Advances in electrochemical cofactor regeneration: enzymatic and non-enzymatic approaches

Nicotinamide adenine dinucleotide(NAD(P)H) is a metabolically interconnected redox cofactor serving as a hydride source for the majority of oxidoreductases, and consequently constituting a significant cost factor for bioprocessing. Much research has been devoted to the development of efficient, affordable, and sustainable methods for the regeneration of these cofactors through chemical, electrochemical, and photochemical approaches. However, the enzymatic approach using formate dehydrogenase is still the most abundantly employed in industrial applications, even though it suffers from system complexity and product purity issues. In this review, we summarize non-enzymatic and enzymatic electrochemical approaches for cofactor regeneration, then discuss recent developments to solve major issues. Issues discussed include Rh-catalyst mediated enzyme mutual inactivation, electron-transfer rates, catalyst sustainability, product selectivity and simplifying product purification. Recently reported remedies are discussed, such as heterogeneous metal catalysts generating H⁺ as the sole byproduct or high activity and stability redox-polymer immobilized enzymatic systems for sustainable organic synthesis.