A biophysical basis for the emergence of the genetic code in protocells

Harrison, Stuart A; Palmeira, Raquel Nunes; Halpern, Aaron; Lane, Nick

doi:10.1016/j.bbabio.2022.148597

Cited by 18 publications

(40 citation statements)

References 68 publications

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“…These data suggest that the metabolic selectivity of these membrane mimics is complex and does not rely solely on basic molecular properties, such as molecular weight or hydrophobicity. Taken together with previous findings, demonstrating that solute hydrophobicity correlates poorly with permeability coefficients of eukaryotic fatty acid or phospholipid membranes [ 36 ] and that amino acid residue hydrophobicity might have not been key for the emergence of the genetic code [ 43 ], our data corroborate the hypothesis that subtle variations in the metabolite atomic structure could contribute to differences in membrane permeability [ 36 , 37 , 44 ]. In fact, we found a significant negative correlation between permeability and rotatable bond number for archaeal 4ME diether G1PC vesicles (Pearson coefficient r = −0.49, *), but not for bacterial diester G3PE-PG-CA vesicles (r = −0.32, nonsignificant at p = 0.05).…”

Section: Resultssupporting

confidence: 89%

“…Such an evolutionary scenario suggests that the early archaeal forms and possibly early proto-prokaryotic forms with an archaeal-type core membrane (before the membrane transition, which marks the Archaea–Bacteria bifurcation and indeed the evolution of membrane transporters) possessed many heterotrophic functions (i.e., the ability to acquire chemical precursors for metabolic function via permeation from an external environment) [ 30 , 71 , 72 ]. Such a scenario does not exclude an early dependency on autotrophic functions at the origins of life [ 19 , 43 , 73 , 74 ] or indeed a metabolic network largely reliant on autotrophic function as the Archaea arose [ 9 , 61 ], nor does it exclude early phases of cellular evolution based on fatty acid membranes [ 30 , 75 ]. However, our results suggest as early life transitioned to prokaryote-type cells the acquisition of a proto-metabolic network within a prokaryotic membrane chassis could more readily be achieved within a core archaeal-type membrane chemistry.…”

Section: Discussionmentioning

confidence: 99%

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Systematic comparison of unilamellar vesicles reveals that archaeal core lipid membranes are more permeable than bacterial membranes

et al. 2023

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One of the deepest branches in the tree of life separates the Archaea from the Bacteria. These prokaryotic groups have distinct cellular systems including fundamentally different phospholipid membrane bilayers. This dichotomy has been termed the lipid divide and possibly bestows different biophysical and biochemical characteristics on each cell type. Classic experiments suggest that bacterial membranes (formed from lipids extracted from Escherichia coli, for example) show permeability to key metabolites comparable to archaeal membranes (formed from lipids extracted from Halobacterium salinarum), yet systematic analyses based on direct measurements of membrane permeability are absent. Here, we develop a new approach for assessing the membrane permeability of approximately 10 μm unilamellar vesicles, consisting of an aqueous medium enclosed by a single lipid bilayer. Comparing the permeability of 18 metabolites demonstrates that diether glycerol-1-phosphate lipids with methyl branches, often the most abundant membrane lipids of sampled archaea, are permeable to a wide range of compounds useful for core metabolic networks, including amino acids, sugars, and nucleobases. Permeability is significantly lower in diester glycerol-3-phosphate lipids without methyl branches, the common building block of bacterial membranes. To identify the membrane characteristics that determine permeability, we use this experimental platform to test a variety of lipid forms bearing a diversity of intermediate characteristics. We found that increased membrane permeability is dependent on both the methyl branches on the lipid tails and the ether bond between the tails and the head group, both of which are present on the archaeal phospholipids. These permeability differences must have had profound effects on the cell physiology and proteome evolution of early prokaryotic forms. To explore this further, we compare the abundance and distribution of transmembrane transporter-encoding protein families present on genomes sampled from across the prokaryotic tree of life. These data demonstrate that archaea tend to have a reduced repertoire of transporter gene families, consistent with increased membrane permeation. These results demonstrate that the lipid divide demarcates a clear difference in permeability function with implications for understanding some of the earliest transitions in cell origins and evolution.

