Structural basis of lipid head group entry to the Kennedy pathway by FLVCR1

Abstract

Phosphatidylcholine and phosphatidylethanolamine, the two most abundant phospholipids in mammalian cells, are synthesizedde novoby the Kennedy pathway from choline and ethanolamine, respectively1–6. Despite the importance of these lipids, the mechanisms that enable the cellular uptake of choline and ethanolamine remain unknown. Here, we show that FLVCR1, whose mutation leads to the neurodegenerative syndrome PCARP7–9, 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 comprised of aromatic and polar residues. Despite binding to a common site, the larger quaternary amine of choline interacts differently with FLVCR1 than does the primary amine of ethanolamine. Structure-guided mutagenesis identified residues that are critical for the transport of ethanolamine, while being dispensable for choline transport, enabling functional separation of the entry points into the two branches of the Kennedy pathway. Altogether, these studies reveal how FLCVR1 is a high-affinity metabolite transporter that serves as the common origin for phospholipid biosynthesis by two branches of the Kennedy pathway.

p53 enables phospholipid headgroup scavenging

“…2a). These results support the finding that ethanolamine uptake through its transporter FLVCR1 is likely driven by the concentration gradient between the cytosol and the extracellular space 19 and indicate that intracellular PEtn levels are constrained by ethanolamine supply.…”

“…Our results demonstrate that p53 helps cells meet these increased demands by facilitating the provision and recapture of the ethanolamine headgroup for PE synthesis. Given that the high-affinity ethanolamine transporter was only recently identified 19 , future work will be needed to identify conditions under which exogenous ethanolamine availability constrains de novo lipid synthesis in cells in vivo .…”

Unearthing FLVCR1a: tracing the path to a vital cellular transporter

“…At the time of writing, different works on FLVCR1a structure have appeared [ 21 , 22 ], although not already peer-reviewed, that seem to confirm at least in part the predicted structure described.…”

“…Moreover, in our opinion, the experiments did not provide a clear resolution regarding whether the observed choline and phosphatidylcholine abnormalities in FLVCR1a-knockout cells are a result of heme metabolism dysregulation or, as suggested by the authors, are directly related to the choline-importing function ascribed to FLVCR1a. However, regarding this point, as previously mentioned, at the time of writing this review, several studies on FLVCR1a and choline have appeared [ 21 , 22 , 14 ]. Although most of them have not yet undergone peer review, these studies provide additional evidence confirming the choline transport capability of FLVCR1a.…”

Biallelic variation in the choline and ethanolamine transporterFLVCR1underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders

“…Both FLVCR1 isoforms are required for murine viability; mice retaining FLVCR1b but lacking FLVCR1a have normal erythropoiesis but develop hemorrhages, edema, and skeletal malformations 9 . The physiologic significance of FLVCR1 heme transport has been called in question especially considering recent evidence that FLVCR1 is a choline and ethanolamine transporter 4,[12][13][14][15][16] .…”