Electrochemical Structure-Reactivity Relationships in NAD+ Mimetics: Towards Recyclable Cofactors for Protein-Catalyzed Reactions

Abstract

The chemical engineering industry relies increasingly on enzyme-catalyzed reactions in the production of fine chemicals, value-added compounds, and commodity chemicals. However, many attractive transformations, such as the selective reduction of ketones and alkenes, depend on cofactors that are prohibitively expensive for application on an industrial scale. One such cofactor, nicotinamide adenine dinucleotide (NAD+/NADH), is utilized by >20% of all enzymes but is required in generally super-stoichiometric amounts and currently has no efficient means for recycling. Direct electrochemical reduction of NAD+ is an attractive approach for regeneration of the biological cofactor; however, electrolysis often results in relatively small amounts of biologically active NADH due to a parasitic dimerization. Recent work has demonstrated the ability of lower-cost NADH mimetics to exhibit enzymatic activity, sometimes exceeding that of NADH itself, although still required in at least stoichiometric amounts. Subsequently, we considered the possibility of designing NADH biomimetics to simultaneously maintain enzymatic activity and minimize deleterious side reactions, thereby allowing them to be electrochemically recycled. We will describe our recent progress in both measuring and modeling the electrochemical dimerization and regeneration rates of NADH mimetics. We have employed Electrochemical Impedance Spectroscopy to quantify rapid dimerization rates observed for electrochemically reduced NADH biomimetics. By combining this electroanalytical approach with density functional theory (DFT) modeling and machine learning algorithms, we are elucidating structure-function relationships to design more efficiently regenerable mimetics.