人5-脂氧合酶催化花生四烯酸转化为白三烯A4的理论研究：氢过氧化和环氧化机制以及花生四烯酸活性位点接入,ACS Catalysis

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人5-脂氧合酶催化花生四烯酸转化为白三烯A4的理论研究：氢过氧化和环氧化机制以及花生四烯酸活性位点接入
ACS Catalysis ( IF 11.3 ) Pub Date : 2023-12-29 , DOI: 10.1021/acscatal.3c04954
Alejandro Cruz ₁ , Àngels González-Lafont _{1,

2} , José M. Lluch _{1,

2}

Affiliation

炎症是许多不同疾病的基础。白三烯 (LT) 是源自花生四烯酸 (AA) 的促炎介质，在急性炎症中发挥重要作用。脂氧素是专门的促消退介质 (SPM)，也是由 AA 形成，可促进急性炎症的消退。然而，如果解决失败，可能会出现慢性炎症过程。人 5-脂氧合酶 (5-LOX) 催化名为 LTA _{4的白三烯的生物合成，但也干预脂氧素 LXA}₄的形成。这两种生物学功能使 5-LOX 异构体成为多种炎症性疾病药物研究的当前目标，寻找阻断白三烯反应途径但不阻断脂氧素形成的抑制剂。然而，由于人类 5-LOX 晶体结构的缺乏，这些选择性抑制剂的开发受到阻碍。在这项工作中，我们使用 AlphaFold 蛋白质结构数据库中的人类 5-LOX 结构作为初始坐标，构建了人类 5-LOX: AA Michaelis 复合物的完整溶剂化模型。我们的目标是在分子水平上分析 5-LOX 的整体催化机制，首先通过氢过氧化反应将 AA 转化为 5( S )-HpETE，然后在环氧化过程后将该氢过氧化物转化为 LTA _{4 。}在方法上，我们进行了分子动力学模拟和量子力学/分子力学计算。AA 进入 5-LOX 结合腔的自由能分布已通过引导分子动力学计算得出。这些详细的分子信息可以解释 human-5-LOX 的体外活性（不存在膜嵌入的 5-脂氧合酶激活蛋白），并有助于设计有利于炎症消退的选择性抑制剂。

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Theoretical Study of the Arachidonic Acid Conversion into Leukotriene A4 Catalyzed by Human 5-Lipoxygenase: Hydroperoxidation and Epoxidation Mechanisms and Arachidonic Acid Active Site Access

Inflammation is at the base of many different diseases. Leukotrienes (LTs) are pro-inflammatory mediators derived from arachidonic acid (AA), which play significant roles in acute inflammation. Lipoxins are specialized pro-resolving mediators (SPMs), also formed from AA, that promote the resolution of acute inflammation. However, if resolution fails, chronic inflammatory processes might develop. The enzyme human-5-lipoxygenase (5-LOX) catalyzes the biosynthesis of leukotriene named LTA₄ but also intervenes in the formation of the lipoxin LXA₄. These two biological functions have made the 5-LOX isoform a current target for pharmaceutical investigations in several inflammatory-based diseases searching for inhibitors that block the leukotriene reaction pathway but not lipoxin’s formation. However, the development of those selective inhibitors has been hampered by the lack of a crystal structure of human 5-LOX. In this work, we have built a complete solvated model of the human-5-LOX: AA Michaelis complex using, as initial coordinates, the human 5-LOX structure from the AlphaFold protein structure database. We aim to analyze at the molecular level the overall catalytic mechanism of 5-LOX that first converts AA into 5(S)-HpETE through a hydroperoxidation reaction and, second, transforms this hydroperoxide into LTA₄ following an epoxidation process. Methodologically, we have performed molecular dynamics simulations and quantum mechanics/molecular mechanics calculations. The free energy profiles for AA entrance into the 5-LOX’s binding cavity have been calculated by steered molecular dynamics. This detailed molecular information can explain human-5-LOX’s in vitro activity (without the presence of the membrane-embedded 5-lipoxygenase-activating protein) and help to design selective inhibitors favoring inflammation resolution.

更新日期：2023-12-29

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