NADH-mediated primordial synthesis of amino acids

Abstract

The pathways that could explain the abiotic synthesis of amino acids are different from those observed in living organisms, which leaves a gap of knowledge between bottom-up approaches towards the understanding of abiogenesis and studies on the emergence and evolution of metabolism. Finding non-enzymatic versions of current key metabolic reactions represents a powerful strategy to fill such a gap, and the use of natural cofactors can be useful to aid that chemistry in the absence of enzymes. In this direction, herein we describe how NADH mediates the reductive amination of α-ketoacids in the presence of ammonia, allowing the production of various amino acids. The reaction occurs at room temperature in ammonium/ammonia solutions at pH > 7, conditions that are compatible with some plausible scenarios on the prebiotic Earth. A combination of NMR and mass spectrometry data with computational calculations supports that the reaction proceeds through a hemiaminal intermediate, which subsequently gets dehydrated into the iminium species. This allows for the overcoming of the low reactivity of NADH as a hydride donor to the carbonyl group of α-ketoacids, while the cofactor loses the nicotinamide ring during the process. Overall, these results demonstrate that NADH can assist in the production of amino acids through a route that was postulated as primordial by the chemoautotrophic theory, thus providing a link of continuity with the chemistry of these important building blocks in ancient protometabolism.