Synthesis of activated nucleotides has been accomplished under 'prebiotically plausible' conditions, but bears little resemblance to the chemistry of life as we know it. Here we argue that life is an ...indispensable guide to its own origins.
The limits of metabolic heredity in protocells Nunes Palmeira, Raquel; Colnaghi, Marco; Harrison, Stuart A ...
Proceedings - Royal Society. Biological sciences/Proceedings - Royal Society. Biological Sciences,
2022-Nov-09, 2022-11-09, 20221109, Letnik:
289, Številka:
1986
Journal Article
Recenzirano
Odprti dostop
The universal core of metabolism could have emerged from thermodynamically favoured prebiotic pathways at the origin of life. Starting with H
and CO
, 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
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
fixation; autocatalysis alone leads to the accumulation of nucleotides at the expense of CO
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
fixation, hydrogenation and phosphorylation important to the emergence of genetic heredity at the origin of life.
The origin of the genetic code is an abiding mystery in biology. Hints of a ‘code within the codons’ suggest biophysical interactions, but these patterns have resisted interpretation. Here, we ...present a new framework, grounded in the autotrophic growth of protocells from CO2 and H2. Recent work suggests that the universal core of metabolism recapitulates a thermodynamically favoured protometabolism right up to nucleotide synthesis. Considering the genetic code in relation to an extended protometabolism allows us to predict most codon assignments. We show that the first letter of the codon corresponds to the distance from CO2 fixation, with amino acids encoded by the purines (G followed by A) being closest to CO2 fixation. These associations suggest a purine-rich early metabolism with a restricted pool of amino acids. The second position of the anticodon corresponds to the hydrophobicity of the amino acid encoded. We combine multiple measures of hydrophobicity to show that this correlation holds strongly for early amino acids but is weaker for later species. Finally, we demonstrate that redundancy at the third position is not randomly distributed around the code: non-redundant amino acids can be assigned based on size, specifically length. We attribute this to additional stereochemical interactions at the anticodon. These rules imply an iterative expansion of the genetic code over time with codon assignments depending on both distance from CO2 and biophysical interactions between nucleotide sequences and amino acids. In this way the earliest RNA polymers could produce non-random peptide sequences with selectable functions in autotrophic protocells.
•We provide a new framework for the origin of the genetic code in protocells growing by CO2 fixation.•Using a simple set of rules we are able allocate the large majority of codon assignments.•These codon assignments are based on biophysical interactions in an expanding protometabolism.•Biophysical interactions between RNA strings and templated amino acids can drive protocell growth.•Autotrophic protocell growth gives a new context for the origin of information in biology.
Life as a Guide to Its Own Origins Harrison, Stuart A; Rammu, Hanadi; Liu, Feixue ...
Annual review of ecology, evolution, and systematics,
11/2023, Letnik:
54, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The origin of life entails a continuum from simple prebiotic chemistry to cells with genes and molecular machines. Using life as a guide to this continuum, we consider how selection could promote ...increased complexity before the emergence of genes. Structured, far-from-equilibrium environments such as hydrothermal systems drive the reaction between CO
2
and H
2
to form organics that self-organize into protocells. CO
2
fixation within protocells generates a reaction network with a topology that prefigures the universal core of metabolism. Positive feedback loops amplify flux through this network, giving a metabolic heredity that promotes growth. Patterns in the genetic code show that genes and proteins arose through direct biophysical interactions between amino acids and nucleotides in this protometabolic network. Random genetic sequences template nonrandom peptides, producing selectable function in growing protocells. This context-dependent emergence of information gives rise seamlessly to an autotrophic last universal common ancestor.
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.
