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

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 β conformation while it is α conformation in lanosterol, finally, it is observed that the rotatable "tail" chain prefers to transfer β conformation to α conformation at the "6-6-5" intermediate state.