Unlocking New Chemistries in Extant Enzymes for Synthesizing Bioactive Molecules

Project Summary/Abstract: Enzymes, supported by their macromolecular structure, can catalyze chemical transformations with exquisite control, delivering products with high selectivity. The mechanisms that enzymes can support, however, are limited, making chemical technologies often the preferred method for synthesis, regardless of cost, toxicity, and environmental burden. Herein are two proposals to expand the activity of enzymes beyond their natural function for synthesizing medicinally important functional groups. Specifically, heme enzymes and methionine sulfoxide reductases are tasked for the first time with performing aminations and oxidations, respectively, toward synthesizing chiral trifluoroethylamines, sulfoxides, and sulfoximines, motifs known to bestow function and drug- like properties to therapeutics and clinical candidates. By engineering enzymes to catalyze reactions beyond their natural capabilities, we are boldly pushing the boundaries of biology and chemistry. This innovation has the potential to revolutionize the way we make molecules and introduce new chemical reactions that can be performed in living organisms. Furthermore, these efforts will unlock activities never before seen in biocatalysis, expanding the repertoire of genetically encoded chemical transformations. The success of this proposal will afford high-value molecules and biorenewable catalysts that may lead to the discovery of new medicines and strategies to regulate biology, with the ultimate objective of informing and improving human health.