Two rare but usually fatal diseases are caused by a failure at different levels of the multistep biosynthetic generation of the three human molybdenum dependent enzymes involved in metabolic processes. In contrast to the more general Moco deficiency (MocoD) affecting all three enzymes, isolated sulfite oxidase deficiency (iSOD) cannot be treated yet. The proposed project is primarily aimed at synthesising a large variety of molybdenum complexes that mimic the natural molybdenum cofactor of the respective enzymes. These compounds will be prepared with a focus on distinct aspects of the biomolecules (first coordination sphere, different functional groups of the complex molybdopterin ligand, hydrogen bonding sites); their stability and ability to catalyse oxygen atom transfer (in particular the oxidation of sulfite) will be assessed and their suitability to bind in the active site pocket of the protein and restore activity will be tested. In addition alternative metals will be investigated with respect to possible benefits regarding stability and activity.
The ultimate aim is to combine all the different synthetic approaches and information about properties to build a compound containing all indispensable functional groups while being stable, active and made with the least possible effort. Consequently this project addresses the human iSOD by developing synthetic structural models for the molybdenum cofactor active site of sulfite oxidase, testing their potential for incorporation into the biotechnologically generated apo-enzyme and evaluating the activity of the resulting semi-synthetic enzymes thereby assessing their suitability as future iSOD treatments. This work will have impact on the way iSOD and MocoD patients will be treated in the future and deepen the understanding of fundamentally important chemical, structural and catalytic aspects of the Moco dependent enzymes.
Fields of science
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Funding SchemeERC-SG - ERC Starting Grant