A Chemo-Mimetic Platform to Reprogram Metalloenzymes for Non-Natural Biocatalytic C-H Functionalization Reactions

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Abstract/Summary The development of methods for molecule construction and functionalization has expedited the drug development process during the past decades. To this end, enzymatic C–H functionalization represents a powerful approach to enable rapid molecular construction. Harnessing the ubiquitous C–H bonds in organic molecules and genetic tunability of protein catalysts, enzymatic C–H functionalization provides sustainable strategies to effect chemical transformations with high selectivity and efficiency. Despite significant advances, the reaction scope of current enzymatic C–H functionalization is restricted to chemical reactivities acquired through natural evolution. This limitation hampers the applications of enzymes for drug development as many medicinally important chemical motifs are rarely present or even completely absent in biology. To expand the chemical space of biosynthesis, we herein aim to develop new biocatalytic systems by repurposing metalloenzymes for C–H functionalization reactions currently not present in biology. By integrating protein engineering, computational modeling, organic synthesis, and biochemical and inorganic spectroscopic analysis, we will create collections of metalloenzyme catalysts that can directly functionalize inert C(sp3)–H bonds to install biomedically relevant chemical moieties. We envision that the enzymes we create will not only provide powerful genetically encoded tools for numerous synthetic and biological applications, but will also offer a fertile ground to enrich our fundamental knowledge of biochemistry and enzymatic catalysis