Biosynthetic Mechanism of Lanosterol: A Completed Story

The remarkable biochemical conversion of acyclic 2,3-oxidosqualene to tetracyclic lanosterol (the common precursor to cholesterol and its relatives) with seven stereocenters constructed, catalyzed by oxidosqualene cyclase (OSC), has fascinated chemists for over a half century. Although many experimental and theoretical efforts have been reported, most of the studies focused on the initial cyclization while the subsequent cascade carbocation rearrangement and deprotonation were ignored, which determine the regio- and stereochemistry of the final product lanosterol associated with the function-related structure domains of cholesterol and its relatives. Herein, continue our previous works on the cyclization (Angew. Chem., Int. Ed. 2015, 54, 8693-8696), the mechanistic details of the remaining part of lanosterol biosynthesis, involving three hydride shifts, two methyl shifts and one deprotonation, were investigated by quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations. We obta...