Abstract
In contrast to the wide spectrum of cytochrome P450 monooxygenases, there are only two heme-based dioxygenases in humans, tryptophan dioxygenase (hTDO) and indoleamine 2,3-dioxygenase (hIDO). hTDO and hIDO catalyze the same oxidative ring cleavage reaction of L-tryptophan (L-Trp) to N-formyl kynurenine (NFK), the initial and rate-limiting step of the kynurenine pathway. Despite immense interest, the mechanism by which the two enzymes execute the dioxygenase reaction remains elusive. Here, we report the first experimental evidence for a key ferryl intermediate of hIDO. It supports a new mechanism, in which the two atoms of dioxygen are inserted into the substrate via a consecutive two-step reaction. This finding introduces a paradigm shift in our understanding of the heme-based dioxygenase chemistry, which was previously believed to proceed via simultaneous incorporation of both atoms of dioxygen into the substrate. The ferryl intermediate is not observable during the hTDO reaction, highlighting the structural differences between the two dioxygenases, as well as the importance of stereoelectronic factors in modulating the reactions.
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