Designing functional enzymes has been a dream of chemists, but most synthetic enzymes have activity that falls far short of those put forward by Mother Nature. Researchers have now achieved a rare success in the field by converting a nonenzymatic metalloprotein into a designed metalloenzyme with cytochrome oxidase activity that nearly matches that of native oxidases (J. Am. Chem. Soc. 2015, DOI: 10.1021/jacs.5b07119). Jiangyun Wang of the Chinese Academy of Sciences’ Institute of Biophysics, in Beijing; Yi Lu of the University of Illinois, Urbana-Champaign; and coworkers began by modifying the iron- and oxygen-binding protein myoglobin with amino acids that are key components of heme-copper oxidases. The modified protein still had activity far below that of native cytochrome oxidases. Speculating that slow electron transfer into the modified enzyme’s catalytic center might be holding it back, the researchers made further amino acid substitutions to improve electrostatic interactions between myoglobin and its redox partner, cytochrome b5. That did the trick, dramatically enhancing activity to a level similar to that of native oxidases. The work could lead to a better understanding of how oxidases work as well as synthetic catalysts for applications such as biofuel cells.