Research School of Chemistry, Australian National University, Canberra, ACT, Australia.
Department of Biochemistry, Key University Laboratory of Metabolism and Health of Guangdong, School of Medicine, Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, Guangdong, China.
Nat Commun. 2024 Aug 22;15(1):7224. doi: 10.1038/s41467-024-51748-1.
The epithelial neutral amino acid transporter BAT1 (SLC6A19) is the major transporter for the absorption of neutral amino acids in the intestine and their reabsorption in the kidney. Mouse models have demonstrated that lack of BAT1 can normalize elevated plasma amino acids in rare disorders of amino acid metabolism such as phenylketonuria and urea-cycle disorders, implying a pharmacological approach for their treatment. Here we employ a medicinal chemistry approach to generate BAT1 inhibitors with IC-values of 31-90 nM. High-resolution cryo-EM structures of BAT1 in the presence of two compounds from this series identified an allosteric binding site in the vestibule of the transporter. Mechanistically, binding of these inhibitors prevents a movement of TM1 and TM6 that is required for the transporter to make a conformational change from an outward open state to the occluded state.
上皮中性氨基酸转运体 BAT1（SLC6A19）是肠道中中性氨基酸吸收和肾脏中再吸收的主要转运体。小鼠模型表明，缺乏 BAT1 可以使苯丙酮尿症和尿素循环障碍等罕见氨基酸代谢紊乱中升高的血浆氨基酸水平正常化，这意味着可以通过药理学方法治疗这些疾病。在这里，我们采用药物化学方法生成 BAT1 抑制剂，其 IC 值为 31-90 nM。该系列两种化合物存在时 BAT1 的高分辨率冷冻电镜结构确定了转运体前庭中的别构结合位点。从机制上讲，这些抑制剂的结合阻止 TM1 和 TM6 的运动，TM1 和 TM6 的运动对于转运体从外向开放状态转变为闭塞状态的构象变化是必需的。
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