Reactions Driven by Primitive Nonbiological Polyesters.

ConspectusAll life on Earth is composed of cells, which are built from and run by biological reactions and structures. These reactions and structures are generally the result of action by cellular biomolecules, which are indispensable for the function and survival of all living organisms. Specifically, biological catalysis, namely by protein enzymes, but also by other biomolecules including nucleic acids, is an essential component of life. How the biomolecules themselves that perform biological catalysis came to exist in the first place is a major unanswered question that plagues researchers to this day, which is generally the focus of the origins of life (OoL) research field. Based on current knowledge, it is generally postulated that early Earth was full of a myriad of different chemicals, and that these chemicals reacted in specific ways that led to the emergence of biochemistry, cells, and later, life. In particular, a significant part of OoL research focuses on the synthesis, evolution, and function of biomolecules potentially present under early Earth conditions, as a way to understand their eventual transition into modern life. However, this narrative overlooks possibilities that other molecules contributed to the OoL, as while biomolecules that led to life were certainly present on early Earth, at the same time, other molecules that may not have strict, direct biological lineage were also widely and abundantly present. For example, hydroxy acids, although playing a role in metabolism or as parts of certain biological structures, are not generally considered to be as essential to modern biology as amino acids (a chemically similar monomer), and thus research in the OoL field tends to perhaps focus more on amino acids than hydroxy acids. However, their likely abundance on early Earth coupled with their ability to spontaneously condense into polymers (i.e., polyesters) make hydroxy acids, and their subsequent products, functions, and reactions, a reasonable target of investigation for prebiotic chemists. Whether "non-biological" hydroxy acids or polyesters can contribute to the emergence of life on early Earth is an inquiry that deserves attention within the OoL community, as this knowledge can also contribute to our understanding of the plausibility of extraterrestrial life that does not exactly use the biochemical set found in terrestrial organisms. While some demonstrations have been made with respect to compartment assembly, compartmentalization, and growth of primitive polyester-based systems, whether these "non-biological" polymers can contribute any catalytic function and/or drive primitive reactions is still an important step toward the development of early life. Here, we review research both from the OoL field as well as from industry and applied sciences regarding potential catalysis or reaction driven by "non-biological" polyesters in various forms: as linear polymers, as hyperbranched polyesters, and as membraneless microdroplets.

Towards a prebiotic chemoton - nucleotide precursor synthesis driven by the autocatalytic formose reaction.

The formose reaction is often cited as a prebiotic source of sugars and remains one of the most plausible forms of autocatalysis on the early Earth. Herein, we investigated how cyanamide and 2-aminooxazole, molecules proposed to be present on early Earth and precursors for nonenzymatic ribonucleotide synthesis, mediate the formose reaction using HPLC, LC-MS and 1H NMR spectroscopy. Cyanamide was shown to delay the exponential phase of the formose reaction by reacting with formose sugars to form 2-aminooxazole and 2-aminooxazolines thereby diverting some of these sugars from the autocatalytic cycle, which nonetheless remains intact. Masses for tetrose and pentose aminooxazolines, precursors for nucleotide synthesis including TNA and RNA, were also observed. The results of this work in the context of the chemoton model are further discussed. Additionally, we highlight other prebiotically plausible molecules that could have mediated the formose reaction and alternative prebiotic autocatalytic systems.

Carbonyl Migration in Uronates Affords a Potential Prebiotic Pathway for Pentose Production.

Carbohydrate biosynthesis is fundamental to modern terrestrial biochemistry, but how this collection of metabolic pathways originated remains an open question. Prebiotic sugar synthesis has focused primarily on the formose reaction and Kiliani-Fischer homologation; however, how they can transition to extant biochemical pathways has not been studied. Herein, a nonenzymatic pathway for pentose production with similar chemical transformations as those of the pentose phosphate pathway is demonstrated. Starting from a C6 aldonate, namely, gluconate, nonselective chemical oxidation yields a mixture of 2-oxo-, 4-oxo-, 5-oxo-, and 6-oxo-uronate regioisomers. Regardless at which carbinol the oxidation takes place, carbonyl migration enables ß-decarboxylation to yield pentoses. In comparison, the pentose phosphate pathway selectively oxidizes 6-phosphogluconate to afford the 3-oxo-uronate derivative, which undergoes facile subsequent ß-decarboxylation and carbonyl migration to afford ribose 5-phosphate. The similarities between these two pathways and the potential implications for prebiotic chemistry and protometabolism are discussed.

