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Diversity of asymmetric thiamine catalysis


Thiamine diphosphate (ThDP)-dependent enzymes catalyze a broad range of reactions, many still to be discovered, especially if non-physiological. The central aim of the proposed Research Unit is to identify and introduce into practice new enzyme-catalyzed transformations through a fundamental understanding of the “Diversity of asymmetric thiamine catalysis”. In particular it should be defined which conditions are essential within the enzyme to enable one cofator to catalyze many diverse reactions. Of particular interest here is the carboligating potential of ThDP-dependent enzymes for the asymmetric synthesis of chiral products yielding pharmaceutically interesting compounds. C-C bond forming reactions require a particular environment within the enzyme with well defined donor or acceptor molecules that need to be positioned appropriately.

The analysis of sequence, structure and function of twelve specifically chosen enzymes, belonging to different families of ThDP- dependent enzymes, will allow the identification and modulation of the structure,function relationships. In this manner, superior parameters such as improved substrate specificity and stereoselectivity can be defined and implemented. Subsequently, the directed design of new biocatalysts could pave the way for new asymmetric syntheses which are currently not yet feasible.

A thorough understanding of the structure-function relationship of ThDP-dependent enzymes is also significant for non-enzymatic catalysis and for theoreticla considerations. New strategies in biomimetic organocatalysis could be developed to mimick the cofactor ThDP that has evolved in nature to catalyze a broad range of reactions. General parameters that stabilize intermediates in the enzyme or play a role in the activation of substrates can influence the development of optimized heterazolium catalysts. Likewise, potential transfer of N-heterocyclic carbene (NHC)-catalyzed new reactions to enzymatic reactions is envisioned.



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