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Enzyme-free synthesis of natural phospholipids in water


All living organisms synthesize phospholipids as the primary constituent of their cell membranes. Enzymatic synthesis of diacylphospholipids requires preexisting membrane-embedded enzymes. This limitation has led to models of early life in which the first cells used simpler types of membrane building blocks and has hampered integration of phospholipid synthesis into artificial cells. Here we demonstrate an enzyme-free synthesis of natural diacylphospholipids by transacylation in water, which is enabled by a combination of ion pairing and self-assembly between lysophospholipids and acyl donors. A variety of membrane-forming cellular phospholipids have been obtained in high yields. Membrane formation takes place in water from natural alkaline sources such as soda lakes and hydrothermal oceanic vents. When formed vesicles are transferred to more acidic solutions, electrochemical proton gradients are spontaneously established and maintained. This high-yielding non-enzymatic synthesis of natural phospholipids in water opens up new routes for lipid synthesis in artificial cells and sheds light on the origin and evolution of cellular membranes.

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Fig. 1: Enzyme-free synthesis of natural phospholipids.
Fig. 2: Predicted effects of thioester charge on phospholipid synthesis.
Fig. 3: Enzyme-free formation of phospholipid membranes.

Data availability

The data that support the findings of this study are available within the paper and its Supplementary Information.


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N.K.D. acknowledges financial support for this work provided by the National Science Foundation (grant no. CHE-1254611) and the National Institutes of Health (grant no. DP2DK111801). K.N.H. acknowledges National Science Foundation (grant no. CHE-1764328), the National Institutes of Health, National Institute of General Medical Sciences (grant no. R01 GM109078), for financial support of this research. S.Q.L. acknowledges financial support for this work provided by National Science Foundation (grant no. OCE-1536702). Computation time was provided by the UCLA Institute for Digital Research and Education (IDRE).

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Authors and Affiliations



L.L. and N.K.D. conceived the project. L.L. designed and performed the synthetic experiments. L.L., A.B. and D.Z. performed microscopy experiments. Y.Z. and K.N.H. performed the theoretical study. L.L., Y.Z., A.B., D.Z., S.Q.L., K.N.H. and N.K.D. analysed the data. L.L., Y.Z. and N.K.D. wrote the manuscript. S.Q.L. and K.N.H. assisted in writing and editing the manuscript.

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Correspondence to Neal K. Devaraj.

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Supplementary information

Supplementary Information

Materials and Methods, Supplementary Text, Figs. 1–27, Table 1, copies of HPLC and NMR Spectra.

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Liu, L., Zou, Y., Bhattacharya, A. et al. Enzyme-free synthesis of natural phospholipids in water. Nat. Chem. 12, 1029–1034 (2020).

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