The broad class of O2-activating coupled-binuclear copper (CBC) metalloenzymes contain a unique [Cu2O2] catalytic core. This core is responsible for catalyzing challenging biochemical transformations, particularly the regioselective monooxygenations/oxidations of substituted phenols. Despite almost four decades of intense experimental and theoretical research, the factors governing the diverse reactivity of CBC enzymes had remained only partially understood. In this review, we highlight the recent synergy between spectroscopy, kinetic experiments, and state-of-the-art computations (including hybrid quantum and molecular mechanical, QM/MM, and advanced wave function theory, WFT, methods) that provided a conclusive mechanistic picture of the initial stages of the ortho-hydroxylation of phenolic substrates catalyzed by the CBC enzyme tyrosinase (Ty). We emphasize the power of calibrated theoretical calculations, supported by experimental spectroscopic and kinetic data on intermediates, in providing definitive insight into the catalytic reaction coordinate. We provide a critical review of previous efforts towards elucidating structure-function correlations over the four CBC protein classes (hemocyanins, catechol oxidases, tyrosinases, o-aminophenol oxygenases). We outline how a systematic mechanistic understanding across the different CBC enzyme classes could uncover their elusive structure-function correlations, opening new possibilities for utilizing the [Cu2O2] catalytic core outside its native biological context for applications in materials and biocatalysis.

Department of Chemistry Stanford University Stanford California 94305 United States

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo náměstí 2 166 10 Praha 6 Czech Republic

Stanford Synchrotron Radiation Lightsource SLAC National Accelerator Laboratory Stanford University Menlo Park California 94025 United States

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