ensity functional calculations (DFT-B3LYP) on a neutral model system L3Cu ... CuL3 have been carried out to probe the mechanism of tyrosinase action. The ligands L are chosen either as ammonia or formimine to model the real histidine ligands. Most of the effort of the project was put into locating the transition state for O-O activation of O-2 for both sets of ligands. It is found that the activation occurs on the antiferromagnetically coupled singlet surface, here modeled as a triplet. This is the ground state of the initially formed peroxide complex. The activation leads to an excited bis-mu-oxo state which is converted exothermically to the closed shell singlet product after the reaction. The peroxide complex is found to have a nonplanar Cu-O-2-Cu arrangement, while the Cu-O-2-Cu ring in the bis-mu-oxo product is planar. The barrier for O-2 activation found for the formimine case is 15.1 kcal/mol and for the ammonia case is 13.6 kcal/mol, both in line with the overall experimental reaction rate for the entire tyrosinase cycle of 10(3) s(-1), indicating that O-2 activation is rate limiting. As an initial attempt toward modeling the subsequent steps of the phenol oxidation, only the computationally simplest approach was tried, which involves transient radical intermediates. The computed energetics suggest that this route might be feasible even though one step may be slightly too endothermic. The relevance of the findings to the enzyme and the limitations of the model are also discussed.