A protometabolic approach to the origins of life assumes that the conserved biochemistry of metabolism has direct continuity with prebiotic chemistry. One of the most important amino acids in modern ...biology is aspartic acid, serving as a nodal metabolite for the synthesis of many other essential biomolecules. Aspartate's prebiotic synthesis is complicated by the instability of its precursor, oxaloacetate. In this paper, we show that the use of the biologically relevant cofactor pyridoxamine, supported by metal ion catalysis, is sufficiently fast to offset oxaloacetate's degradation. Cu
-catalysed transamination of oxaloacetate by pyridoxamine achieves around a 5% yield within 1 h, and can operate across a broad range of pH, temperature, and pressure. In addition, the synthesis of the downstream product β-alanine may also take place in the same reaction system at very low yields, directly mimicking an archaeal synthesis route. Amino group transfer supported by pyridoxal is shown to take place from aspartate to alanine, but the reverse reaction (alanine to aspartate) shows a poor yield. Overall, our results show that the nodal metabolite aspartate and related amino acids can indeed be synthesised via protometabolic pathways that foreshadow modern metabolism in the presence of the simple cofactor pyridoxamine and metal ions.
Resistance against the leaf mold fungus Cladosporium fulvum is mediated by the tomato Cf proteins which belong to the class of receptor-like proteins and indirectly recognize extracellular avirulence ...proteins (Avrs) of the fungus. Apart from triggering disease resistance, Avrs are believed to play a role in pathogenicity or virulence of C. fulvum. Here, we report on the avirulence protein Avr4, which is a chitin-binding lectin containing an invertebrate chitin-binding domain (CBM14). This domain is found in many eukaryotes, but has not yet been described in fungal or plant genomes. We found that interaction of Avr4 with chitin is specific, because it does not interact with other cell wall polysaccharides. Avr4 binds to chitin oligomers with a minimal length of three N-acetyl glucosamine residues. In vitro, Avr4 protects chitin against hydrolysis by plant chitinases. Avr4 also binds to chitin in cell walls of the fungi Trichoderma viride and Fusarium solani f. sp. phaseoli and protects these fungi against normally deleterious concentrations of plant chitinases. In situ fluorescence studies showed that Avr4 also binds to cell walls of C. fulvum during infection of tomato, where it most likely protects the fungus against tomato chitinases, suggesting that Avr4 is a counter-defensive virulence factor.
The genetic code conceals a 'code within the codons', which hints at biophysical interactions between amino acids and their cognate nucleotides. Yet, research over decades has failed to corroborate ...systematic biophysical interactions across the code. Using molecular dynamics simulations and NMR, we have analysed interactions between the 20 standard proteinogenic amino acids and 4 RNA mononucleotides in 3 charge states. Our simulations show that 50% of amino acids bind best with their anticodonic middle base in the -1 charge state common to the backbone of RNA, while 95% of amino acids interact most strongly with at least 1 of their codonic or anticodonic bases. Preference for the cognate anticodonic middle base was greater than 99% of randomised assignments. We verify a selection of our results using NMR, and highlight challenges with both techniques for interrogating large numbers of weak interactions. Finally, we extend our simulations to a range of amino acids and dinucleotides, and corroborate similar preferences for cognate nucleotides. Despite some discrepancies between the predicted patterns and those observed in biology, the existence of weak stereochemical interactions means that random RNA sequences could template non-random peptides. This offers a compelling explanation for the emergence of genetic information in biology.
Objective Establish a relationship between digital health intervention (DHI) and health system challenges (HSCs), as defined by the World Health Organization; within the context of hazard ...identification (HazID), leading to safety claims. To improve the justification of safety of DHIs and provide a standardised approach to hazard assessment through common terminology, ontology and simplification of safety claims. Articulation of results, to provide guidance for health strategy and regulatory/standards-based compliance. Methods We categorise and analyse hazards using a qualitative HazID study. This method utilises a synergy between simplicity of DHI intended use and the interaction from a multidisciplinary team (technologists and health informaticians) in the hazard analysis of the subject under assessment as an influencing factor. Although there are other methodologies available for hazard assessment. We examine the hazards identified and associated failures to articulate the improvements in the quality of safety claims. Results Applying the method provides the hazard assessment and helps generate the assurance case. Justification of safety is made and elicits confidence in safety claim. Controls to hazards contribute to meeting the HSC. Conclusions This method of hazard assessment, analysis and the use of ontologies (DHI & HSC) improves the justification of safety claim and evidence articulation.
PDF
