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Research ArticleArticle

Defining Substrate and Blocker Activity of Alanine-Serine-Cysteine Transporter 2 (ASCT2) Ligands with Novel Serine Analogs

Thomas Albers, William Marsiglia, Taniya Thomas, Armanda Gameiro and Christof Grewer
Molecular Pharmacology March 2012, 81 (3) 356-365; DOI: https://doi.org/10.1124/mol.111.075648
Thomas Albers
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William Marsiglia
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Taniya Thomas
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Armanda Gameiro
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Christof Grewer
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Abstract

The neutral amino acid transporter alanine-serine-cysteine transporter 2 (ASCT2) belongs to the solute carrier 1 (SLC1) family of solute transporters and transports small, neutral amino acids across the membrane, including the physiologically important and ubiquitous amino acid glutamine. Our understanding of the involvement of ASCT2 in the physiological processes involving glutamine is hampered by a lack of understanding of its pharmacology and the absence of high-affinity inhibitors. In this study, we combined an in silico docking approach with experimental investigation of binding parameters to develop new ASCT2 inhibitors and substrates, a series of serine esters, and to determine structural parameters that govern their functional effects. The series of compounds was synthesized using standard methods and exhibited a range of properties, from inhibitors to partial substrates and full substrates. Our results suggest that amino acid derivatives with small side-chain volume and low side-chain hydrophobicity interact strongly with the closed-loop form of the binding site, in which re-entrant loop 2, the presumed extracellular gate for the substrate binding site, is closed off. However, these derivatives bind weakly to the open-loop form (external gate open to the extracellular side), acting as transported substrates. In contrast, inhibitors bind preferentially to the open-loop form. An aromatic residue in the side chain is required for high-affinity interaction. One of the compounds, the l-serine ester serine biphenyl-4-carboxylate reversibly inhibits ASCT2 function with an apparent affinity of 30 μM.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant 2R01-NS049335-06A1] (to C.G.); and the Binational Science Foundation [Grant 2007051] (to C.G.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.111.075648.

  • ABBREVIATIONS:

    ASCT
    alanine-serine-cysteine transporter
    EAAT
    excitatory amino acid transporter
    HEK
    human embryonic kidney
    DMSO
    dimethyl sulfoxide
    NaMes
    sodium methanesulfonate
    GltPh
    glutamate transporter homolog from Pyrococcus horikoshii
    PDB
    Protein Data Bank
    RL
    re-entrant loop
    TBOA
    dl-threo-β-benzyloxyaspartic acid
    LAT
    system l-amino acid transporter.

  • Received September 8, 2011.
  • Accepted November 23, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Research ArticleArticle

Structure and Activity of ASCT2 Ligands

Thomas Albers, William Marsiglia, Taniya Thomas, Armanda Gameiro and Christof Grewer
Molecular Pharmacology March 1, 2012, 81 (3) 356-365; DOI: https://doi.org/10.1124/mol.111.075648

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Research ArticleArticle

Structure and Activity of ASCT2 Ligands

Thomas Albers, William Marsiglia, Taniya Thomas, Armanda Gameiro and Christof Grewer
Molecular Pharmacology March 1, 2012, 81 (3) 356-365; DOI: https://doi.org/10.1124/mol.111.075648
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