大家好，今天分享一篇2020年发表在Chemistry—A European Journal的文章——How Lanthanide Ions Affect the Addition–Elimination Step of Methanol Dehydrogenases，通讯作者是意大利卡拉布里亚大学的Tiziana Marino教授。
近年来，微生物中镧系元素(Lns)的发现丰富了无机生物化学领域。镧系元素参与甲烷循环，并与特定金属依赖型醇脱氢酶催化甲醇和乙醇的氧化过程密切相关。目前，镧系元素已被广泛研究并应用于多个领域，钆的复合物是磁共振成像中的有效造影剂，镧系氧化物由于其导电性被用作电器架构中的催化剂，甚至新一代混合动力汽车的电池和部件同样有镧系成分。
2014年，Arjan Pol等人首次报道了镧系元素依赖型甲醇脱氢酶(MDH)的X射线结构，结构显示辅因子2，7，9-三羧基吡咯并喹啉醌(PQQ)直接与铈离子（Ce）结合(PDB:4MAE)。有趣的是，甲基嗜酸杆菌仅在含有靠前的镧系元素存在时生长。这一发现使人们对Ln在MDH氧化甲醇及细菌代谢过程中的作用产生了浓厚的兴趣。
四年后，与铕结合的MDH（Eu-MDH）的3D结构被报道（PDB：6FKW）。相比于Ce-MDH，Eu-MDH的催化活性明显降低。此外，与镱结合的MDH（Yb-MDH）未检测到活性。这种现象被归因于镧系收缩效应，即镧系元素的原子半径和离子半径随着原子序数的增加而逐渐减小，从而导致了与镧系元素结合的MDH的稳定性和反应性降低。矛盾的是，原子序数的增加也意味着镧系元素的路易斯酸度（LA）和电荷密度增加，理应有利于Ln-MDH催化过程中的电子转移。为了解释这一矛盾，Tiziana Marino等人对Ln-MDH的催化机理进行了深入分析。
以Eu-MDH的3D结构为初始结构，基于不受限制的 Kohn-Sham (UKS) 计算，考虑到不同的自旋多重性，对 Ln3+-MDH (Ln3+=Pr-Yb) ES-PQQ 复合物进行了系统研究，发现所有金属的配位数 (CN) 为 9，甲醇直接与金属中心配位。随着原子序列增大，可以观察到金属与甲醇的氧原子（Osub）之间的键长逐渐由2.56 Å减小到2.34 Å，这体现了镧系元素的收缩效应。同时，金属的平均配位范围也在减小，这可能是Eu-MDH催化活性降低、Yb-MDH活性消失的原因。
作者指出由 MDH 介导的甲醇氧化成甲醛是通过“加成-消除-质子化”三步反应完成的。第一步加成，底物甲醇的氧攻击并连接PQQ的C5，同时将其质子提供给第一配位的残基Asp299。在随后的消除步骤中，由于PQQ的第一次质子化，形成的甲醛被释放。最后一步，通过第二次质子转移，PQQH2和去质子化的Asp299同步形成。PQQH2会在细胞色素C的作用下完成辅因子的再生。
作者进一步计算了Ce-MDH、Eu-MDH和Yb-MDH催化甲醇过程中的势能面。从图中可以看出三个系统的能量有明显不同，2.1 kcal/mol左右的能垒差异足以影响动力学行为，这为金属的重要作用提供了进一步的证据。原子序数的增加使阳离子配位壳中的平均距离减少，从而导致了能垒的增加，这体现了镧系收缩效应对活性的影响。特别的是，质子化步骤中Yb-MDH的能垒反而最低，这是由于在半醌 (PQQH) 的质子化过程中，镱的较小离子半径能产生更有利的几何重排。
关于第二步消除步骤，此前有研究假设反应的驱动力来自PQQ的π键系统和甲醛的π键形成之间的排斥力。但是本文的作者通过计算分析，证明这种相互作用是不存在的，因为最高占据分子轨道（HOMO）并不涉及PQQ部分。在Ce-MDH中，经计算HOMO位于Ce轨道上，该轨道靠近反应中心，这同样可以解释为何相比之下Ce-MDH的催化活性较高。
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