School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
Translational Cancer Metabolism Laboratory, School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW, Australia.
Neurochem Res. 2020 Jun;45(6):1268-1286. doi: 10.1007/s11064-019-02934-x. Epub 2020 Jan 24.
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 Glt and Glt 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.
溶质载体 1A（SLC1A）家族包括两种主要的哺乳动物转运系统——丙氨酸-丝氨酸-半胱氨酸转运体（ASCT1-2）和人类谷氨酸转运体，也称为兴奋性氨基酸转运体（EAAT1-5）。EAATs 在维持突触中谷氨酸这一主要兴奋性神经递质的低浓度方面发挥着关键作用，因此多年来一直受到广泛研究。最近，中性氨基酸交换器 ASCT2 因其在癌症生物学中的重要作用及其作为癌症治疗分子靶点的潜力而受到关注。其作用机制仍在探索中，已经开发出了几类 ASCT2 抑制剂。然而，它们的效力和选择性都不足以用于临床。尽管在生物学上具有不同的功能，但 SLC1A 家族的成员显示出结构和功能上的相似性。自 2004 年以来，古细菌同源物 Glt 和 Glt 的可用结构阐明了家族中共同的转运和抑制机制。最近 EAAT1 和 ASCT2 结构的确定可能有助于未来设计有效的 ASCT2 抑制剂。这篇综述将重点介绍 ASCT2，目前其在肿瘤生物学中的作用的知识状态，以及结构生物学如何用于推进抑制剂的开发。
