Enzyme Design of Medical Interest

Enzymes are the most efficient, specific and selective catalysts known up to date. Despite the enzyme advantages, not all synthetic processes present a natural enzyme to catalyze and accelerate the reactions. Hence, the design of new stable enzymes for those processes where no biocatalyst is known represents a major challenge for protein engineering and a stringent test to understand how natural enzymes work. In addition to that, the ability of designing specific active enzymes is of great interest due to the potential applications in biotechnology, biomedicine and industrial processes. In this proposal, the design of three enzymes of biological/medical interest will be fulfilled. First, an enzyme to reverse the formation of Advanced Glycation End-Products (AGEs), mainly associated to diabetes-related disorders, but also to Alzheimer’s disease will be designed. Second, the design of an enzyme presenting Glucose-6-Phosphate Dehydrogenase (G6PD) activity will be pursued. The latter might avoid the oxidative stress induced by many drugs in G6PD-deficient persons. Finally, the third objective of this proposal is the design of an enzyme with superoxide dismutase activity to avoid the oxidative stress produced in most of neurodegenerative diseases (i.e. Alzheimer’s, Parkinson’s, Huntington’s disorders). All designs will be performed following the research methodology developed by the Prof. Houk group which was already successfully applied for the design of active Kemp elimination and retro-aldolase enzymes. However, new QM/MM-MD strategies and DFT functionals developed at the return host organization (IQC) will be introduced to improve some parts of the design process. The fellow researcher will have the chance to work on this pioneer project in a world leading research group and to transfer this knowledge to one of the best EU research institutes.