Heinisch, Max Tillmann. Structure-based design of artificial metalloenzymes and beyond. 2013, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10521
Human carbonic anhydrase II is a well-characterized monomeric protein and numerous arylsulfonamide inhibitors with nanomolar and subnanomolar affinities for this enzyme are described in the literature. The potential of this protein to act as a host for the creation of an artificial transfer hydrogenase is evaluated by the structural characterization of an arylsulfonamide-tethered transition metal piano stool complex bound to human carbonic anhydrase II. This study is also investigating the structural origins of the high affinities of piano stool arylsulfonamide complexes for human carbonic anhydrase II and the implications for future metallodrug design.
A number of ruthenium-arene piano stool complexes have been demonstrated to strongly inhibit the growth of human cancer cell lines by unspecific interactions with nucleobases. To introduce DNA-specificity via second coordination sphere interactions, two ruthenium arene complexes have been biotinylated and bound to streptavidin. The structural basis of the DNA-specificity governed by the streptavidin-ruthenium arene complex is investigated.
The in vivo activity of artificial metalloenzymes is a prerequisite for their genetic optimization by directed evolution. Moreover, hybrid enzymes have the potential to be used in vivo to complement metabolic pathways or to act as bioorthogonal catalyst in the activation of prodrugs. The strategy of enzyme-encapsulation into cell-penetrating nanoreactors is investigated which allows the shuttling of artificial metalloenzymes into cells.
|Advisors:||Ward, Thomas R.|
|Committee Members:||Schirmer, Tilman|
|Faculties and Departments:||05 Faculty of Science > Departement Chemie > Chemie > Bioanorganische Chemie (Ward)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||168 S.|
|Last Modified:||30 Jun 2016 10:53|
|Deposited On:||04 Oct 2013 14:45|
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