Concerted Cyclization of Lanosterol C-Ring and D-Ring Under Human Oxidosqualene Cyclase Catalysis: An ab Initio QM/MM MD Study
Concerted Cyclization of Lanosterol C-Ring and D-Ring Under Human Oxidosqualene Cyclase Catalysis: An ab Initio QM/MM MD Study
复制标题
人氧化角鲨烯环化酶催化下羊毛甾醇 C 环和 D 环的协同环化：从头开始 QM/MM MD 研究
DOI：
10.1021/ct400949b
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发表时间：
2014-03-01
影响因子：
5.5
通讯作者：
Wu, Ruibo
中科院分区：
文献类型：
--
作者：
Chen, Nanhao;Zhou, Jingwei;Wu, Ruibo
人氧化角鲨烯环化酶（OSC）是胆固醇生物合成的关键酶之一。它可以催化直链2，3-氧化角鲨烯形成羊毛甾醇，四环（A-B-C-D环为6-6-6-5元）胆固醇前体。它也已被视为一种新的抗高脂血症的目标。此外，植物中环萜的结构多样性来源于2，3-氧化角鲨烯的环化。酶的催化机理被认为是自然界中最复杂的机理之一，在过去的半个世纪里，关于酶的催化机理一直存在着许多争论。在此，最先进的从头算QM/MM MD模拟研究详细的环化反应机理的C-环和D-环的形成。我们的研究表明，C环和D环是由稳定的“6-6-5”环中间体几乎同步形成的。有趣的是，这种协同反应的过渡态呈现出“6-6-6”结构基序，而在我们的模拟中，这种不稳定的“6-6-6”结构被认为是大多数先前假设机制中的稳定中间态。此外，由于2，3-氧化角鲨烯的尾侧链显示β构象，而其在羊毛甾醇中为α构象，最后，观察到可旋转的“尾”链倾向于在“6-6-5”中间状态下将β构象转移至α构象。
Human oxidosqualene cyclase (OSC) is one key enzyme in the biosynthesis of cholesterol. It can catalyze the linear-chain 2,3-oxidosqualene to form lanosterol, the tetracyclic (6-6-6-5 members for A-B-C-D rings) cholesterol precursor. It also has been treated as a novel antihyperlipidemia target. In addition, the structural diversity of cyclic terpenes in plants originates from the cyclization of 2,3-oxidosqualene. The enzyme catalytic mechanism is considered to be one of the most complicated ones in nature, and there are a lot of controversies about the mechanism in the past half a century. Herein, state-of-the-art ab initio QM/MM MD simulations are employed to investigate the detailed cyclization mechanism of C-ring and D-ring formation. Our study reveals that the C and D rings are formed near-synchronously from a stable "6-6-5" ring intermediate. Interestingly, the transition state of this concerted reaction presents a "6-6-6" structure motif, while this unstable "6-6-6" structure in our simulations is thought to be a stable intermediate state in most previous hypothetical mechanisms. Furthermore, as the tailed side chain of 2,3-oxidosqualene shows a beta conformation while it is alpha conformation in lanosterol, finally, it is observed that the rotatable "tail" chain prefers to transfer beta conformation to alpha conformation at the "6-6-5" intermediate state.