(15) The abiotic chemistries underlying the synthesis of canonical nucleotides (the building blocks of RNA and DNA) may not be considered by some as challenging or fascinating in the context of conventional organic synthesis since most of them have become standardized procedures. The discovery and successful demonstration of many catalytic functions of RNA (10−13) gave a strong boost to the “RNA world” hypothesis in the 1980s and subsequently led to a renewed vigor (14) and focus on the chemistry of abiotic synthesis of RNA building blocks in a prebiotic context and subsequent conversion of the nucleotides to RNA. (5) This hypothesis is based on the ideas that were originally developed in the 1960s by Rich, Woese, Crick, and Orgel that RNA could have played a crucial part in the evolutionary stage of early life on primordial earth, (6−9) wherein abiotically synthesized primordial RNA could have functioned both as the genetic material (genotype) as well as a catalyst (phenotype)-as self-sustaining and self-replicating entities. (2−4) In particular, the wide-ranging roles played by RNA in biology-with the demonstrated capability of acting as carrier of encoded information for replication and protein synthesis and as catalysts (ribozymes)-coupled with the ubiquitous presence of nucleic acid cofactors has led to the “RNA world” hypothesis. (1) Their synthesis continues to occupy a central place, not only for endeavors in extant- and synthetic-biology but also for developing an understanding of chemical evolution and the chemical origins of life. Nucleotides are the building blocks of nucleic acids RNA and DNA ( Figure 1), which (apart from proteins) are the essential biopolymers responsible for life’s biochemistry. We wrap up the review with a cautionary note in this context about coming to conclusions as to whether the problem of chemistry of prebiotic nucleotide synthesis has been solved.
The review will emphasize that there are-and will continue to be-many more questions than answers from the synthetic, mechanistic, and analytical perspectives. We start with a brief primer on the biological synthesis of nucleotides, followed by an extensive focus on the prebiotic formation of the components of nucleotides-either via the synthesis of ribose and the canonical nucleobases and then joining them together or by building both the conjoined sugar and nucleobase, part-by-part-toward the ultimate goal of forming RNA and DNA by polymerization. How did (or how can) the nucleotides form and assemble from the small molecule inventories and under conditions that prevailed on early earth 3.5–4 billion years ago? This review provides a background and up-to-date progress that will allow the reader to judge where the field stands currently and what remains to be achieved. The chemistry of abiotic nucleotide synthesis of RNA and DNA in the context of their prebiotic origins on early earth is a continuing challenge.
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