Unusual structures and unknown roles of FeS clusters in metalloenzymes seen from a resonance Raman spectroscopic perspective

The universe of known biological FeS clusters is constantly enlarging. Besides the conventional, well described [2Fe–2S], [3Fe–4S] and cubane [4Fe–4S] clusters, novel, unprecedented structures are emerging. They include unusually coordinated clusters, with additional sulfur atoms, e.g., [4Fe–5S], [5Fe–5S], [4Fe–4S]-5S-[4Fe–4S], [8Fe–7S], [8Fe–9S] and [8Fe–8S–C] and heteronuclear clusters, e.g., [Ni–4Fe–4S], [2Ni–4Fe–4S], [4Fe–4S]-[2Ru], [Me–7Fe–9S–C–(homocitrate)] that undertake versatile physiological roles in the activation of small molecules (H₂, CO₂, CO and N₂) and in the sulfuration of different compounds (e.g., t-RNAs, biotin and lipoic acid) in biology. A few structures are characterized by highly distorted geometries, e.g., the non-cubane [4Fe–4S] center and the hydrogenase-related [4Fe–3S] cluster, and contain atypical ligations or vacant coordination sites, which confer them novel functions far from the common electron transfer. Herein, we single out clusters found in i) hydrogenases that ensure sustainable hydrogen cycling, promising a clean fuel production in the future, ii) radical-SAM enzymes that can inspire applied catalysis due to an intrinsic flexibility of the radical chemistry, and iii) standard [4Fe–4S] cluster with still unknown function in DNA repair enzymes, which offer a possibility to interfere with DNA repair in pathogens or improve it in humans. Focusing on the abovementioned enzymes, we demonstrate the unique power of resonance Raman spectroscopy to unveil remarkable features in FeS centers, which has contributed to our understanding of unusual structures and disentangling of unknown functions.