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Amino Acid Transporters and Exchangers from the SLC1A Family: Structure, Mechanism and Roles in Physiology and Cancer

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Abstract

The Solute Carrier 1A (SLC1A) family includes two major mammalian transport systems—the alanine serine cysteine transporters (ASCT1-2) and the human glutamate transporters otherwise known as the excitatory amino acid transporters (EAAT1-5). The EAATs play a critical role in maintaining low synaptic concentrations of the major excitatory neurotransmitter glutamate, and hence they have been widely researched over a number of years. More recently, the neutral amino acid exchanger, ASCT2 has garnered attention for its important role in cancer biology and potential as a molecular target for cancer therapy. The nature of this role is still being explored, and several classes of ASCT2 inhibitors have been developed. However none have reached sufficient potency or selectivity for clinical use. Despite their distinct functions in biology, the members of the SLC1A family display structural and functional similarity. Since 2004, available structures of the archaeal homologues GltPh and GltTk have elucidated mechanisms of transport and inhibition common to the family. The recent determination of EAAT1 and ASCT2 structures may be of assistance in future efforts to design efficacious ASCT2 inhibitors. This review will focus on ASCT2, the present state of knowledge on its roles in tumour biology, and how structural biology is being used to progress the development of inhibitors.

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Acknowledgements

This work was supported by the Australian National Health and Medical Research Council Project Grant APP1164494 and Research Training Program Scholarships to NF and IC.

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Authors and Affiliations

  1. School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

    Natasha Freidman, Ichia Chen, Qianyi Wu, Chelsea Briot, Josep Font, Robert Vandenberg & Renae Ryan

  2. Translational Cancer Metabolism Laboratory, School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW, Australia

    Jeff Holst

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  1. Natasha Freidman
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  2. Ichia Chen
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Freidman, N., Chen, I., Wu, Q. et al. Amino Acid Transporters and Exchangers from the SLC1A Family: Structure, Mechanism and Roles in Physiology and Cancer. Neurochem Res 45, 1268–1286 (2020). https://doi.org/10.1007/s11064-019-02934-x

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