Reduction of NAD and NMN on mineral surfaces with H2 reveals a functional role for the AMP moiety in a prebiotic context

Many cofactors share a molecular structure – adenosine monophosphate (AMP) – that otherwise occurs in nucleic acids. The presence of AMP in cofactors has presented an evolutionary puzzle. Is it a biochemical ‘handle’ that allows proteins to bind the cofactor more tightly, or a relic from a prebiotic time when cofactors arose? Using the example of nicotinamide adenine dinucleotide (NAD), we find a previously unknown property of its AMP handle. Experiments with hydrogen gas on mineral surfaces show that the handle-free nicotinamide mononucleotide (NMN) overreduces quickly, while NAD gets reduced specifically. The handle allows NAD to function in a hydrothermal, mineral-based setting, indicating that it is a form of protection against a harsh environment. Our findings uncover a specific functional role for the AMP moiety of NAD under environmental conditions capable of non-enzymatic NAD reduction, thereby identifying a structural element of a redox cofactor that is older than the enzymes using it.