Concerted Cyclization of Lanosterol C-Ring and D-Ring Under Human Oxidosqualene Cyclase Catalysis: An ab Initio QM/MM MD Study

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• 作者：Nanhao Chen ; Jingwei Zhou ; Jiabo Li ; Jun Xu ; Ruibo Wu
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2014
• 出版时间：March 11, 2014
• 年：2014
• 卷：10
• 期：3
• 页码：1109-1120
• 全文大小：817K
• 年卷期：v.10,no.3(March 11, 2014)
• ISSN：1549-9626

文摘

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鈥?鈥?鈥? members for A鈥揃鈥揅鈥揇 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 鈥?鈥?鈥?鈥?ring intermediate. Interestingly, the transition state of this concerted reaction presents a 鈥?鈥?-6鈥?structure motif, while this unstable 鈥?鈥?-6鈥?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 尾 conformation while it is 伪 conformation in lanosterol, finally, it is observed that the rotatable 鈥渢ail鈥?chain prefers to transfer 尾 conformation to 伪 conformation at the 鈥?鈥?鈥?鈥?intermediate state.