Enzymatic hydroxylation reactions carried Out by 2-oxoglutarate (2OG) dependent iron-containing oxygenases were recently implicated in oxyzgen sensing. In addition to oxygen depletion, two metals. cobalt and nickel, are capable of inducing hypoxic stress ill cells by inhibiting oxygenase activity. Two possible scenarios have been proposed for the explanation of the hypoxic effects of cobalt and nickel: oxidation of enzyme-bound iron following cobalt or nickel exposure, and substitution of iron by cobalt or nickel. Here. by using density functional theory calculations, we modeled the reaction route from the reaction components to the high-spin metal-oxide intermediate in the activation of oxygen molecule by 2OG-dependent enzymes for three metal ions Fe(II), Ni(II), and Co(II) in the active site. An initial molecular model was constructed based on the crystal structure of iron-containing asparaginyl hydroxylase (FIH-1). Nickel- and cobalt-containing enzymes were modeled by a consequent replacement of the iron in the active center. The energy profiles connecting stationary points on the potential surfaces were computed by using the intrinsic reaction coordinate (IRC) technique from the located transition states. The results of calculations show that the substitution of iron by nickel or cobalt modifies the reaction energy profile- however, qualitatively, the reaction mechanism remains essentially the same. Thus, we would postulate that if the iron ion in the active site were substitutable by nickel and/or cobalt ions enzyme activity Would be considerably altered due to high activation barriers.