Understanding the Molecular Mechanism of the Ala-versus-Gly Concept Controlling the Product Specificity in Reactions Catalyzed by Lipoxygenases: A Combined Molecular Dynamics and QM/MM Study of Coral 8R-Lipoxygenase
Understanding the Molecular Mechanism of the Ala-versus-Gly Concept Controlling the Product Specificity in Reactions Catalyzed by Lipoxygenases: A Combined Molecular Dynamics and QM/MM Study of Coral 8R-Lipoxygenase
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DOI：
10.1021/acscatal.7b00842
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发表时间：
2017-06
期刊：
影响因子：
12.9
通讯作者：
Patricia Saura;R. Suardíaz;Laura Masgrau;Àngels González-Lafont;E. Rosta;J. M. Lluch
中科院分区：
文献类型：
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作者：
Patricia Saura;R. Suardíaz;Laura Masgrau;Àngels González-Lafont;E. Rosta;J. M. Lluch
脂氧合酶（LOX）是一类催化多不饱和脂肪酸（如花生四烯酸）高度特异性氢过氧化的酶。不同的立体异构体或/和区域异构体氢过氧化产物随后导致不同的代谢物，其在动物体内发挥相反的生理作用，并在炎症过程中发挥核心作用。单个残基的Gly-Ala开关对于许多脂氧合酶中的立体和区域控制是至关重要的。在此，我们结合分子动力学模拟与量子力学/分子力学计算研究的氢提取步骤和分子氧加成步骤的花生四烯酸的氢过氧化反应催化的野生型珊瑚8 R-LOX和其Gly 427 Ala突变体。我们已经获得了一个详细的分子理解，这丙氨酸与甘氨酸的概念。在野生型中，分子氧以R立体化学添加到花生四烯酸的C8。在突变体中，Ala 427推动Leu 385，阻断C8上的区域，…
Lipoxygenases (LOXs) are a family of enzymes that catalyze the highly specific hydroperoxidation of polyunsaturated fatty acids, such as arachidonic acid. Different stereo- or/and regioisomer hydroperoxidation products lead later to different metabolites that exert opposite physiological effects in the animal body and play a central role in inflammatory processes. The Gly-Ala switch of a single residue is crucial for the stereo- and regiocontrol in many lipoxygenases. Herein, we have combined molecular dynamics simulations with quantum mechanics/molecular mechanics calculations to study the hydrogen abstraction step and the molecular oxygen addition step of the hydroperoxidation reaction of arachidonic acid catalyzed by both wild-type Coral 8R-LOX and its Gly427Ala mutant. We have obtained a detailed molecular understanding of this Ala-versus-Gly concept. In wild type, molecular oxygen adds to C8 of arachidonic acid with an R stereochemistry. In the mutant, Ala427 pushes Leu385, blocks the region over C8,...