Phosphatidylcholine and phosphatidylethanolamine, the two most abundant phospholipids in mammalian cells, are synthesized de novo by the Kennedy pathway from choline and ethanolamine, respectively^1,2,3,4,5,6. Despite the essential roles of these lipids, the mechanisms that enable the cellular uptake of choline and ethanolamine remain unknown. Here we show that the protein encoded by FLVCR1, whose mutation leads to the neurodegenerative syndrome posterior column ataxia and retinitis pigmentosa^7,8,9, transports extracellular choline and ethanolamine into cells for phosphorylation by downstream kinases to initiate the Kennedy pathway. Structures of FLVCR1 in the presence of choline and ethanolamine reveal that both metabolites bind to a common binding site comprising aromatic and polar residues. Despite binding to a common site, FLVCR1 interacts in different ways with the larger quaternary amine of choline in and with the primary amine of ethanolamine. Structure-guided mutagenesis identified residues that are crucial for the transport of ethanolamine, but dispensable for choline transport, enabling functional separation of the entry points into the two branches of the Kennedy pathway. Altogether, these studies reveal how FLVCR1 is a high-affinity metabolite transporter that serves as the common origin for phospholipid biosynthesis by two branches of the Kennedy pathway.

磷脂酰胆碱和磷脂酰乙醇胺是哺乳动物细胞中含量最高的两种磷脂，分别通过 Kennedy 途径由胆碱和乙醇胺从头合成^1,2,3,4,5,6。尽管这些脂质起着重要作用，但使细胞摄取胆碱和乙醇胺的机制仍然未知。在这里，我们表明由 FLVCR1 编码的蛋白质，其突变导致神经退行性综合征后柱共济失调和视网膜色素变性^7,8,9，将细胞外胆碱和乙醇胺转运到细胞中，被下游激酶磷酸化，从而启动 Kennedy 通路。在胆碱和乙醇胺存在下，FLVCR1 的结构表明，两种代谢物都与包含芳香族和极性残基的共同结合位点结合。尽管与一个共同位点结合，但 FLVCR1 与乙醇胺伯胺中较大的胆碱季胺相互作用的方式不同。结构引导的诱变确定了对乙醇胺运输至关重要但对胆碱运输可有可无的残基，从而能够对进入 Kennedy 通路两个分支的入口点进行功能分离。总而言之，这些研究揭示了 FLVCR1 如何成为一种高亲和力代谢物转运蛋白，它是 Kennedy 途径的两个分支进行磷脂生物合成的共同来源。