L-DOPA is currently the gold standard of pharmacological interventions in the treatment of Parkinson's disease. The drug is a precursor of dopamine. Its use is associated with oxidative stress because at elevated pH levels, dopamine autoxidizes to form reactive oxygen species. L-DOPA is also capable of autoxidation where reactive oxygen species are formed. The drug can be incorporated into proteins due to its structural similarity to aromatic amino acids. It has not yet been known whether the autoxidation of L-DOPA can take place within a protein environment. This MSc thesis was designed to understand the autoxidation of L-DOPA at the molecular level. The rate-limiting step in the autoxidation of L-DOPA is the cyclisation of the dopaquinone, which proceeds by a Michael addition mechanism with proton transfer. We were interested in whether the reaction can take place within a protein environment. We have carried out the investigation at the quantum chemical level of theory using the cluster model method. We have chosen dopaquinone for the reaction which is incorporated into the active site of monoamine oxidase B reacting with OH-. We have obtained the activation free energy and the reaction free energy, which are 19,35 kcal/mol and -13,65 kcal/mol respectively, at a pH of 7,4 and 37°C. From the activation free energy of the reaction, we also calculated the rate constant and the half-life of the reaction, which are 0,16 s-1 and 4,33 s respectively. The reaction rate is pH dependent. We found that L-DOPA incorporated in proteins enters intermolecular Michael addition with proton transfer, which is mechanistically equivalent to the corresponding reaction in aqueous solution.
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