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最丰富的两种磷脂，分别由胆碱和乙醇胺通过肯尼迪途径从头合成^1,2,3,4,5,6。尽管这些脂质具有重要作用，但细胞摄取胆碱和乙醇胺的机制仍然未知。在这里，我们表明， 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色素性视网膜炎^7,8,9）将细胞外胆碱和乙醇胺转运到细胞内，通过下游激酶进行磷酸化，从而启动肯尼迪通路。在胆碱和乙醇胺存在下，FLVCR1 的结构表明，两种代谢物均与包含芳香族和极性残基的共同结合位点结合。尽管结合到一个共同位点，FLVCR1 以不同的方式与胆碱中较大的季胺和乙醇胺的伯胺相互作用。结构引导诱变鉴定出对乙醇胺转运至关重要但对胆碱转运而言可有可无的残基，从而实现肯尼迪途径两个分支的入口点的功能分离。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，作为肯尼迪途径两个分支磷脂生物合成的共同起点。