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

10 October 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


prebiotic chemistry
origin of life

Supplementary materials

Supporting Information
Materials and Methods, Supplementary Text, Figs. S1 to S89, Tables S1 to S70 (PDF).


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.