The ability to redesign enzymes to catalyze non-cognate chemical transformations would have wide-ranging applications. We developed a computational method for repurposing the reactivity of active site functional groups of metalloenzymes to catalyze new reactions. Using this method, we engineered a zinc-containing murine adenosine deaminase to catalyze the hydrolysis of a model organophosphate with a catalytic efficiency kcat/Km ~104 M−1s−1 after directed evolution. In the high-resolution crystal structure of the enzyme, all but one of the designed residues adopt the designed conformation. The designed enzyme efficiently catalyzed the hydrolysis of the RP-isomer of a coumarinyl analog of the nerve agent cyclosarin, and showed striking substrate selectivity for coumarinyl leaving-groups. Computational redesign of native enzyme active sites complements directed evolution methods and offers a general approach for exploring their untapped catalytic potential for new reactivities.