Inspired by the seminal publication by Wilson in Whitesides in 1978, The Ward group has been active in the field of artificial metalloenzymes since 2000. Artificial metalloenzymes (ArMs) result from the incorporation of an abiotic metal cofactor within a host protein. Thanks to the remarkable supramolecular affinity of biotin for streptavidin, linking a biotin anchor to an organometallic catalyst ensures that, upon addition of streptavidin, the abiotic cofactor is quantitatively incorporated within the streptavidin. Alternatively, human carbonic anhydrase has proven versatile for the development of artificial metalloenzymes relying on aryl-sulfonamide anchors to ensure the localization of the abiotic metallocofactors within the host protein. My group has relied on both chemical- (i.e. variation of the anchor-spacer-ligand moiety) and genetic-means (i.e. mutation of the host protein) to optimize the catalytic performance of the resulting ArMs. These chemo-genetic schemes were applied to improve the performance for thirteen different catalyzed transformations as well multiple reaction cascades in the presence of natural enzymes, either in vitro or in vivo. This presentation will highlight the group’s effort to implement and evolve artificial metalloenzymes with activities that are complementary to natural enzymes. These include: C–H activation, hydroxylation, olefin metathesis, imine reduction, cross-coupling reactions etc.

Looking back at twenty years of research on artificial metalloenzymes: Challenges and opportunities

ACS Fall 2021

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