Double-cubane iron-sulfur clusters: a new cofactor in biology

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Anaerobic bacteria employ complex metalloenzymes based on iron-sulfur clusters to convert gaseous substrates. Several of the catalyzed reactions are reductions attractive for energy conversion and conservation, among them the reduction of protons to dihydrogen and of carbon dioxide to carbon monoxide. When the reducing power of physiological electrons are not enough the achieve these conversions, electron may be energized beyond the physiological window by coupling ATP-hydrolysis to electron transfer against a redox potential gradient. The electron-accepting proteins typically contain unusual iron-sulfur clusters at which the catalytic reactions occur.Within this project I want to investigate the occurrence and function of a novel cofactor associated with ATP-driven electron transfer. The cofactor is formed by bridging two [Fe4S4]-clusters by a sulfide-ligand, forming an [Fe8S9]-cluster. This [Fe8S9]-cluster has been detected by us in an enzyme capable of reducing acetylene and hydrazine. However, based on sequence comparison and a conserved cluster-binding motif, we speculate that the [Fe8S9]-cluster is wide-spread in nature and occurs in at least three different classes of enzymes. Within this project, I want (I) to produce and study members of all three classes potentially containing the [Fe8S9]-cluster, to see if there are indeed three enzymes classes of distinct structure carrying the novel cofactor. (II) I want to reveal the potential physiological role(s) of the cofactor by studying its reactivity and the substrate binding selectivity of the associated protein matrizes. Characterizing a novel iron-sulfur cluster and novel enzymes, requires input from different expertise ranging from physiological assays to the biophysical characterization of iron-sulfur proteins and is therefore attempted within the priority program "Iron-Sulfur for Life". In a side project, I want to continue a joint approach within the same priority program in which we combine vibrational spectroscopy and X-ray crystallography at single crystals to gain further insights into the mechanism of reversible hydrogen cycling of a [NiFe]-containing hydrogenase.