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首页> 外文期刊>The journal of physical chemistry, A. Molecules, spectroscopy, kinetics, environment, & general theory >Mechanism of Kynurenine 3-Monooxygenase-Catalyzed Hydroxylation Reaction: A Quantum Cluster Approach
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Mechanism of Kynurenine 3-Monooxygenase-Catalyzed Hydroxylation Reaction: A Quantum Cluster Approach

机译：鸡蛋碱3-单氧基酶催化羟基化反应的机制：量子簇方法

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摘要

The mechanism of the hydroxylation reaction between L-Kyn and model flavin adenine dinucleotide (FAD)-hydroperoxide was investigated via density functional theory (DFT) calculations in the absence and in the presence of the kynurenine 3-monooxygenase (KMO) enzyme by considering possible pathways that can lead to the product 3-hydroxykynurenine (3-HK). Crystal structure (pdb code: 5NAK)-based calculations involved a quantum cluster model in which the active site of the enzyme with the substrate L-Kyn was represented with 348 atoms. According to the deduced mechanism, KMO-catalyzed hydroxylation reaction takes place with four transformations. In the initial transition state, FAD delivers its peroxy hydroxyl to the L-Kyn ring, creating an sp(3)- hybridized carbon center. Then, the hydrogen on the hydroxyl moiety is immediately transferred back to the proximal oxygen that remained on FAD. These consequent transformations are in line with the somersault rearrangement previously described for similar enzymatic systems. The second step corresponds to a hydride shift from the sp(3)-hybridized carbon of the substrate ring to its adjacent carbon, producing the keto form of 3-HK. Then, keto-3-HK is transformed into its enol form (3-HK) with a water-assisted tautomerization. Lastly, FAD is oxidized with a water-assisted dehydration, which also involves 3-HK as a catalyst. In the proposed pathway, Asn54, Pro318, and a crystal water molecule were seen to play significant roles in the proton relays. The energies obtained via the cluster approach were calculated at the B3LYP/6-311+G(2d,2p)//B3LYP/6-31G(d,p) level with solvation (polarizable continuum model) and dispersion (DFT-D3(BJ)) corrections.
机译：通过密度官能理论（DFT）计算，通过密度官能理论（DFT）计算，在不考虑的情况下，通过密度官能理论（DFT）计算来研究L-kyn和模型腺嘌呤二核苷酸（FAD）-酰氧化酯之间的羟基化反应的机理通过密度函数理论（DFT）计算，通过考虑可以导致产品3-羟基脲烯酮（3-HK）的途径。基晶结构（PDB代码：5NAK）涉及量子簇模型，其中酶的活性位点用348个原子表示酶L-kyn。根据推导的机制，MAC催化的羟基化反应用四种转化进行。在初始过渡状态下，FAD将其过氧羟基与L-kyn环一起，产生SP（3） - 杂交的碳中心。然后，将羟基部分上的氢立即转移回留在FAD上的近端氧。这些改变与先前针对类似酶系统描述的翻膜重新排列。第二步骤对应于从基板环的SP（3） - 壁的碳化碳转移到其相邻的碳，产生3-HK的酮形式。然后，将Keto-3-HK转化为其烯醇形式（3-HK），水辅助互变异化。最后，使用水辅助脱水氧化，其还涉及作为催化剂的3-HK。在所提出的途径中，观察到在质子继电器中发挥显着的作用，在拟议的途径中，在质子继电器中起显着的作用。通过溶液（可极化连续模型）和分散（DFT-D3（DFT-D3）计算通过聚类方法获得的通过聚类方法获得的能量。（可极化连续体模型）和分散（DFT-D3（ bj））更正。

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