Coordination Funds

• Applicant: Professorin Dr. Silke Leimkühler
• Subject Area: Biochemistry
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 310614238

Iron-sulfur (FeS) centers are essential protein cofactors in all forms of life. They are involved in many of the key biological processes including respiration, photosynthesis, metabolism of nitrogen, sulfur, carbon and hydrogen, biosynthesis of antibiotics, gene regulation, protein translation, replication and DNA repair, protection from oxidizing agents, and neurotransmission. In particular, FeS centers are not only involved as enzyme cofactors in catalysis and electron transfer, but they are also indispensable for the biosynthesis of complex metal-containing cofactors. A prominent example is represented by the family of radical/S-adenosylmethionine-dependent enzymes, which were discovered in 2001. Members of this family play essential roles in the biosynthesis of metal centers as complex as the iron-molybdenum cofactor (FeMoco) of nitrogenase, the molybdenum cofactor (Moco) of various molybdoenzymes, the active sites of [Fe-Fe]- and [Fe]-hydrogenases and the tetrapyrrole cofactors of hemes, corrins and chlorins. In spite of the recent fundamental breakthroughs in metalloenzyme research, it has become evident that studies on single enzymes have to be transformed into the broader context of a living cell where biosynthesis, function, and disassembly of these fascinating metal cofactors are coupled in a dynamic fashion. The various biosynthetic pathways were found to be tightly interconnected through a complex crosstalk mechanism that involves the dependence on the bio-availability of distinct metal ions, in particular molybdenum, iron, tungsten and nickel. The current lack of knowledge of such interaction networks is due to the sheer complexity of the metal cofactor biosynthesis with regard to both the (genetic) regulation and (chemical) metal center assembly. Recent pioneering technical developments allowed the detailed investigation of the assembly, biosynthesis and catalysis of FeS-dependent enzymes in a cellular context, opening up a new era in studying metalloenzymes. Such studies are not only important for understanding fundamental cellular processes but they are also a prerequisite for providing a comprehensive view of the complex biosynthesis and the catalytic mechanism of metalloenzymes that underlie metal-related human diseases. These key features of metalloenzymes can only be implemented in a cellular context. Understanding the crosstalk of metal ions on a cellular basis requires multidisciplinary cooperative approaches that span the entire range from molecular biology, inorganic chemistry, biochemistry, cell biology, and structural biology to theory and spectroscopy. In the SPP it is planned to study novel enzyme mechanisms, innovative model complexes, and new biogenesis pathways in the physiological context of metalloenzymes in living organisms.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1927: Iron-Sulfur for Life