Dear Editor,

Vitamins B₁ and B₆ are two water-soluble vitamins. Their active forms thiamine pyrophosphate and pyridoxal 5′-phosphate serve as cofactors for numerous enzymes involved in multiple biochemical reactions that are essential to maintain the composition and energy metabolism of the human body.¹ Consequently, their deficiency leads to a variety of diseases, such as neurological abnormalities and cardiovascular diseases.² Humans cannot synthesize these vitamins de novo and must obtain them from the diet. Two specific transporters, thiamine transporter 1 (ThTr1 or SLC19A2) and thiamine transporter 2 (ThTr2 or SLC19A3), have been identified to be the major transmembrane transporters that are involved in the uptake of both vitamins thus far.^3,4,5,6 Interestingly, the clinical antineoplastic drug fedratinib, a Janus kinase 2 (JAK2) inhibitor used in treating myelofibrosis, induces Wernicke’s-like encephalopathy in some myelofibrosis patients due to thiamine scarcity.^7,8 This is caused by its off-target inhibitory activity against both SLC19A2 and SLC19A3.⁹ Here, we report the cryo-electron microscopy (cryo-EM) structures of human SLC19A3 in complex with vitamins B₁, B₆, or fedratinib. Remarkably, all these compounds bind to the same site on SLC19A3 via a closely related structural element. Mutagenesis studies further revealed the critical residues of SLC19A3 for substrate and drug recognition. In summary, our work provides a structural framework for understanding the substrate diversity of SLC19A3.

亲爱的编辑，

维生素 B ₁和 B ₆是两种水溶性维生素。它们的活性形式焦磷酸硫胺素和 5'-磷酸吡哆醛可作为参与多种生化反应的多种酶的辅助因子，这些酶对于维持人体的组成和能量代谢至关重要。¹因此，它们的缺乏会导致多种疾病，例如神经系统异常和心血管疾病。²人类无法从头合成这些维生素，必须从饮食中获取。两种特定的转运蛋白，硫胺素转运蛋白 1（ThTr1 或 SLC19A2）和硫胺素转运蛋白 2（ThTr2 或 SLC19A3），已被确定为迄今为止参与两种维生素摄取的主要跨膜转运蛋白。^3,4,5,6有趣的是，临床抗肿瘤药物 fedratinib（一种用于治疗骨髓纤维化的 Janus 激酶 2 (JAK2) 抑制剂）会因硫胺素缺乏而在一些骨髓纤维化患者中诱发韦尼克样脑病。^7,8这是由于其针对 SLC19A2 和 SLC19A3 的脱靶抑制活性所致。^{9在此，我们报告了人 SLC19A3 与维生素 B} ₁、 B ₆或 fedratinib复合物的冷冻电子显微镜 (cryo-EM) 结构。值得注意的是，所有这些化合物都通过密切相关的结构元件结合到 SLC19A3 上的同一位点。诱变研究进一步揭示了 SLC19A3 对于底物和药物识别的关键残基。总之，我们的工作为理解 SLC19A3 的底物多样性提供了一个结构框架。