Reactivity of [Fe₄S₄] Clusters toward C1 Substrates: Mechanism, Implications, and Potential Applications

FeS proteins are metalloproteins prevalent in the metabolic pathways of most organisms, playing key roles in a wide range of essential cellular processes. A member of this protein family, the Fe protein of nitrogenase, is a homodimer that contains a redox-active [Fe₄S₄] cluster at the subunit interface and an ATP-binding site within each subunit. During catalysis, the Fe protein serves as the obligate electron donor for its catalytic partner, transferring electrons concomitant with ATP hydrolysis to the cofactor site of the catalytic component to enable substrate reduction. The effectiveness of Fe protein in electron transfer is reflected by the unique reactivity of nitrogenase toward small-molecule substrates. Most notably, nitrogenase is capable of catalyzing the ambient reduction of N₂ and CO into NH₄⁺ and hydrocarbons, respectively, in reactions that parallel the important industrial Haber-Bosch and Fischer-Tropsch processes. Other than participating in nitrogenase catalysis, the Fe protein also functions as an essential factor in nitrogenase assembly, which again highlights its capacity as an effective, ATP-dependent electron donor. Recently, the Fe protein of a soil bacterium, Azotobacter vinelandii, was shown to act as a reductase on its own and catalyze the ambient conversion of CO₂ to CO at its [Fe₄S₄] cluster either under in vitro conditions when a strong reductant is supplied or under in vivo conditions through the action of an unknown electron donor(s) in the cell. Subsequently, the Fe protein of a mesophilic methanogenic organism, Methanosarcina acetivorans, was shown to catalyze the in vitro reduction of CO₂ and CO into hydrocarbons under ambient conditions, illustrating an impact of protein scaffold on the redox properties of the [Fe₄S₄] cluster and the reactivity of the cluster toward C1 substrates. This reactivity was further traced to the [Fe₄S₄] cluster itself, as a synthetic [Fe₄S₄] compound was shown to catalyze the reduction of CO₂ and CO to hydrocarbons in solutions in the presence of a strong reductant. Together, these observations pointed to an inherent ability of the [Fe₄S₄] clusters and, possibly, the FeS clusters in general to catalyze C1-substrate reduction. Theoretical calculations have led to the proposal of a plausible reaction pathway that involves the formation of hydrocarbons via aldehyde-like intermediates, providing an important framework for further mechanistic investigations of FeS-based activation and reduction of C1 substrates. In this Account, we summarize the recent work leading to the discovery of C1-substrate reduction by protein-bound and free [Fe₄S₄] clusters as well as the current mechanistic understanding of this FeS-based reactivity. In addition, we briefly discuss the evolutionary implications of this discovery and potential applications that could be developed to enable FeS-based strategies for the ambient recycling of unwanted C1 waste into useful chemical commodities.