Although enzymes perform redox reactions at milder reaction conditions than heterogeneous solid catalysts, the origin of this reactivity difference still needs to be resolved. In the present study, the mechanisms and kinetics of methanol oxidation by the aqueous bioinorganic vanadium haloperoxidase (VHPO) enzyme mimic and the heterogeneous solid oxide supported VO4/SiO2 catalyst operating in the gas-solid reaction are compared in order to address the origin of the different reactivities. The molecular level chemical transformations during methanol oxidation by the aqueous VHPO enzyme mimic, possessing the oxo-peroxo O=VO2(-O-C) functionalities, and heterogeneous supported VO4/SiO2 catalysts, containing isolated vanadyl O=V(-O-Si)(3) sites, were monitored with time-resolved in situ vibrational spectroscopy (Raman and IR). Both catalytic reactions proceed via the same methoxy (V-OCH3) reaction intermediate formed upon methanol chemisorption at the bridging V-O-C/V-O-Si bonds. The difference in reactivity is related to the much lower activation energy for breaking the C-H bond of the V-OCH3 intermediate, the rate-determining step, by the highly reactive vanadium peroxo VO2 sites only present for bioinorganic enzyme mimics and absent from heterogeneous catalysts under reaction conditions.