PDF(Pubmed)
Abstract：
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 substrate l-Arg hydroxylation. Although both enzymes initially bind 2OG by using an off-line 2OG coordination mode, in PHF8, the substrate oxidation requires a transition to an in-line mode, whereas EFE is catalytically productive for ethylene production from 2OG in the off-line mode. 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 the in-line FeIII -OO⋅- intermediate in PHF8 and the off-line FeIII -OO⋅- intermediate in EFE.
摘要：
这项研究通过两种模型非血红素Fe（II）/2OG酶研究了双氧结合和2-酮戊二酸（2OG）配位：一种7类组蛋白脱甲基酶（PHF8），可催化其H3K9me2组蛋白底物的羟基化，从而导致脱甲基化反应性和乙烯形成酶（EFE），可催化乙烯生成和底物L-Arg羟基化的两个竞争性反应。尽管两种酶最初都使用离线2OG协调模式结合2OG，在PHF8中，底物氧化需要过渡到串联模式，而EFE通过离线模式催化生产从20G生产乙烯。我们利用了经典的分子动力学,量子力学/分子力学(QM/MM)MD和QM/MM元动力学模拟揭示了它是双氧结合过程，最终,控制在线Fe（III）-OO-形成的蛋白质环境。PHF8中的中间体和离线Fe(III)-OO-。在EFE中间。
