All-in-One CO₂ Capture and Transformation: Lessons from Formylmethanofuran Dehydrogenases

Carbon-one-unit (C1) feedstocks are generally used in the chemical synthesis of organic molecules, such as solvents, drugs, polymers, and fuels. Contrary to the dangerous and polluting carbon monoxide mostly coming from fossil fuels, formate and formamide are attractive alternative feedstocks for chemical synthesis. As these are currently mainly obtained from the oil industry, novel synthetic routes have been developed based on the transformation of the greenhouse gas CO₂. Such developments are motivated by the urgent need for carbon chemical recycling, leading to a sustainable future. The inert nature of CO₂ represents a challenge for chemists to activate and specifically convert the molecule through an affordable and efficient process. The chemical transformation could be inspired by biological CO₂ activation, in which highly specialized enzymes perform atmospheric CO₂ fixation through relatively abundant metal catalysts. In this Account, we describe and discuss the potential of one of the most efficient biological CO₂-converting systems: the formylmethanofuran dehydrogenase (abbreviated as FMD).FMDs are multienzymatic complexes found in archaea that capture CO₂ as a formyl group branched on the amine moiety of the methanofuran (MFR) cofactor. This overall reaction leading to formyl-MFR production does not require ATP hydrolysis as compared to the CO₂-fixing microbes relying on the reductive Wood-Ljungdahl pathway, highlighting a different operative mode that saves cellular energy. FMD reaction represents the entry point in hydrogenotrophic methanogenesis (H₂ and CO₂ dependent or formate dependent) and operates in reverse in other methanogenic pathways and microbial metabolisms. Therefore, FMD is a key enzyme in the planetary carbon cycle. After decades of investigations, recent studies have provided a description of the FMD structure, reaction mechanism, and potential for the electroreduction of CO₂, to which our laboratory has been actively contributing. FMD is an "all-in-one" enzyme catalyzing a redox-active transformation coupled to a redox-neutral transformation at two very different metal cofactors where new C-H and C-N bonds are made. First, the principle of the overall reaction consisting of an exergonic CO₂ reduction coupled with an endergonic formate condensation on MFR is resumed. Then, this Account exposes the molecular details of the active sites and provides an overview of each catalytic mechanism. It also describes the natural versatility of electron-delivery modules fueling CO₂ reduction and extends it to the possibilities of using artificial systems such as electrodes. A perspective concludes on how the mechanistic of FMD could be applied to produce CO₂-based chemical intermediates to synthesize organic molecules. Indeed, through its biochemical properties, the enzyme opens opportunities for CO₂ electroreduction to generate molecules such as formate and formamide derivatives, which are all intermediates for synthesizing organic compounds. Transferring the chemical knowledge acquired from these biological systems would provide coherent models that can lead to further development in the field of synthetic biology and bio-inspired synthetic chemistry to perform large-scale CO₂ conversion into building blocks for chemical synthesis.