Expanding the synthetic toolbox of ruthenium-based artificial metalloenzymes (Ru-ArMs)

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Although enzymes are characterized by their exquisite catalytic performance, thus enabling nearly all vital chemical transformations in organisms, the number of manageable reactions is limited to processes that have emerged during natural evolution. Artificial Metalloenzymes (ArMs) are hybrids of proteins that contain an abiotic cofactor, metal complexes which do not occur in nature. Building on preliminary works by Whitesides and Kaiser from the late 1970’s, ArMs have gained significant attention again in the past years, due to breakthroughs in recombinant protein production, an abundance of versatile organometallic cofactors, as well as an increased appreciation of the potential benefits of combining the attractive features of both homogeneous and enzymatic catalysis.This technology combines classical synthetic chemistry with biotechnology. To optimize ArMs for the respective application, the cofactors will be modified synthetically, while the protein host can be tuned by directed evolution. Both targeted synthetic variations and random mutagenesis can be used to optimize ArMs for reactions that nature itself can not provide.In this project, a library of ruthenium-based ArMs (Ru-ArMs) shall be prepared and screened for catalytic properties in enyne transformations, diyne cylizations as well as isomerization reactions of allylic and propargylic alcohols. Ruthenium-based cofactors proved to be very versatile, robust, have already been applied in the periplasm and cytoplasm of cells and thus provide great prospects for the success of the proposed project. We will try to expand the currently narrow field of application of Ru-ArMs for in vivo applications, i.e. in living organisms such as E. coli (coliform bacterium), and thus create chemical reactivities that are not found in nature. Ru-ArMs will be optimized for the respective application both by synthetic modification as well as mutagenesis of the protein host.Previous progress made in the field and projects such as the here proposed research plan could build the foundation for novel biochemical/medicinal applications such as the in situ formation of biologically active agents exactly and only in (cancer) cells where they are needed, thus not affecting undamaged tissue. Furthermore, the ArMs technology bears the potential of producing commodity chemicals from renewable feedstocks and might contribute to the inevitable transition of our petroleum-based economy towards sustainable production pathways.