| Abstract
| - Human homogentisate dioxygenase is an FeII-dependent enzyme responsible for aromatic ringcleavage. The mechanism of its catalytic reaction has been investigated with the hybrid density functionalmethod B3LYP. A relatively big model of the active site was first used to determine the substrate bindingmode. It was found that binding of the substrate dianion with a vacant position trans to Glu341 is mostfavorable. The model was then truncated to include only the most relevant parts of the active-site residuesinvolved in iron coordination and substrate binding. Thus, methylimidazole was used to model His292,His335, His365, and His371, while propionate modeled Glu341. The computational results suggest thatthe catalytic reaction of homogentisate dioxygenases involves three major chemical steps: formation ofthe peroxo intermediate, homolytic cleavage of the O−O bond leading to an arene oxide radical, and finally,cleavage of the six-membered ring. Calculated barriers for alternative reaction paths are markedly higherthan for the proposed mechanism, and thus the computational results successfully explain the productspecificity of the enzyme. Interestingly, the results indicate that the type of ring scission, intra or extra withrespect to the substituents coordinating to iron, is controlled by the barrier heights for the decay of thearene oxide radical intermediate.
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