The Apparently Unreactive Substrate Facilitates the Electron Transfer for Dioxygen Activation in Rieske Dioxygenases.
The Apparently Unreactive Substrate Facilitates the Electron Transfer for Dioxygen Activation in Rieske Dioxygenases.
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DOI：
10.1002/chem.202103937
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发表时间：
2022-03-16
影响因子：
4.3
通讯作者：
Reiher, Markus
中科院分区：
文献类型：
--
作者：
Csizi, Katja-Sophia;Eckert, Lina;Brunken, Christoph;Hofstetter, Thomas B.;Reiher, Markus
关键词：
Rieske双加氧酶属于加氧酶的非血红素铁家族，并催化重要的顺式二羟基化以及O-/N-脱烷基化和氧化环化反应。然而，在非血红素亚铁中心缺乏底物配位，使得描绘底物在生产性活化中的作用特别具有挑战性。在这里，我们从理论的角度研究了底物在导致活化的关键基元反应中的作用，系统地考虑了（i）非血红素Fe II在提取水配体时的6-配位到5-配位的转换，（ii）与Rieske簇的结合，以及（iii）从Rieske簇转移电子。我们使用萘双加氧酶作为典型的Rieske双加氧酶，系统地评估了在存在和不存在底物的情况下三个基本过程的所有组合的活性位点处的自旋状态依赖的反应能量和结构效应。我们发现，通过热中性H2O重取向和Rieske簇氧化之前的放热结合在非血红素Fe中心产生配位空位的反应能对萘的存在很大程度上不敏感，并且不会导致形成任何已知的活性Fe-氧物种。相比之下，在Rieske簇氧化后，基底的作用变得明显，并且仅对于6配位非血红素Fe位点，因为在基底处而不是在铁和氧原子处发现了额外的电子。我们的研究结果表明，在非血红素Fe发生变化之前，底物对Rieske双加氧酶反应性的变构控制与避免非生产性激活的策略一致。 模型复合物的量子化学研究发现，通过水重定向和双氧结合在萘双加氧酶的Fe中心产生配位空位的反应能量对萘的存在不敏感。底物的作用仅在Rieske簇氧化后对于6配位Fe活性位点变得明显，其中额外的电子可能首先转移到萘底物。这些结果意味着底物对Rieske双加氧酶反应性的变构控制。
Rieske dioxygenases belong to the non‐heme iron family of oxygenases and catalyze important cis‐dihydroxylation as well as O‐/N‐dealkylation and oxidative cyclization reactions for a wide range of substrates. The lack of substrate coordination at the non‐heme ferrous iron center, however, makes it particularly challenging to delineate the role of the substrate for productive activation. Here, we studied the role of the substrate in the key elementary reaction leading to activation from a theoretical perspective by systematically considering (i) the 6‐coordinate to 5‐coordinate conversion of the non‐heme FeII upon abstraction of a water ligand, (ii) binding of , and (iii) transfer of an electron from the Rieske cluster. We systematically evaluated the spin‐state‐dependent reaction energies and structural effects at the active site for all combinations of the three elementary processes in the presence and absence of substrate using naphthalene dioxygenase as a prototypical Rieske dioxygenase. We find that reaction energies for the generation of a coordination vacancy at the non‐heme Fe center through thermoneutral H2O reorientation and exothermic binding prior to Rieske cluster oxidation are largely insensitive to the presence of naphthalene and do not lead to formation of any of the known reactive Fe‐oxygen species. By contrast, the role of the substrate becomes evident after Rieske cluster oxidation and exclusively for the 6‐coordinate non‐heme Fe sites in that the additional electron is found at the substrate instead of at the iron and oxygen atoms. Our results imply an allosteric control of the substrate on Rieske dioxygenase reactivity to happen prior to changes at the non‐heme Fe in agreement with a strategy that avoids unproductive activation. A quantum chemical study of model complexes finds that reaction energies for the generation of a coordination vacancy at the Fe center of naphthalene dioxygenase through water reorientation and dioxygen binding are insensitive to the presence of naphthalene. The role of the substrate only becomes evident after Rieske cluster oxidation for the 6‐coordinate Fe active site where an additional electron is likely to be first transfered to the naphthalene substrate. These results imply allosteric control of the substrate on Rieske dioxygenase reactivity.
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