Alternating co-synthesis of glycol nucleic acid (GNA) monomers with dicarboxylic acids via drying.

We report the co-polymerization of glycol nucleic acid (GNA) monomers with unsubstituted and substituted dicarboxylic acid linkers under plausible early Earth aqueous dry-down conditions. Both linear and branched co-polymers are produced. Mechanistic aspects of the reaction and potential roles of these polymers in prebiotic chemistry are discussed.

Spectroscopic and Biophysical Methods to Determine Differential Salt-Uptake by Primitive Membraneless Polyester Microdroplets.

α-Hydroxy acids are prebiotic monomers that undergo dehydration synthesis to form polyester gels, which assemble into membraneless microdroplets upon aqueous rehydration. These microdroplets are proposed as protocells that can segregate and compartmentalize primitive molecules/reactions. Different primitive aqueous environments with a variety of salts could have hosted chemistries that formed polyester microdroplets. These salts could be essential cofactors of compartmentalized prebiotic reactions or even directly affect protocell structure. However, fully understanding polyester-salt interactions remains elusive, partially due to technical challenges of quantitative measurements in condensed phases. Here, spectroscopic and biophysical methods are applied to analyze salt uptake by polyester microdroplets. Inductively coupled plasma mass spectrometry is applied to measure the cation concentration within polyester microdroplets after addition of chloride salts. Combined with methods to determine the effects of salt uptake on droplet turbidity, size, surface potential and internal water distribution, it was observed that polyester microdroplets can selectively partition salt cations, leading to differential microdroplet coalescence due to ionic screening effects reducing electrostatic repulsion forces between microdroplets. Through applying existing techniques to novel analyses related to primitive compartment chemistry and biophysics, this study suggests that even minor differences in analyte uptake can lead to significant protocellular structural change.

Erythrose and Threose: Carbonyl Migrations, Epimerizations, Aldol, and Oxidative Fragmentation Reactions under Plausible Prebiotic Conditions.

The prebiotic generation of sugars in the context of origins of life studies is of considerable interest. Among the important intramolecular processes of sugars are carbonyl migrations and accompanying epimerizations. Herein we describe the carbonyl migration-epimerization process occurring down the entire carbon chain of chirally pure d-tetroses sugars under mild conditions. Employing chirally pure 1-13 C-erythrose, 4-13 C-erythrose and 1-13 C-threose, we (1) identify all the species formed as the carbonyl migrates down the four-carbon chain and (2) assess the rates associated with the production of each of these species. Competing aldol reactions and oxidative fragmentation processes were also observed. Further observations of self-condensation of glycolaldehyde mainly yielding 2-keto-hexoses (sorbose and tagatose) and tetrulose also provides a basis for understanding the effect of carbonyl migrations on the product distribution in plausible prebiotic scenarios.

A Physicochemical Consideration of Prebiotic Microenvironments for Self-Assembly and Prebiotic Chemistry.

The origin of life on Earth required myriads of chemical and physical processes. These include the formation of the planet and its geological structures, the formation of the first primitive chemicals, reaction, and assembly of these primitive chemicals to form more complex or functional products and assemblies, and finally the formation of the first cells (or protocells) on early Earth, which eventually evolved into modern cells. Each of these processes presumably occurred within specific prebiotic reaction environments, which could have been diverse in physical and chemical properties. While there are resources that describe prebiotically plausible environments or nutrient availability, here, we attempt to aggregate the literature for the various physicochemical properties of different prebiotic reaction microenvironments on early Earth. We introduce a handful of properties that can be quantified through physical or chemical techniques. The values for these physicochemical properties, if they are known, are then presented for each reaction environment, giving the reader a sense of the environmental variability of such properties. Such a resource may be useful for prebiotic chemists to understand the range of conditions in each reaction environment, or to select the medium most applicable for their targeted reaction of interest for exploratory studies.

Correction: Simultaneous synthesis of thioesters and iron-sulfur clusters in water: two universal components of energy metabolism.

