Metal Ions Turn on a Stereoselective Nonenzymatic Reduction of Keto Acids by the Coenzyme NADH

The relationship between genetic molecules and metabolism is one of the longest standing problems for the origin of life. A central molecule within early metabolism is the coenzyme nicotinamide adenine dinucleotide (NAD(H)), a modified ribonucleotide and reducing agent. Yet, without enzymes, NADH does not reduce carbonyl compounds, its primary metabolic substrates, leading to an apparent paradox regarding its role in the evolution of metabolism. We now report that abundant metal ions turn on a nonenzymatic, stereoselective, and potentially primordial reduction reaction of keto acids by NADH. Kinetic, mechanistic, and computational studies elucidate the reaction mechanism and the way stereochemistry is transferred. Complexes of metals with RNA-derived coenzymes could have mediated the transition from inorganic to organic reducing agents and the propagation of chirality in early metabolism.