Sulfido dithiolene complexes modeling molybdenum and tungsten dependent oxiodreductases - investigating synthesis, catalysis and biological activity to elucidate structural uncertainties, structure-function relationships and biosynthesis

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Iron-sulfur cluster are critically important for the biosynthesis and function of essential molybdenum and tungsten oxidoreductases. Crucial aspects will be investigated of the maturation and catalytic activity of molybdenum and tungsten co-factors, being directly dependent on FeS cluster proteins (keyword: crosstalk). A better understanding of the respective enzymes and their synergy shall be facilitated by chemical model syntheses, spectroscopic characterization, catalytic and kinetic evaluation and the biological interaction with proteins (chaperones/apo-enzymes). Important issues specifically concern the role of the sulfido ligand in the Mo and W active sites, which is introduced/transferred in vivo by IscS. Sulfido coordination and its function for the enzymes’ reactivity in particular, will be chemically studied on model compounds. The catalytic mechanisms will be elucidated and all analytical results used to competently discriminate between actual and artefactual presence of this sulfido ligand in the active sites of respective enzymes (in some of which its presence being not unambiguously clear). Isotopically labelling the sulfido ligand in model complexes selectively will further the respective required insight. Highly developed ligand systems, having recently been shown to induce binding to natural proteins, will have significant impact in this context and further the understanding of cellular processes; in particular of sulfur transfer and insertion, which is specifically relevant for the dithiolene-derived molybdopterin (MPT) ligands and sulfido coordination. Sophisticated mono-oxido bis-dithiolene complexes of molybdenum (and tungsten), mimicking various aspects of natural MPT, shall be modified by exchanging sulfido (=S) for oxido (=O) ligation for which the application of bis-carbonyl precursors was established as the most feasible procedure. Electrochemical oxidation and the concomitant presence of SH– ions will be investigated for the synthesis of MVIOS species. The synthesis of azide dithiolene molybdenum complexes constitutes another important aim. Such complexes are needed for elucidating the inhibition of Mo-dependent E. coli formate dehydrogenase (FDH) by comparison of enzymatic and model complex spectroscopic data. Being isoelectronic to the enzymatic product CO2, azide binding to protein will serve the understanding of FDH’s reaction mechanism, which again has implications for CO2 chemistry. Comprehensively characterising all synthesised complexes spectroscopically, studying their catalytic potential and the kinetics of such reactions plus investigating their biological activity will provide intimate insight into nature’s strategies to foster reactivity and concomitant stability. The biological activity will be assessed by investigating specific binding to proteins, which participate in molybdenum or tungsten cofactor maturation, as well as to apoenzymes and the catalytic activity of respective semi-synthetic enzymes.