Amino Acid Transporters and Exchangers from the SLC1A Family: Structure, Mechanism and Roles in Physiology and Cancer
Amino Acid Transporters and Exchangers from the SLC1A Family: Structure, Mechanism and Roles in Physiology and Cancer
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DOI：
10.1007/s11064-019-02934-x
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发表时间：
2020-01-24
影响因子：
4.4
通讯作者：
Ryan, Renae
中科院分区：
文献类型：
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作者：
Freidman, Natasha;Chen, Ichia;Ryan, Renae
溶质载体 1A (SLC1A) 家族包括两个主要的哺乳动物转运系统 - 丙氨酸丝氨酸半胱氨酸转运蛋白 (ASCT1-2) 和人谷氨酸转运蛋白（也称为兴奋性氨基酸转运蛋白 (EAAT1-5)）。 EAAT 在维持主要兴奋性神经递质谷氨酸的低突触浓度方面发挥着关键作用，因此多年来对它们进行了广泛的研究。最近，中性氨基酸交换剂 ASCT2 因其在癌症生物学中的重要作用以及作为癌症治疗分子靶点的潜力而受到关注。这种作用的本质仍在探索中，并且已经开发了几类 ASCT2 抑制剂。然而，没有一个药物达到足够的效力或选择性供临床使用。尽管 SLC1A 家族的成员在生物学中具有不同的功能，但它们表现出结构和功能的相似性。自 2004 年以来，古细菌同源物 Glt(Ph) 和 Glt(Tk) 的可用结构阐明了该家族常见的转运和抑制机制。最近对 EAAT1 和 ASCT2 结构的确定可能有助于未来设计有效的 ASCT2 抑制剂。本综述将重点关注 ASCT2、其在肿瘤生物学中的作用的目前知识状况，以及如何利用结构生物学来推进抑制剂的开发。
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(Ph) and Glt(Tk) 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.