The challenges of using NAD⁺-dependent formate dehydrogenases for CO₂ conversion

In recent years, CO₂ reduction and utilization have been proposed as an innovative solution for global warming and the ever-growing energy and raw material demands. In contrast to various classical methods, including chemical, electrochemical, and photochemical methods, enzymatic methods offer a green and sustainable option for CO₂ conversion. In addition, enzymatic hydrogenation of CO₂ into platform chemicals could be used to produce economically useful hydrogen storage materials, making it a win-win strategy. The thermodynamic and kinetic stability of the CO₂ molecule makes its utilization a challenging task. However, Nicotine adenine dinucleotide (NAD⁺)-dependent formate dehydrogenases (FDHs), which have high selectivity and specificity, are attractive catalysts to overcome this issue and convert CO₂ into fuels and renewable chemicals. It is necessary to improve the stability, cofactor necessity, and CO₂ conversion efficiency of these enzymes, such as by combining them with appropriate hybrid systems. However, metal-independent, NAD⁺-dependent FDHs, and their CO₂ reduction activity have received limited attention to date. This review outlines the CO₂ reduction ability of these enzymes as well as their properties, reaction mechanisms, immobilization strategies, and integration with electrochemical and photochemical systems for the production of formic acid or formate. The biotechnological applications of FDH, future perspectives, barriers to CO₂ reduction with FDH, and aspects that must be further developed are briefly summarized. We propose that constructing hybrid systems that include NAD⁺-dependent FDHs is a promising approach to convert CO₂ and strengthen the sustainable carbon bio-economy.