Enzymatic reduction of nitro compounds to amines with nitroreductases
Park, Jonathan Taejoo
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NRs are enzymes that catalyze the reduction of nitroaromatics to their corresponding nitroso, hydroxylamine, and, in limited cases, amine They have gathered interest in many scientific communities, and are currently actively researched bioremediation and prodrug activation. Here we attempt to utilize them for the purpose of synthesizing substituted aromatic amines that are found in a number of active pharmaceutical ingredients (APIs). As NRs described in the literature have varying product distribution ranges (from those that produce hydroxylamine to others that yield amine) several similar and different NRs were studied for their selectivity. Additionally, a quantitative structure-activity relationship (QSAR) was determined to characterize the substrate specificity of NRs. To employ the use of flavoenzymes in synthesis, multiple reaction- and protein-engineering approaches were devised. One scheme was to establish an enzymo-chemical synthesis where NRs were paired with reducing agents for a chemical reduction. Another method was to create a monomeric NR through directed evolution from ER scaffolds for future immobilization applications. Protein engineering techniques were also utilized on NADH oxidases which we characterized and developed for nicotinamide cofactor regeneration. As a whole, this dissertation expands our current understanding on NRs and demonstrates the possibility of using several flavoenzymes in the synthesis of organic molecules.