transporter families mediate the transport of amino acids, including members of the SLC1, SLC6, SLC7, SLC17, SLC32, SLC38, and SLC43 families. 86, 87 The amino acid transporters have been previously grouped into ‘systems’ based on the amino acid type that they transport; 27, 28 however, this classification scheme may include evolutionarily unrelated members which can be confusing in the fold assignment step during modeling. For example, System L amino acid transporters (LAT) transport Leucine and other large neutral amino acids, and include members of the SLC7 (LAT-1 and LAT-2) and SLC43 families (LAT-3 and LAT-4), which are predicted to have LeuT-like and MFS folds, respectively.…”

Section: Neutral Amino Acid Exchangers: Asct2 and Lat-1mentioning

confidence: 99%

SLC transporters: structure, function, and drug discovery

2016

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The human Solute Carrier (SLC) transporters are important targets for drug development. Structure-based drug discovery for SLC transporters requires the description of their structure, dynamics, and mechanism of interaction with small molecule ligands and ions. The recent determination of atomic structures of human SLC transporters and their homologs, combined with improved computational power and prediction methods have led to an increased applicability of structure-based drug design methods for human SLC members. In this review, we provide an overview of the SLC transporters’ structures and transport mechanisms. We then describe computational techniques, such as homology modeling and virtual screening that are emerging as key tools to discover chemical probes for human SLC members. We illustrate the utility of these methods by presenting case studies in which rational integration of computation and experiment was used to characterize SLC members that transport key nutrients and metabolites, including the amino acid transporters LAT-1 and ASCT2, the SLC13 family of citric acid cycle intermediate transporters, and the glucose transporter GLUT1. We conclude with a brief discussion about future directions in structure-based drug discovery for the human SLC superfamily, one of the most structurally and functionally diverse protein families in human.

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Na+ Interactions with the Neutral Amino Acid Transporter ASCT1

Abstract: Background: Na ϩ interactions with the alanine serine cysteine transporters (ASCT) have not been well established.

Cited by 24 publications

References 41 publications

Characterization of ferroptosis in murine models of hemochromatosis

Characterization of ferroptosis in murine models of hemochromatosis

Supramolecular Probes for Assessing Glutamine Uptake Enable Semi-Quantitative Metabolic Models in Single Cells

SLC transporters: structure, function, and drug discovery

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