Prebiotic synthesis of α-amino acids and orotate from α-ketoacids potentiates transition to extant metabolic pathways

The Strecker reaction of aldehydes is the pre-eminent pathway to explain the prebiotic origins of α-amino acids. However, biology employs transamination of α-ketoacids to synthesize amino acids which are then transformed to nucleobases, implying an evolutionary switch—abiotically or biotically—of a prebiotic pathway involving the Strecker reaction into today’s biosynthetic pathways. Here we show that α-ketoacids react with cyanide and ammonia sources to form the corresponding α-amino acids through the Bucherer–Bergs pathway. An efficient prebiotic transformation of oxaloacetate to aspartate via N-carbamoyl aspartate enables the simultaneous formation of dihydroorotate, paralleling the biochemical synthesis of orotate as the precursor to pyrimidine nucleobases. Glyoxylate forms both glycine and orotate and reacts with malonate and urea to form aspartate and dihydroorotate. These results, along with the previously demonstrated protometabolic analogues of the Krebs cycle, suggest that there can be a natural emergence of congruent forerunners of biological pathways with the potential for seamless transition from prebiotic chemistry to modern metabolism. The apparent disconnect between prebiotic aldehyde-based Strecker synthesis of amino acids and the α-ketoacid-based metabolism of extant biochemistry necessitates an evolutionary switch between these disparate chemistries. Now it has been shown that Bucherer–Bergs reactions of α-ketoacids produce α-amino acids and dihydroorotate, paralleling the biochemical synthesis of orotate and suggesting a more congruent evolutionary pathway from cyanide-based chemistries.