Prebiotic Synthesis of α-Amino Acids and Orotate from α-Ketoacids Potentiates Transition to Extant Metabolic Pathways

Abstract The Strecker reaction of aldehydes is the preeminent pathway to explain the prebiotic origins of a-amino acids. However, biology employs transamination of a-ketoacids to give rise to amino acids which are then transformed to nucleobases, implying subsequent evolution of the biosynthetic pathways – abiotically or biotically. Herein, we show that a-ketoacids react with cyanide and ammonia sources to form the corresponding a-amino acids – via 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 analogs 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.