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Abstract
Two histidine-ligated heme-dependent monooxygenase proteins, TyrH and SfmD, have recently been shown to resemble enzymes from the dioxygenase superfamily currently named after tryptophan 2,3-dioxygenase (TDO). that is, the TDO superfamily. These latest findings have prompted us to rethink the structure and function of the superfamily. The enzymes of this superfamily share a similar central architecture and a histidine ligated heme. Their main functions are to promote the transfer of oxygen atoms to an aromatic metabolite. TDO and indoleamine 2,3-dioxygenase (IDO), the founding members, promote oxygenation through a two-step monooxygenation pathway. However, new members of the superfamily, including PrnB, SfmD, TyrH, and MarE, extend its limits and mediate monooxygenation over a wider set of aromatic substrates. We found that the extended superfamily contains eight protein clades. Overall, this protein group is a larger, structure-based, heme dependent, histidine-linked, and functionally diverse superfamily for the oxidation of aromatics. The concept of TDO superfamily or heme dependent dioxygenase superfamily is no longer appropriate to define this growing superfamily. Therefore, there is an urgent need to redefine it as the heme dependent aromatic oxygenase (HDAO) superfamily. The revised concept places HDAO in the context of heme-based enzymes ligated alongside cytochrome P450 and peroxygenase. It will update what we understand about the choice of axial heme ligand. Hemoproteins may not be as strict on the type of axial ligand for oxygenation, although thiolate-bound hemes (P450 and peroxygenases) more frequently catalyze oxygenation reactions. The histidine-bound hemes found in HDAO enzymes can also mediate oxygenation when confronted with a suitable substrate.
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