Was a Pyrimidine‐Pyrimidine Base Pair the Ancestor of Watson‐Crick Base Pairs? Insights from a Systematic Approach to the Origin of RNA

Abstract

Uncovering the origin of RNA is essential for understanding the origins of life. The persistent inability of chemists to identify a plausible prebiotic route to RNA polymers, along with the seemingly optimal structure of RNA for its functions in extant life, argue in favor of the hypothesis that RNA is a product of chemical or biological evolution. To understand the origin of RNA, we must consider which molecules could have originally acted in place of RNA’s substructures (i.e., nucleobases (the recognition units), ribose (a trifunctional connector), and phosphate (an ionized linker)) in the oldest ancestor of RNA (or proto‐RNA). Major challenges to uncovering the chemical structure of proto‐RNA include finding molecules that would have spontaneously undergone molecular selection and covalent assembly into an RNA‐like polymer, within the complex mixture of the “prebiotic soup” and without the aid of enzymes. In this review, we discuss progress towards identifying the recognition units of proto‐RNA and mechanisms by which the ancestral nucleobases might have been originally selected and incorporated into polymers. We consider possible proto‐nucleobases within the chemical space of the heterocycles defined by the purines and pyrimidines that have H, NH2, or O as exocyclic groups (which includes the extant nucleobases). Taking into account the results of numerous experiments that have explored nucleic acids with alternative backbones and noncanonical nucleobases, we are able to remove about half of these 81 molecules from candidacy as ancestral nucleobases. A particularly encouraging result of this approach is the identification of two molecules, 2,4,6‐triaminopyrimidine and barbituric acid, which look very promising as possible nucleobases of proto‐RNA.

Ultrafast excited-state dynamics of isocytosine

“…Perhaps the most compelling hypotheses are related to the emergence of RNA from formamide 5,6 or the indirect but efficient synthesis of pyrimidine nucleosides from one-and two-carbon feedstock molecules. 14 In this latter case, the possible participation of alternative nucleobases in molecular evolution attracted a lot of attention. 14 In this latter case, the possible participation of alternative nucleobases in molecular evolution attracted a lot of attention.…”

“…[7][8][9] Other ideas suggest that RNA might have evolved from a prebiotic ancestor, [10][11][12][13] sometimes referred to as XNA. 13,14 The most noticeable of the alternative nucleobases are hypoxantine and diaminopurines found in carbonaceous mete-orites, 15 isocytosine which can be formed in the presence of ironsulphur minerals, 16 and 2,4,6-triaminopyrimidine which readily undergoes glycosylation with ribose as opposed to many other nucleobases. 13,14 The most noticeable of the alternative nucleobases are hypoxantine and diaminopurines found in carbonaceous mete-orites, 15 isocytosine which can be formed in the presence of ironsulphur minerals, 16 and 2,4,6-triaminopyrimidine which readily undergoes glycosylation with ribose as opposed to many other nucleobases.…”

Taming Prebiotic Chemistry: The Role of Heterogeneous and Interfacial Catalysis in the Emergence of a Prebiotic Catalytic/Information Polymer System

“…The rapid decomposition of nucleobases [12] and sugars [13] in aqueous solution also questions the concept of the RNA world. All of these observations have led some researchers to doubt the prebiotic assembly of “pristine” RNA, as the first ancestral information molecules [14,15,16]. In fact, the properties of RNA and their perfect suitability for current RNA functions suggest that RNA may be “an emergent, highly refined molecule” [16].…”

“…From the point of view of the origins of life, the use of non-canonical nucleobases may be extremely relevant, as it is likely that other non-canonical nucleobase were formed simultaneously to the canonical ones [15]. The replacement of the phosphodiester bonds or even the phosphate-ribose backbones has been proposed to solve the difficulties inherent to the synthesis of RNA from a chemical point of view [16,61].…”

Orotidine‐Containing RNA: Implications for the Hierarchical Selection (Systems Chemistry Emergence) of RNA

“…This is based on the vital functional role they play in extant biology and the ease of formation under potentially prebiotic conditions . Apart from these canonical nucleobases, there is a whole set of pyrimidines (and purines), with functional group substitutions at various positions, that are produced under the same prebiotic conditions . Particularly, pyrimidines with functional groups (NH 2 , OH, or COOH) at the 5‐ or 6‐position are formed, sometimes with greater abundance in the HCN polymerization reactions .…”