Activation of human carbonic anhydrase II (hCA II) holds great promise for treating memory loss symptoms associated with Alzheimer's disease. Despite its importance, the activation mechanism of hCA II has been largely overlooked in favor of the well-studied inhibition mechanism. To address this unexplored realm, we use first-principles calculations to tease out the activation mechanism of hCA II using 2-(2-aminoethyl)-pyridine (2-2AEPy), a promising in vitro activator. We explored both stepwise and concerted mechanisms via both available nitrogen sites of 2-2AEPy: (i) aminoethyl group (Nα) and (ii) pyridine ring (Nβ). Our results show that a concerted mechanism via Nα holds the key to hCA II activation. The activation process of the concerted mechanism exhibits the characteristics of an exergonic reaction, wherein the transition state resembles the reactant with a notably low imaginary frequency of 452.4i cm⁻¹ and barrier height of 5.2 kcal mol⁻¹. Such meager transition barriers propel the activation of hCA II at in vivo temperatures. These findings initiate future research into hCA II activation mechanisms and the development of efficient activators, which may lead to promising therapeutic interventions for Alzheimer's disease.

中文翻译：

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通过 2-(2-氨基乙基)-吡啶深入了解碳酸酐酶 (II) 的激活机制：增强酶活性的一条有希望的途径

人碳酸酐酶 II (hCA II) 的激活对于治疗与阿尔茨海默氏病相关的记忆丧失症状具有广阔的前景。尽管它很重要，但 hCA II 的激活机制在很大程度上被忽视，而人们更倾向于充分研究的抑制机制。为了解决这个未探索的领域，我们使用第一性原理计算来梳理使用 2-(2-氨乙基)-吡啶 (2-2AEPy)（一种有前途的体外激活剂）的 hCA II 激活机制。我们通过2-2AEPy 的两个可用氮位点探索了逐步和协调的机制：(i) 氨乙基 (Nα) 和 (ii) 吡啶环 (Nβ)。我们的结果表明，通过Nα的协同机制是 hCA II 激活的关键。协同机制的激活过程表现出放能反应的特征，其中过渡态类似于具有452.4i cm ^-1的虚部频率和5.2 kcal mol ^-1的势垒高度的显着低的反应物。这种微弱的转变势垒促进了 hCA II 在体内温度下的激活。这些发现启动了对 hCA II 激活机制和有效激活剂开发的未来研究，这可能会为阿尔茨海默病带来有希望的治疗干预措施。