A Direct Prebiotic Synthesis of Nicotinamide Nucleotide

The “RNA World” hypothesis proposes an early episode of the natural history of Earth, where RNA was used as the only genetically encoded molecule to catalyze steps in its metabolism. This, according to the hypothesis, included RNA catalysts that used RNA cofactors. However, the RNA World hypothesis places special demands on prebiotic chemistry, which must now deliver not only four ribonucleosides, but also must deliver the “functional” portion of these RNA cofactors. While some (e.g., methionine) present no particular challenges, nicotinamide ribose is special. Essential to its role in biological oxidations and reductions, its glycosidic bond that holds a positively charged heterocycle is especially unstable with respect to cleavage. Nevertheless, we are able to report here a prebiotic synthesis of phosphorylated nicotinamide ribose under conditions that also conveniently lead to the adenosine phosphate components of this and other RNA cofactors. Nicotinamide nucleotide, the functional portion of RNA cofactor nicotinamide adenine dinucleotide (NAD+), is produced from the reaction of ribose 1,2‐cyclic phosphate and nicotinamide in prebiotic conditions that also yield adenylic acid, the structural part of NAD+ and also the subunit of RNA. These results illustrate how prebiotic chemical reactions that target genetic molecules can also be relevant to early metabolic processes.