Metalloenzymes catalyze some of the most challenging reactions, such as the conversion of H2O to O2, O2 to H2O, N2 to NH3 and H+ to H2, under mild physiological conditions. However, these metalloenzymes are usually huge membrane protein complexes, are hard to produce in large amount, and are difficult to engineer to suit for industrial applications. The central aim in our laboratory is to use small, soluble protein scaffold, and the genetic incorporation of unnatural amino acid to design easy-to-characterize, easy-to-produce, and easy-to-optimize metalloenzymes which catalyze these important reactions with equal or greater efficiency/selectivity than that of the natural systems.  For example, Heme-copperoxidase (HCO) performs efficient four-electron reduction of oxygen to water without releasing toxic, reactive oxygen species (ROS).  Through the genetic incorporation of the Tyr-His ligand and CuB site into myoglobin, we recapitulated important features of HCO into this small soluble protein. These results support that Tyr-His crosslink present in HCO is indeed important for its function, and creates the exciting opportunity to rapidly evolve better HCO model proteins to achieve higher activity/selectivity, which may be suitable as alternatives to precious metal catalyst in fuel cells.1. Zhou Q. � Wang J. Y �Probing the Function of the Tyr-Cys Crosslink in Metalloenzymes through the Genetic Incorporation of 3-Methylthiotyrosine� Angew. Chem. Intl. Ed. 2013, 52(4), 1203-7.2. Liu, X. H. � Lu, Y.; Wang, J. Y, �Significant Increase of Oxidase Activity through the Genetic Incorporation of a Tyrosine-Histidine Cross-Link in a Myoglobin Model of Heme-Copper Oxidase� Angew. Chem. Intl. Ed. 2012, 51 (18), 4312-6. (News of the Week, Chemical and Engineering News)3. Liu, X. H. � Wang, J. Y.,  �Genetic Incorporation of a Metal Chelating Amino Acid as a Probe for Protein Electron Transfer� Angew. Chem. Intl. Ed. 2012, 51(41), 10261-5. (Very Important Paper and Cover Article)

Metalloprotein design through the genetic incorporation of unnatural amino acids

246th National Meeting (2013)

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