Ring Opening of Glycerol Cyclic Phosphates Leads to a Diverse Array of Potentially Prebiotic Phospholipids

Abstract

Phospholipids are the primary constituents of cell membranes across all domains of life, but how and when phospholipids appeared on early Earth remains unknown. Pressingly, most prebiotic syntheses of complex phospholipids rely upon substrates not yet shown to have been available on early Earth. Here, we describe potentially prebiotic syntheses of a diverse array of complex phospholipids and their building blocks. First, we show that choline could have been produced on early Earth by stepwise Nmethylation of ethanolamine. Second, taking a systems chemistry approach, we demonstrate that the intrinsically activated glycerol-2,3-cyclic phosphate undergoes ring opening with combinations of prebiotic amino alcohols to yield complex phospholipid headgroups. Importantly, this pathway selects for the formation of 2-amino alcohol-bearing phospholipid headgroups and enables the accumulation of their natural regioisomers. Finally, we show that the drystate ring opening of cyclic lysophosphatidic acids leads to a range of self-assembling lysophospholipids. Our results provide new prebiotic routes to key intermediates on the way toward modern phospholipids and illuminate the potential origin and evolution of cell membranes.

Mg2+-driven selection of natural phosphatidic acids in primitive membranes

“…The literature on prebiotic phosphorylation of glycerol [21][22][23][24][25] suggests that this requirement would rarely have been met on early Earth, especially when hydrolysis of glycerol-1,2-cyclic phosphate is taken into account. 13,20,28 The acylation of glycerol phosphates in solution proceeds via the established phosphate-assisted mechanism in which formation of mixed anhydride intermediate precedes intramolecular acyl transfer to a hydroxyl group (Fig. S4).…”

“…1b and S5). The positional isomers, G2P and MDG2PA are probably formed on hydrolysis of G>P and MDG>P, respectively, 13,29 or phosphoryl migration under the ultimately acidic conditions of the reaction. 27 Similarly, the reaction of G2P afforded MDG2PA and DDG2PA in yields of 14% and 4%, respectively, along with the same array of products as obtained in the reaction starting from G1P (Fig.…”

“…Our group recently demonstrated that hydrolysis provides an efficient mechanism for the selection of natural phospholipids and their headgroups. 13 We thus wondered if G1PAs and G2PAs would hydrolyze at different rates and so offer a molecular level selection process for natural phosphatidic acids. Accordingly, the C10-lipids DDG1PA and DDG2PA were synthesized 31,32 and subjected to hydrolysis at room temperature, pH 10, either in homogeneous solution in acetonitrile/aqueous carbonate buffer (1:1, v/v), or in liposomes in carbonate buffer.…”

“…Due to the molecular heterogeneity of prebiotic building blocks present on early Earth, efficient mechanisms would have been required for the selection of relevant biomolecules. In relation to the emergence of phospholipids, recent studies showed that the selection of natural phospholipid headgroups could have resulted from the preferential hydrolysis of their non-natural analogues 13 and that liposomes composed of nonnatural phosphatidic acids are poorly tolerant to pH changes and metal ions. 14,16 However, no study has addressed whether processes operating at the molecular level (prebiotic synthesis) or the supramolecular level (membrane properties) could have driven the selection of natural phospholipids from heterogeneous mixtures available on early Earth.…”

“…Two recent reports have begun to address the selection of natural phospholipids. In work on the emergence of amino alcohol bearing phospholipids, our group 13 described a general prebiotic synthesis and hydrolysis scheme that selects for natural phospholipid headgroups comprising G1P over those comprising G2P. Then, in work advancing the prebiotic chemistry of cyclophospholipids, Krishnamurthy and co-workers 14 showed that liposomes formed of glycerol monodecanoate and phospholipid comprising G1P are more tolerant of pH changes and metal ions, such as those required for prebiotic RNA chemistry, 15 than those made with phospholipid comprising G2P.…”