Correction for 'Simultaneous synthesis of thioesters and iron-sulfur clusters in water: two universal components of energy metabolism' by Sebastian A. Sanden et al., Chem. Commun., 2020, 56, 11989-11992, DOI: 10.1039/D0CC07078A.

Simultaneous synthesis of thioesters and iron-sulfur clusters in water: two universal components of energy metabolism.

Thioesters are important intermediates in both synthetic organic and biosynthetic reaction pathways. Here we show that thioesters can be synthesized in an aqueous reaction between thioacetate and thiols. The reaction can be coupled to a second reaction between sulfide and either ferrous or ferric iron, which drives the reaction forward. We furthermore demonstrate that sulfide released during thioester formation can be used in the synthesis of peptide bound [Fe-S] clusters, which like thioesters, are ancient components of metabolism. Together our results reveal a primordial linkage between high-energy ester formation and redox chemistry.

A continuous reaction network that produces RNA precursors.

Continuous reaction networks, which do not rely on purification or timely additions of reagents, serve as models for chemical evolution and have been demonstrated for compounds thought to have played important roles for the origins of life such as amino acids, hydroxy acids, and sugars. Step-by-step chemical protocols for ribonucleotide synthesis are known, but demonstrating their synthesis in the context of continuous reaction networks remains a major challenge. Herein, compounds proposed to be important for prebiotic RNA synthesis, including glycolaldehyde, cyanamide, 2-aminooxazole, and 2-aminoimidazole, are generated from a continuous reaction network, starting from an aqueous mixture of NaCl, NH4Cl, phosphate, and HCN as the only carbon source. No well-timed addition of any other reagents is required. The reaction network is driven by a combination of γ radiolysis and dry-down. γ Radiolysis results in a complex mixture of organics, including the glycolaldehyde-derived glyceronitrile and cyanamide. This mixture is then dried down, generating free glycolaldehyde that then reacts with cyanamide/NH3 to furnish a combination of 2-aminooxazole and 2-aminoimidazole. This continuous reaction network models how precursors for generating RNA and other classes of compounds may arise spontaneously from a complex mixture that originates from simple reagents.

Estimating the capacity for production of formamide by radioactive minerals on the prebiotic Earth.

Water creates special problems for prebiotic chemistry, as it is thermodynamically favorable for amide and phosphodiester bonds to hydrolyze. The availability of alternative solvents with more favorable properties for the formation of prebiotic molecules on the early Earth may have helped bypass this so-called "water paradox". Formamide (FA) is one such solvent, and can serve as a nucleobase precursor, but it is difficult to envision how FA could have been generated in large quantities or accumulated in terrestrial surface environments. We report here the conversion of aqueous acetonitrile (ACN) via hydrogen cyanide (HCN) as an intermediate into FA by γ-irradiation under conditions mimicking exposure to radioactive minerals. We estimate that a radioactive placer deposit could produce 0.1‒0.8 mol FA km-2 year-1. A uraninite fission zone comparable to the Oklo reactors in Gabon can produce 0.1‒1 mol m-2 year-1, orders of magnitude greater than other scenarios of FA production or delivery for which reaching sizeable concentrations of FA are problematic. Radioactive mineral deposits may be favorable settings for prebiotic compound formation through emergent geologic processes and FA-mediated organic chemistry.

Synthesis of imidazole-activated ribonucleotides using cyanogen chloride.

We report the syntheses of ribonucleoside 5'-monophosphates activated with imidazole, using a mechanism which relies on the in situ generation of cyanogen chloride from the reaction of cyanide anion with hypochlorous acid. Cyanogen chloride reacts rapidly with imidazole to form diimidazole imine as the major product, a species which affords the activation of ribonucleoside 5'-monophosphates to their 5'-phosphorimidazolides.

Convergent synthesis of 4,5-branched inner-core oligosaccharides of lipopoly- and lipooligosaccharides.

The convergent synthesis of branched inner-core oligosaccharides of lipopoly- and lipooligosaccharide with a 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) disaccharide acceptor was achieved. The l-glycero-d-manno-heptopyranose (Hep) units for the branched core oligosaccharide Galß(1-4)Glcß(1-4)Hep and Hepα(1-3)Hep were prepared from the corresponding Hep building blocks. To obtain 4,5-branched core oligosaccharide structures, the common acceptor Kdoα(2-4)Kdo was glycosylated with the Hep units.