Dioxygen Binding Is Controlled by the Protein Environment in Non‐heme Fe II and 2‐Oxoglutarate Oxygenases: A Study on Histone Demethylase PHF8 and an Ethylene‐Forming Enzyme
Dioxygen Binding Is Controlled by the Protein Environment in Non‐heme Fe II and 2‐Oxoglutarate Oxygenases: A Study on Histone Demethylase PHF8 and an Ethylene‐Forming Enzyme
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非血红素 Fe II 和 2-氧化戊二酸加氧酶中的双氧结合受蛋白质环境控制：组蛋白脱甲基酶 PHF8 和乙烯形成酶的研究
DOI：
10.1002/chem.202300138
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Karabencheva‐Christova, Tatayana G.
中科院分区：
文献类型：
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作者：
Chaturvedi, Shobhit S.;Thomas, Midhun George;Rifayee, Simahudeen Bathir Jaber Sathik;White, Walter;Wildey, Jon;Warner, Cait;Schofield, Christopher J.;Hu, Jian;Hausinger, Robert P.;Karabencheva‐Christova, Tatayana G.
本研究通过两种模型非血红素FeII/2 OG酶研究了双氧结合和2-酮戊二酸（2 OG）配位：一类7组蛋白脱甲基酶（PHF 8），催化其H3 K9 me 2组蛋白底物的羟基化，导致脱甲基反应性;以及乙烯形成酶（EFE），催化乙烯生成和底物-Arg羟基化的两个竞争反应。 虽然两种酶最初都是通过使用离线2 OG配位模式结合2 OG，但在PHF 8中，底物氧化需要过渡到在线模式，而EFE在离线模式中对从2 OG产生乙烯具有催化活性。我们使用经典分子动力学（MD），量子力学/分子力学（QM/MM）MD和QM/MM元吸附动力学（QM/MM-MetD）模拟来揭示，是分子氧结合过程，最终是蛋白质环境控制了PHF 8中的在线FeIII-OO β-中间体和EFE中的离线FeIII-OO β-中间体的形成。
This study investigates dioxygen binding and 2‐oxoglutarate (2OG) coordination by two model non‐heme FeII/2OG enzymes: a class 7 histone demethylase (PHF8) that catalyzes the hydroxylation of its H3K9me2 histone substrate leading to demethylation reactivity and the ethylene‐forming enzyme (EFE), which catalyzes two competing reactions of ethylene generation and substratel‐Arg hydroxylation. Although both enzymes initially bind 2OG by using anoff‐line2OG coordination mode, in PHF8, the substrate oxidation requires a transition to anin‐linemode, whereas EFE is catalytically productive for ethylene production from 2OG in theoff‐linemode. We used classical molecular dynamics (MD), quantum mechanics/molecular mechanics (QM/MM) MD and QM/MM metadynamics (QM/MM‐MetD) simulations to reveal that it is the dioxygen binding process and, ultimately, the protein environment that control the formation of thein‐lineFeIII‐OO⋅−intermediate in PHF8 and theoff‐lineFeIII‐OO⋅−intermediate in EFE.