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Section: Resultssupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Systematic comparison of unilamellar vesicles reveals that archaeal core lipid membranes are more permeable than bacterial membranes

et al. 2023

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“…The centrality of these cofactors to intermediary metabolism, combined with their ability to catalyse the same reactions in the absence of enzymes [ 11 – 14 ], suggests that adenosine arose very early in biology, possibly even in a monomer world before the advent of RNA, DNA, and proteins [ 15 , 16 ]. This hypothesis is consistent with the idea that life acts as a guide to its own origin [ 17 , 18 ]. Phylogenetics indicates that the earliest cells grew autotrophically from H 2 and CO 2 [ 16 , 19 – 23 ].…”

Section: Introductionsupporting

confidence: 90%

“…Which catalysts would best promote ATP hydrolysis coupled to phosphorylation in the aqueous prebiotic environments discussed here is a separate question that will be addressed elsewhere; metal ions, amino acids, short peptides, short ribozymes, or nucleotide cofactors all deserve consideration. We suspect that ATP only displaced earlier phosphorylating agents such as AcP or CP when coupled by catalysts to polymerization reactions linked to the hydrolysis of pyrophosphate, as discussed in the Introduction, or potentially as an autocatalytic feedback loop in purine synthesis, which could have amplified purine nucleotide availability in early evolution [ 18 , 129 ]. Nonetheless, the work presented here shows that ATP might have entered protometabolism at an earlier stage than generally supposed and could have contributed to the transition from a monomer to a polymer world.…”

Section: Discussionmentioning

confidence: 99%

A prebiotic basis for ATP as the universal energy currency

et al. 2022

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ATP is universally conserved as the principal energy currency in cells, driving metabolism through phosphorylation and condensation reactions. Such deep conservation suggests that ATP arose at an early stage of biochemical evolution. Yet purine synthesis requires 6 phosphorylation steps linked to ATP hydrolysis. This autocatalytic requirement for ATP to synthesize ATP implies the need for an earlier prebiotic ATP equivalent, which could drive protometabolism before purine synthesis. Why this early phosphorylating agent was replaced, and specifically with ATP rather than other nucleoside triphosphates, remains a mystery. Here, we show that the deep conservation of ATP might reflect its prebiotic chemistry in relation to another universally conserved intermediate, acetyl phosphate (AcP), which bridges between thioester and phosphate metabolism by linking acetyl CoA to the substrate-level phosphorylation of ADP. We confirm earlier results showing that AcP can phosphorylate ADP to ATP at nearly 20% yield in water in the presence of Fe3+ ions. We then show that Fe3+ and AcP are surprisingly favoured. A wide range of prebiotically relevant ions and minerals failed to catalyse ADP phosphorylation. From a panel of prebiotic phosphorylating agents, only AcP, and to a lesser extent carbamoyl phosphate, showed any significant phosphorylating potential. Critically, AcP did not phosphorylate any other nucleoside diphosphate. We use these data, reaction kinetics, and molecular dynamic simulations to infer a possible mechanism. Our findings might suggest that the reason ATP is universally conserved across life is that its formation is chemically favoured in aqueous solution under mild prebiotic conditions.

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“…Selection for fast growth is likely to oppose the accumulation of catalytic nucleotides within protocells, albeit positive feedbacks favouring the synthesis of an energy currency can increase nucleotide concentrations somewhat. Most importantly, the model gives a new context for the emergence of the genetic code in autotrophic protocells [ 99 ]. Whatever processes allowed polymerization of nucleotides in this setting, the introduction of short, random RNA sequences inside replicating protocells offers an immediate informational context.…”

Section: Discussionmentioning

confidence: 99%

The limits of metabolic heredity in protocells

et al. 2022

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The universal core of metabolism could have emerged from thermodynamically favoured prebiotic pathways at the origin of life. Starting with H 2 and CO 2 , the synthesis of amino acids and mixed fatty acids, which self-assemble into protocells, is favoured under warm anoxic conditions. Here, we address whether it is possible for protocells to evolve greater metabolic complexity, through positive feedbacks involving nucleotide catalysis. Using mathematical simulations to model metabolic heredity in protocells, based on branch points in protometabolic flux, we show that nucleotide catalysis can indeed promote protocell growth. This outcome only occurs when nucleotides directly catalyse CO 2 fixation. Strong nucleotide catalysis of other pathways (e.g. fatty acids and amino acids) generally unbalances metabolism and slows down protocell growth, and when there is competition between catalytic functions cell growth collapses. Autocatalysis of nucleotide synthesis can promote growth but only if nucleotides also catalyse CO 2 fixation; autocatalysis alone leads to the accumulation of nucleotides at the expense of CO 2 fixation and protocell growth rate. Our findings offer a new framework for the emergence of greater metabolic complexity, in which nucleotides catalyse broad-spectrum processes such as CO 2 fixation, hydrogenation and phosphorylation important to the emergence of genetic heredity at the origin of life.

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A biophysical basis for the emergence of the genetic code in protocells

Cited by 18 publications

References 68 publications

Systematic comparison of unilamellar vesicles reveals that archaeal core lipid membranes are more permeable than bacterial membranes

Systematic comparison of unilamellar vesicles reveals that archaeal core lipid membranes are more permeable than bacterial membranes

A prebiotic basis for ATP as the universal energy currency

The limits of metabolic heredity in protocells

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