Two histidine-ligated heme-dependent monooxygenase proteins, TyrH and SfmD, have recently been found to resemble enzymes from the dioxygenase superfamily currently named after tryptophan 2,3-dioxygenase (TDO), that is, the TDO superfamily. These latest findings prompted us to revisit the structure and function of the superfamily. The enzymes in this superfamily share a similar core architecture and a histidine-ligated heme. Their primary functions are to promote O-atom transfer to an aromatic metabolite. TDO and indoleamine 2,3-dioxygenase (IDO), the founding members, promote dioxygenation through a two-step monooxygenation pathway. However, the new members of the superfamily, including PrnB, SfmD, TyrH, and MarE, expand its boundaries and mediate monooxygenation on a broader set of aromatic substrates. We found that the enlarged superfamily contains eight clades of proteins. Overall, this protein group is a more sizeable, structure-based, histidine-ligated heme-dependent, and functionally diverse superfamily for aromatics oxidation. The concept of TDO superfamily or heme-dependent dioxygenase superfamily is no longer appropriate for defining this growing superfamily. Hence, there is a pressing need to redefine it as a heme-dependent aromatic oxygenase (HDAO) superfamily. The revised concept puts HDAO in the context of thiol-ligated heme-based enzymes alongside cytochrome P450 and peroxygenase. It will update what we understand about the choice of heme axial ligand. Hemoproteins may not be as stringent about the type of axial ligand for oxygenation, although thiolate-ligated hemes (P450s and peroxygenases) more frequently catalyze oxygenation reactions. Histidine-ligated hemes found in HDAO enzymes can likewise mediate oxygenation when confronted with a proper substrate.

最近发现两种组氨酸连接的血红素依赖性单加氧酶蛋白 TyrH 和 SfmD 类似于目前以色氨酸 2,3-双加氧酶 (TDO) 命名的双加氧酶超家族中的酶，即 TDO 超家族。这些最新发现促使我们重新审视超家族的结构和功能。这个超家族中的酶具有相似的核心结构和组氨酸连接的血红素。它们的主要功能是促进 O 原子向芳香族代谢物转移。创始成员 TDO 和吲哚胺 2,3-双加氧酶 (IDO) 通过两步单加氧途径促进双加氧。然而，超家族的新成员，包括 PrnB、SfmD、TyrH 和 MarE，扩大了其边界并在更广泛的芳香底物上介导单氧合。我们发现扩大的超家族包含八个蛋白质进化枝。总体而言，该蛋白质组是一个更大的、基于结构的、组氨酸连接的血红素依赖性且功能多样的芳香族化合物氧化超家族。TDO 超家族或血红素依赖性双加氧酶超家族的概念不再适合定义这个不断增长的超家族。因此，迫切需要将其重新定义为血红素依赖性芳香加氧酶 (HDAO) 超家族。修改后的概念将 HDAO 置于硫醇连接的血红素酶以及细胞色素 P450 和过氧合酶的背景下。它将更新我们对血红素轴向配体选择的理解。血红蛋白可能对氧合的轴向配体类型没有那么严格，尽管硫醇连接的血红素（P450s 和过氧化酶）更频繁地催化氧化反应。当遇到适当的底物时，在 HDAO 酶中发现的组氨酸连接的血红素同样可以介导氧化作用。