Biosynthetic Mechanism of Lanosterol: Cyclization

The remarkable cyclization mechanism of the formation of the 6-6-6-5 tetracyclic lanosterol (a key triterpenoid intermediate in the biosynthesis of cholesterol) from the acyclic 2,3-oxidosqualene catalyzed by oxidosqualene cyclase (OSC) has stimulated the interest of chemists and biologists for over a half century. Herein, the elaborate, state-of-the-art two-dimensional (2D) QM/MM MD simulations have clearly shown that the cyclization of the A-C rings involves a nearly concerted, but highly asynchronous cyclization, to yield a stable intermediate with 6-6-5 rings followed by the ring expansion of the C-ring concomitant with the formation of the D-ring to yield the 6-6-6-5 protosterol cation. The calculated reaction barrier of the rate-limiting step (approximate to 22kcalmol(-1)) is comparable to the experimental kinetic results. Furthermore all previous experimental mutagenic evidence is highly consistent with the identified reaction mechanism.