Deciphering the function of Fe/S cofactors with alternative cluster ligands: model studies using synthetic analogues

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Iron-sulfur (Fe/S) clusters are among the most widespread and ancient biological cofactors, occurring in virtually all domains of life. Their most prominent role is electron transfer (ET) in diverse pathway, and a range of Fe/S clusters of different nuclearity is available for that task. They mostly contain a sulfide-bridged iron cluster core that is ligated by terminal cysteine (Cys) thiolates from the protein. Chemically synthesized analogues of the active sites of Fe/S proteins have contributed significantly to our understanding of the electronic structures and intrinsic properties of the biological cofactors. In recent years, an increasing number of proteins containing Fe/S clusters with non-cysteine ligands, called alternative cluster ligands, is being discovered. This goes along with a rapidly increasing number of functions beyond electron transfer that are recognized for biological Fe/S cofactors, including their involvement in sensing of small molecules such as NO, DNA repair, radical reactions and catalysis.Continuing along the lines of the first SPP funding period and building upon the results achieved so far, this projects ultimately aims at deciphering the function of Fe/S cofactors with alternative cluster ligands in a synthetic analogue approach. Specific objectives are: (A) Elucidating intrinsic trends for the thermodynamic and kinetic parameters of proton coupled electron transfer (PCET) reactions at Fe/S clusters, mainly [2Fe-2S] clusters with His-like terminal ligands, to demonstrate a potential PCET role of His-ligation beyond the Rieske centers. (B) Unravelling intrinsic ligand rearrangement and exchange processes at specifically designed [2Fe-2S] clusters, which is relevant for understanding ligand exchange during biological Fe/S cluster maturation and transfer; specifically, the generation of [2Fe-2S] units and larger fragments from the polymeric structure of solid thioferrates (MFeS2) will be investigated. (C) Characterizing the species that form upon reaction of mixed S/N ligated [2Fe-2S] clusters with nitric oxide in order to enlighten the effect of cluster oxidation state and His protonation state on NO reactivity pathways, and on potential crosstalk between NO, H2S and other small signaling molecules. (D) Emulating radical reactivity at auxiliary Fe/S cofactors in radical SAM enzymes and elucidating factors that control sulfur donation from the Fe/S cluster to a substrate, as seen in biotin synthase (BioB) or lipoyl synthase (LipA). (E) Providing suitable chemically synthesized Fe/S model systems, which serve as benchmark systems for new spectroscopic or analytical methods, for other groups in the SPP network. In particular, synthetic strategies will be pursued towards a first Fe/S cluster that contains a carbide (C) or carbyne unit (CR) within the cluster core.